O-Phosphination of Aldehydes/Ketones toward Phosphoric Esters: Experimental and Mechanistic Studies

Article abstract of DOI:10.1021/acs.orglett.0c01537

Addition of P-H species to carbonyl groups, namely the Pudovik reaction, normally delivers hydroxyl phosphorus compounds, along with phosphate byproducts in some cases. A few controllable systems starting from phosphites were set up to mainly provide the phosphates. Herein, we present a highly selective protocol starting from phosphonate precursors leading to phosphinate derivatives. Enantioenriched phosphinates were successfully achieved from chiral phosphine oxide precursors. Experimental and theoretical investigations were conducted to understand the mechanistic details.

Full text of DOI:10.1021/acs.orglett.0c01537

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Letter
O‑Phosphination of Aldehydes/Ketones toward Phosphoric Esters:
Experimental and Mechanistic Studies
Yanyan Qian, Qiang Dai, Zhiming Li,* Yu Liu,* and Junliang Zhang*
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ABSTRACT: Addition of P−H species to carbonyl groups,
namely the Pudovik reaction, normally delivers hydroxyl
phosphorus compounds, along with phosphate byproducts in
some cases. A few controllable systems starting from phosphites
were set up to mainly provide the phosphates. Herein, we present a
highly selective protocol starting from phosphonate precursors
leading to phosphinate derivatives. Enantioenriched phosphinates were successfully achieved from chiral phosphine oxide precursors.
Experimental and theoretical investigations were conducted to understand the mechanistic details.
which could not be unambiguously discerned experimentally
(Scheme 1).
rganophosphorus compounds are frequently presented
1
synthetic agents,2
Oscaffolds in bioactive molecules,
pharmecuticals,3 and materials,4 among others,5 stimulating
extensive interests in exploring convenient and practical
methods for the preparation of these analogues. During the
past decades, a number of synthetic tools toward phosphoric
esters have been developed.5,6 Traditional methods for P−O
bond construction involve nucleophilic substitution of highly
air sensitive and hazardous phosphorus reagents with alcohols
or phenols.7 In recent years, many methods have been
developed to synthesize phosphate esters.8 As a practical
method for the preparation of hydroxyl phosphorus com-
pounds from the addition of P−H species to carbonyl motifs,
the Pudovik reaction9 delivers phosphates as minor products in
some cases.10 Recent explorations by several groups including
Scheme 1. Reaction Patterns of Phosphine Oxides and
Aldehydes/Ketones
̈
Kaim’s and Chakravarty’s established conditions for selective
preparation of the phosphate derivatives starting from
phosphites bearing two alkoxyl groups.11 To the best of our
knowledge, other types of phosphine oxide precursors have
seldom been applied in such a strategy to prepare the
corresponding phosphoric esters in high selectivity.12 In
addition, the existing methods often suffer from limitations,
such as low functional group tolerance and harsh conditions.
Moreover, although phospha-Brook rearrangement is believed
to be operative in all reported cases,6d,11 definitive evidence is
still lacking to prove the mechanistic proposal. As part of our
ongoing interest in organophosphorus compounds,13 we
disclose herein a mild and efficient protocol toward phosphoric
esters, especially phosphinates. The reaction features wide
functional group tolerance and mild conditions. Furthermore,
chiral phosphinates can be facilely derived from enantioen-
riched phosphine oxides. DFT calculation was resorted to
discriminate the three mechanistic proposals, namely, the
Brook rearrangement, antiregioselective addition to the
carbonyl group, and [1 + 2 + 2]/elimination pathways,
As a starting point, the reaction of diphenylphosphine oxide
1a and benzaldehyde 2a in the presence of K3PO4 at 80 °C in
ethyl acetate (EA) delivered a 49% NMR yield of O-
phosphination product 4aa along with 13% NMR yield of
the normal Pudovik adduct 3aa (Table 1, entry 1). Inspired by
Received: May 5, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01537
© XXXX American Chemical Society
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a
a
Table 1. Reaction Optimization
Table 2. Scope of Aldehydes/Ketones
b
b
entry
base
solvent
EA
3aa (%)
4aa (%)
1
2
3
4
5
6
7
8
K3PO4
13
trace
49
35
48
15
93
NaOtBu
KOtBu
EA
EA
EA
EA
EA
EA
n-hexane
toluene
dioxane
THF
EA
LiOtBu
Cs2CO3
K2CO3
9
24
41
33
trace
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
77
64
64
27
73
69
72
66
9
10
11
12
13
14
c
29
d
EA
EA
EA
EA
e
f
15
16
a
g
Reaction conditions: Ph2P(O)H (0.2 mmol), aldehyde (0.3 mmol),
Cs2CO3 (40 mol %), ethyl acetate (2 mL) under N2 at 80 °C for 10 h.
a
Reaction conditions: diphenylphosphine oxide (0.2 mmol),
b
c
d
Isolated yield. 100 °C. Ph2P(O)H (0.4 mmol), ketone (0.6
benzaldehyde (0.3 mmol), base (40 mol %), solvent (2 mL) under
e
b
mmol), Cs2CO3 (40 mol %), ethyl acetate (4 mL). Ph2P(O)H (0.4
mmol), ketone (0.6 mmol), Cs2CO3 (40 mol %), ethyl acetate (4
mL), 120 °C, 5 h.
N2 at 80 °C for 10 h. NMR yield with the use of CH2Br2 as the
c
d
internal standard. Reaction temp: rt. Reaction temp: 60 °C.
e
f
g
Reaction temp: 100 °C. Reaction time: 8 h. 2.0 equiv of
benzaldehyde was added.
tolerance of the thiophene moiety, as product 4ar was afforded
in moderate yield. Delightfully, ketones are also applicable,
albeit affording the products in relatively lower yields, probably
due to the lower reactivity and steric hindrance of the
substrates (4as−4av).
this delightful result, we conducted careful screening of the
reaction factors to improve the reaction outcome.14 As
expected, base exerts a profound influence on the reactivity.
Thus, the product 4aa was obtained in moderate yield with
NaOtBu or KOtBu, but only in trace amounts with LiOtBu
(Table 1, entries 2−4). Gratifyingly, the yield was dramatically
improved to 93% using Cs2CO3 as base (Table 1, entry 5). In
contrast, trace or no desired O-phosphination product was
detected in the presence of K2CO3 or Na2CO3, offering only
3aa in low yields (Table 1, entries 6 and 7). Although the
reaction was suppressed in n-hexane, other solvents, such as
toluene, dioxane, and tetrahydrofuran could be employed,
furnishing 4aa in good yields (Table 1, entries 8−11). The
reaction temperature also played a pivotal role, as inferior
results were obtained at lower or higher temperatures (Table 1,
entries 12−15). Finally, increasing the loading of benzaldehyde
had a deleterious effect, resulting in significant erosion of the
yield (Table 1, entry 16).
As depicted in Table 3, a series of secondary phosphine
oxides phosphonates and phosphinate efficiently coupled with
benzaldehyde to produce the corresponding O-phosphination
a
Table 3. Scope of SPO Compounds.
With the optimal conditions in hand, the generality of our
protocol was explored (Table 2). As shown, benzaldehydes
decorated with a diverse set of substituents could be well
accommodated. Substrates bearing o-, m-, or p-methyl groups
all proceeded smoothly under the standard conditions (4ab−
4ad), suggesting the insensitivity of the reaction to steric effect.
An electron-donating methoxy substituent was also tolerated
(4ae−4ag, 4al). Aldehydes containing electron-withdrawing
trifluoromethyl and ester groups could be well accommodated,
delivering the desired products in good yields (4ak, 4ap).
Various halogen-containing products were afforded unevent-
fully (4ah−4aj, 4an−4ao), leaving space for further derivatiza-
tion. Biphenyl and naphthyl aldehydes could also be applied,
providing the phosphinates in high yields (4am, 4aq). The
generality of the system was further showcased by the
a
Reaction conditions: secondary phosphine oxide (0.2 mmol),
aldehyde (0.3 mmol), Cs2CO3 (40 mol %), ethyl acetate (2 mL)
under N2 at 80 °C for 10 h. Isolated yield. Tetrahydrofuran (2 mL)
was used as solvent.
b
c
B
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products. All diarylphosphine oxide substrates bearing an
alkyl-, methoxy-, chloro-, or phenyl group on the phenyl ring
could be tolerated, providing the corresponding phosphinate
products 4ba−4ga facilely. Binaphthyl phosphinate 4ha could
also be achieved in 86% yield. However, sterically hindered
bis(2-tolyl)phosphine oxide showed no reactivity in the
protocol, since no expected product 4ia was observed. The
applicability of the reaction system was further demonstrated
with various unsymmetric phosphine oxides. Thus, benzyl
phenyl(o-tolyl)phosphinate 4ja was generated in 78% yield.
Moreover, phosphine oxides with an alkyl substituent such as a
methyl, benzyl, or isopropyl group on the P atom could all be
transformed into the corresponding products 4ka−4ma,
although the yields were lower. Notably, phosphonates 4na
and phosphate 4oa6d could both be prepared in moderate to
good yields, respectively. With THF as solvent, bisalkyl
phosphinate 4pq was also delivered in moderate yield.
synthetic potential of the reaction was further demonstrated by
subjecting the obtained enantioenriched phosphinate (S)-4rc
to CH3Li. SN2 nucleophilic substitution17 took place to furnish
the chiral phosphine oxide (S)-6 in good yield and high
enantioselectivity (eq 2).
Additional experiments were conducted in order to clarify
the reaction mechanism. When potential intermediates
(hydroxy(phenyl)methyl)diphenylphosphine oxide 3aa and
3ag were tested under the standard conditions, phosphinates
4aa and 4ag were delivered, respectively. 4-Methoxybenzalde-
hyde was also observed in the latter case (Scheme 3, a). 4-
Scheme 3. Control Experiments for Mechanistic Study
Optically active phosphinate derivatives are important
compounds with diverse biological activities and potential
applications in asymmetric synthesis.15 However, methods for
their preparation are rather limited.16 In this regard, we
examined the reaction of two different chiral secondary
phosphine oxide precursors. As shown in Scheme 2, the
Scheme 2. Synthesis of Chiral Phosphinate Compounds via
Chirality Transfer
reaction of (R)-(4-(tert-butyl)phenyl)(phenyl)phosphine oxide
(1q) and (R)-[1,1′-biphenyl]-4-yl(phenyl)phosphine oxide
(1r) proceeded smoothly in the current transformation,
providing the corresponding products (SP)-4 in good yields
and high ee values. A handful of aryl aldehydes could all be
tolerated, with no or slight erosion on the enantioselectivity.
The reaction could be performed on gram-scale, delivering
the target compound 4aa in excellent yield (eq 1). The
Methylbenzaldehyde (2b) reacted with 3aa leading to both
4aa and 4ad as final products (Scheme 3, b). These results
suggest that the nucleophilic addition of phosphine oxide to
aldehyde leading to generate 3aa is reversible. In comparison,
the reaction between 3ag and 2-methylbenzaldehyde (2d) only
afforded 3ab as a single product, without the formation of 4ag,
indicating that the electron-donating group on the aldehyde
deactivates the reactivity (Scheme 3, c). The crossover
experiments by feeding 3aa and 3bb into the optimal
conditions lead to all of the four possible phosphinate
products, further confirming the reversibility of the addition
process. (Scheme 3, d). During the reaction between
dibutylphosphine oxide and 2-naphthaldehyde under the
standard conditions, ethyl acetate involved product 5 was
observed along with 3pq and 4pq (Scheme 3, e).
Three reaction pathways as shown in Scheme 4 are proposed
on the basis of the above experiments. Initially, substrates 1
and 2 underwent a Cs2CO3-facilitated nucleophilic addition
leading to intermediate I. This process turned out to be
C
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intermediate C via a low barrier of 9.5 kcal/mol. Subsequently,
a concerted phospha-Brook rearrangement through TSCD and
protonation gives product 4 with a barrier of 20.4 kcal/mol.
Obviously, the lower activation energy of phospha-Brook
rearrangement pathway is confirmed to be more favorable.
In summary, we have developed a mild and practical route to
prepare phosphoric ester compounds. Aldehydes and ketones
were both coupled with secondary phosphine oxides, forming
P−O bond in the presence of base. Enantioenriched
phosphoric esters could be facilely prepared from chiral
phosphine oxide precursors. Three different reaction mecha-
nisms including phospha-Brook rearrangement, direct anti-
regioselective addition, and [3 + 2] cycloaddition/elimination
were proposed according to the experimental results. The
former was proved to take effect by DFT calculations. Further
investigations on the reaction system are ongoing in our lab.
Scheme 4. Proposed Reaction Mechanism
reversible according to the experimental results (Scheme 3).
1,2-Brook rearrangement would deliver the phosphinates as
final products (path a).6d,11 Alternatively, the involvement of
another aryl aldehyde molecule through [3 + 2] cycloaddition
may result in a five-membered species II, which eliminates the
aldehyde to afford the final product 4 upon protonation (path
b). In the presence of ethyl acetate, intermediate I might be
captured leading to byproduct 5 (path c). Direct nucleophilic
attack of cesium phosphite on the O atom of the carbonyl
group to create intermediate III cannot be excluded (path d).
To gain further insight into the reaction mechanism and
distinguish the three possibilities mentioned above, density
functional theory (DFT) calculations were carried out using
the Gaussian 09 software package (for details, see the SI).18,19
The free energy profiles are shown in Figure 1. First, Cs-
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01537.
Computational details, experimental procedures, and
characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Zhiming Li − Department of Chemistry, Fudan University,
Shanghai 200438, P.R. China; Email: zmli@fudan.edu.cn
Yu Liu − College of Chemistry and Life Science, Jilin Provincial
Key Laboratory of Carbon Fiber Development and Application,
Changchun University of Technology, Changchun 130012, P.R.
China; orcid.org/0000-0003-1304-9498; Email: yuliu@
ccut.edu.cn
Junliang Zhang − Department of Chemistry, Fudan University,
Shanghai 200438, P.R. China; Zhuhai Fudan Innovation
Institute, Zhuhai 519000, P.R. China; orcid.org/0000-
0002-4636-2846; Email: junliangzhang@fudan.edu.cn
Authors
Yanyan Qian − College of Chemistry and Life Science, Jilin
Provincial Key Laboratory of Carbon Fiber Development and
Application, Changchun University of Technology, Changchun
130012, P.R. China
Qiang Dai − Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai 200062,
P.R. China
Figure 1. Computed free energy profiles for the reaction process.
mediated [3 + 2] cycloaddition leading to the five-membered
species E (TSBE) was found to require a barrier of 24.3 kcal/
mol. A stepwise cycloaddition path was also located, which is
less favored due to a slightly higher barrier (Figure S1). The
following elimination process is stepwise according to our
computation results, since no concerted elimination transition
states can be located despite many attempts. From E,
elimination occurs to form intermediate F. Further elimination
of benzaldehyde delivers the final intermeidate D with a barrier
of 13.0 kcal/mol. Direct nucleophilic attack of cesium
phosphite on the O atom of the carbonyl group required a
barrier of 29.5 kcal/mol through TSAD. Alternatively, cesium
phosphite attacks benzaldehyde nucleophilically leading to
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21971066, 21772042) and the Science and
Technology Commission of Shanghai Municipality
(18JC1412300) for financial support.
D
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Orthaber, A. Organophosphorus Compounds in Organic Electronics.
Chem. - Eur. J. 2016, 22, 10718−10753.
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