Activation of the P-H bond by a frustrated Lewis pair and its application in catalytic: Z -selective hydrophosphonylation of terminal ynones

Article abstract of DOI:10.1039/c7cc05028c

The frustrated Lewis pair (FLP) comprised of B(C₆F₅)₃ and 1,2,2,6,6-pentamethylpiperidine (PMP) can efficiently catalyze Z-selective hydrophosphonylation of terminal ynones with a Z/E selectivity of up to 20:1. Mechanistic studies suggest that the trans arrangement of the phosphite nucleophilic attack and hydrogen bond formation on the alkyne moiety is responsible for the observed Z-selectivity.

Full text of DOI:10.1039/c7cc05028c

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Activation of P-H Bond by a Frustrated Lewis Pair and its
Application in Catalytic Z-selective Hydrophosphonylation of
Terminal Ynones
Received 00th January 20xx,
Accepted 00th January 20xx
Yizhen Liu, Xiaoting Fan, Zhen Hua Li, * Huadong Wang *
DOI: 10.1039/x0xx00000x
www.rsc.org/
The frustrated Lewis pair (FLP) comprised of B(C6F5)3 and 1,2,2,6,6- of terminal alkynes was also reported, which affords 1:1 Z/E
6
pentamethylpiperidine (PMP) can efficiently catalyze Z-selective mixtures.
Selective synthesis of less thermodynamically
hydrophosphonylation of terminal ynones with Z/E selectivity up favored (Z)-vinylphosphonate through hydrophosphonylation
to 20:1. Mechanism studies suggest that trans arrangement of the still remains a challenge. 7
phosphite nucleophilic attack and hydrogen bond formation on
the alkyne moiety is responsible for the observed Z-selectivity.
The concept of frustrated Lewis pair (FLP), recently
developed by Stephan and Erker groups, provides
a
conceptually different strategy for E-H bond (such as H-H, B-H,
C-H, Si-H and N-H bonds) activation and reduction of
unsaturated organic substrates. Surprisingly, so far no FLP
1
Hydrophosphonylation reactions
have emerged as a
8
powerful tool for the synthesis of phosphonate compounds
which are widely applied in organic synthesis, biochemistry
2
3
mediated P-H bond activation has been reported. We
envisioned that the coordination of a Lewis acid to the P=O
moiety of dialkyl phosphonate would allow a relatively weak
base to deprotonate the P-H bond (Scheme 1). The resulting
cation could then interact with the alkyne moiety to increase
its electrophilicity, thus facilitating the nucleophilic attack by
the phosphite anion. We speculated that, if the base is bulky
enough to disfavor the syn addition, Z-hydrophosphonylation
products could be obtained.
4
and materials.
One of the mostly applied
hydrophosphonylation reagents is dialkyl phosphonate which
often functions as a phosphorus nucleophile in the reaction
process. As the equilibrium of phosphonate-phosphite
tautomerization strongly favors the unreactive phosphonate
form (eq. (1)), strong bases are usually required to shift the
equilibrium to the more nucleophilic phosphite form. 5 Despite
of the success of this strategy in hydrophosphonylation of
To begin our investigation, we first examined the
stoichiometric reaction of diethylphosphonate with a FLP
comprised of B(C6F5)3 and 1,2,2,6,6-pentamethylpiperidine
1a,b
aldehydes, ketones, imines and electron deficient olefins,
there has been no report of base promoted
hydrophosphonylation of alkynes, possibly due to the low
electrophilicity of alkyne substrates. An alternative strategy
pioneered by Han and Takada provided the solution for alkyne
hydrophosphonylation by employing transition metal (such as
1c,d
Ni, Rh and Pd) complexes as catalyst.
It is believed that the
catalytic cycle starts with the oxidative addition of P-H bond to
the transition metal center followed by alkyne insertion and
subsequent reductive elimination. As a result, only E-selective
hydrophosphonylation product can be obtained with terminal
alkynes. More recently, photo induced hydrophosphonylation
Scheme
1
Working hypothesis
for FLP-catalyzed Z-selective alkyne
hydrophosphonylation
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2 show tetrahedral
and phosphorus atoms in compound
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DOI: 10.1039/C7CC05028C
coordination geometries. The distance of P-B bond is 2.026(2)
11
Å, typical for a B(C6F5)3-phosphine adduct.
hydrogen bond was also observed between the cation and
anion (d(N-H) = 0.87(2) Å, d(O H) = 1.87(2) Å). Therefore,
compound can be considered as a rare example of
borane/amine stabilized phosphite. related BH3/NEt3
A N⋯H⋯O
⋯
3
A
stabilized phosphite [HNEt3][(MeO)2P(OBH3)] is known,
although it was synthesized from trimethylsilyl stabilized
phosphite instead of directly from dialkyl phosphonate. 12
Scheme 2 Reaction between PMP and 1
The formation of compound
deprotonation of compound with PMP, which leads to the
formation of intermediate , an isomer of compound . As the
phosphorus atom in is likely more basic than the P=O moiety
in (EtO)2P(O)H, one B(C6F5)3 molecule will transfer from
compound to compound , yielding compound and free
(EtO)2P(O)H. In order to observe compound in solution, we
2 possibly starts with the
1
4
3
(PMP) which was recently applied as catalyst for Mannich-type
and amination reactions by Wasa group. Upon addition of 1
9
4
eq. of PMP to the CH2Cl2 solution of the known B(C6F5)3-
10
1
4
2
(EtO)2P(O)H adduct (
1
)
at room temperature, a new species
4
2
was immediately formed along with 0.5 eq. of unreacted
decided to increase the amount of (EtO)2P(O)H to suppress
the B(C6F5)3 transfer. After 10 eq. of (EtO)2P(O)H and 1 eq. of
PMP and free (EtO)2P(O)H remaining in the reaction mixture
(Scheme 2). Subsequently, by decreasing the molar ratio of
PMP were added to the CD2Cl2 solution of
for
, a new signal was observed at 133.2 ppm in the 31P NMR
spectrum (Figure S1). This signal gradually disappeared at
room temperature along with appearance of the signal for
As this low field resonance is comparable to those reported
phosphite species, 13 this signal was assigned to intermediate
To confirm this assignment, density functional theory (M06-2X)
1, besides the signal
PMP and
65% yield after 5 minutes of stirring at room temperature. The
11B NMR spectrum of compound
features two distinct signals
1 to 1:2, compound 2 was isolated as a white solid in
2
2
3
.
in a 1:1 ratio, one as a singlet at δ = -2.62 ppm and the other as
a doublet at δ = -15.06 ppm (1JB-P = 175 Hz). The former was
assigned to a B(C6F5)3 moiety coordinating to an oxygen atom,
and the latter to another B(C6F5)3 moiety coordinating to the
phosphorus atom. This was corroborated by the 31P NMR
4
.
14
15
with GIAO method
was employed to calculate the
in 31P NMR spectrum and the calculated
1
chemical shift of
4
signal at δ = 53.75 ppm as a quartet with the same JB-P
value (130.7 ppm) matches nicely with that observed
experimentally. Calculations were also carried out to compare
coupling constant. The identity of
HRMS analysis. Compound is not stable in the presence of
PMP and (EtO)2P(O)H. After stirring with equimolar of PMP
and (EtO)2P(O)H in CH2Cl2 at room temperature for 3 days,
compound can be quantitatively converted to compound
which can be isolated in 75% yield after recrystallization.
Compound can be also synthesized directly from equimolar
of PMP and after 3 days of stirring with similar yield.
Compound
2 was also confirmed by
2
the stability of isomers
3
and
4
. Compound
3
was found to be
2
4.2 kcal/mol more stable than compound
298 K. As the thermodynamically favored
4 in free energy at
3
lacks the required
2
3
nucleophilicity for hydrophosphonylation reactions,
relatively electron-deficient alkyne would be necessary to
ensure compound undergoes nucleophilic addition on the
alkyne moiety before it converts to compound or 3.
a
3
4
1
2
3
is characterized by a 11B NMR doublet signal at δ
= -16.59 ppm and a 31P NMR quartet signal at δ = 54.67 ppm
Therefore, we decided to choose ynones as the
hydrophosphonylation substrates. Although there is a recent
report about hydrophosphonylation of the carbonyl moiety of
ynones, 16 chemoselective hydrophosphonylation of the alkyne
moiety of ynones still remains unknown, despite that related
(Z)-vinylphosphonate derivatives have shown interesting
antibacterial activity. 17
(1JB-P = 179 Hz), in agreement with a direct B-P connection. The
structure of compound
3 was confirmed by an X-ray crystal
structure analysis (Figure 1). In the solid state, both the boron
Phenylprop-2-yn-1-one (5a) was selected as the model
substrate to evaluate the B(C6F5)3/PMP system. After stirring
equimolar of 5a and (EtO)2P(O)H with 10 mol% of B(C6F5)3 and
PMP at room temperature for 24 hours in dichloromethane,
vinylphosphonate 6a was obtained in 67% yield with a Z/E
selectivity of 7 : 1. Increasing the loading of PMP to 30%
resulted in improving the Z/E selectivity to 11 : 1. Further
increasing the amount of base has little effect on the yield and
selectivity. Replacing PMP with other organic bases, such as
NEt3, 2,2,6,6-tetramethylpiperidine, 2,6-lutidine or pyridine,
led to inferior results (see Supporting Information). A control
reaction with only B(C6F5)3 or PMP as catalyst showed no
formation of 6a. After determining the optimal conditions, we
Figure 1 Molecular structure of 3 (thermal ellipsoids are shown with 30% probability).
Hydrogen atoms except N-H are omitted for clarity.
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Table 1 Hydrophosphonylation of Terminal Ynones
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DOI: 10.1039/C7CC05028C
Entry
1
R
Yield (%)a
67
Z:Eb
11:1
6a
6b
6c
2
3
4
82
68
>20:1
15:1
Figure 2 The Gibbs free energy profile at 298 K for the reaction between 5i, (EtO)2P(O)H,
PMP and B(C6F5)3
63c
7:1
13:1
10:1
>20:1
6d
6e
6f
suggested that upon mixing of B(C6F5)3, PMP, (EtO)2P(O)H and
5i, adduct
1 is formed, which is -19.2 kcal/mol more stable
than the free B(C6F5)3 and (EtO)2P(O)H in free energy.
Subsequently, the P-H bond is deprotonated by PMP to afford
5
6
7
64
80
72
compound
of 10.8 kcal/mol. The next step is the nucleophilic attack of the
phosphite anion of on the terminal carbon of the alkyne
4, which needs to overcome a free-energy barrier
4
moiety of 5i with the concomitant formation of a hydrogen
bond between the internal carbon atom of the alkyne moiety
and the nitrogen atom of PMP to produce the intermediate
IM1. This step proceeds through the transition state TS2 with a
17.7 kcal/mol free-energy barrier. The hydrogen bond was
found trans to the newly formed C-P bond and this orientation
is crucial for the Z/E selectivity: transformation from IM1 to
6g
8
9
66
55
8:1
6h
6i
B(C6F5)3 coordinated phosphate (Z)-
7
and PMP is essentially
and PMP
19:1
barrierless, 18 whereas the conversion of IM1 to (E)-
7
needs to go through TS3 with a free-energy barrier of 6.1
kcal/mol. The release of final product (Z)-6i and (E)-6i needs to
overcome a binding energy of 25.0 and 21.5 kcal/mol,
respectively, and this step appears as the rate-limiting step.
Although the overall free-energy barrier for the formation of
10
62
4:1
6j
a Isolated yields. b Z:E was determined via 31P NMR. c 1 equiv. PMP was added.
(Z)-6i is 3.5 kcal/mol higher than (E)-6i, the ratio of (Z)-
(E)- in the reaction mixture also affects the selectivity of the
final products. As the conversion of (Z)- to (E)- requires to
surpass a relatively high free-energy barrier (29.6 kcal/mol)
through IM1, the ratio of (Z)- and (E)- is largely defined by
the energy difference between TS3 and TS3’, which is about
7 and
investigated this FLP catalytic system with a series of different
functionalized terminal ynones (Table 1). For aryl substituted
ynones (entry 1–8), both electron donating and withdrawing
groups are tolerated, with the latter showing better selectivity.
Heteroaryl substituent, such as thiophenyl, is also compatible
with the catalytic system (entry 8). Alkyl substituted ynones
were also tested and the target vinylphosphonates were
obtained in moderate yields with moderate to good selectivity
(entry 9 and 10). However, internal ynones, such as pent-3-yn-
2-one, showed no reactivity in this catalytic system.
7
7
7
7
7
18
6.1 kcal/mol.
Therefore, the formation of (Z)-6i is still
favored over (E)-6i by a ratio of 80:1 (calculation details see
Supporting Information), in relative well agreement with the
experimental Z/E ratio of 19:1.
In summary, we have found that the frustrated Lewis pair
comprised of B(C6F5)3 and PMP can activate the P-H bond of a
dialkyl phosphonate and shift the equilibrium between
phosphonate and phosphite by formation of a borane/amine
stabilized phosphite. This frustrated Lewis pair can be applied
To shed light on the reaction mechanism, we tested the
activity of compounds
2 and 3 for the hydrophsophonylation
reaction and discovered that neither of them proved
catalytically competent, thus ruling them out as catalytical
relevant intermediates. To further investigate the reaction
mechanism, DFT (M06-2X) calculations were performed with
ynone 5i chosen as the substrate (Figure 2). Our study
as
catalyst
to
realize
unprecedented
Z-selective
hydrophosphonylation of terminal ynones. This reaction is
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15 K. Wolinski, J. F. Hilton and P. Pulay, J. Am. Chem. Soc., 1990,
metal-free and shows good chemo-, regio- and Z/E selectivities
under ambient conditions. Our mechanism studies revealed
that the trans arrangement of the phosphite nucleophilic
attack and hydrogen bond formation on the alkyne moiety is
responsible for the observed Z-selectivity of this
hydrophosphonylation reaction.
View Article Online
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18 The lower of the free energy of transition state than the
intermediate is caused by the rigid-rotor and harmonic-
oscillator approximation since the potential energy of the
transition state is just 0.8 kcal/mol higher than that of the
intermediate.
Financial support from the National Natural Science
Foundation of China (21372048, 21573044, 21672039) and
Shanghai Science and Technology Committee (16DZ2270100)
is gratefully acknowledged. We also thank the High
Performance Computer Center of Fudan University for the
allocation of computing time. We thank Dr. Yue-Jian Lin for
help on crystallography study.
Conflict of interest
There are no conflicts to declare.
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DOI: 10.1039/C7CC05028C
Z-selective hydrophosphonlyation of terminal ynones was achieved by employing frustrated
Lewis pair catalyst.