Double role of the hydroxy group of phosphoryl in palladium(II)-catalyzed ortho -olefination: A combined experimental and theoretical investigation

Article abstract of DOI:10.1021/jo402307x

Density functional theory calculations have been carried out on Pd-catalyzed phosphoryl-directed ortho-olefination to probe the origin of the significant reactivity difference between methyl hydrogen benzylphosphonates and dimethyl benzylphosphonates. The overall catalytic cycle is found to include four basic steps: C-H bond activation, transmetalation, reductive elimination, and recycling of catalyst, each of which is constituted from different steps. Our calculations reveal that the hydroxy group of phosphoryl plays a crucial role almost in all steps, which can not only stabilize the intermediates and transition states by intramolecular hydrogen bonds but also act as a proton donor so that the η¹-CH₃COO^- ligand could be protonated to form a neutral acetic acid for easy removal. These findings explain why only the methyl hydrogen benzylphosphonates and methyl hydrogen phenylphosphates were found to be suitable reaction partners. Our mechanistic findings are further supported by theoretical prediction of Pd-catalyzed ortho-olefination using methyl hydrogen phenylphosphonate, which is verified by experimental observations that the desired product was formed in a moderate yield.

Full text of DOI:10.1021/jo402307x

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Article
Double Role of the Hydroxy Group of phosphoryl in Palladium(II)-catalyzed
ortho-Olefination: A Combined Experimental and Theoretical Investigation
Liu Liu, Hang Yuan, Tingting Fu, Tao Wang, Xiang Gao, Zhiping Zeng, Jun Zhu, and Yufen Zhao
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Dec 2013
Downloaded from http://pubs.acs.org on December 7, 2013
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Double Role of the Hydroxy Group of phosphoryl in Palladium(II)ꢀcatalyzed
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orthoꢀOlefination: A Combined Experimental and Theoretical Investigation
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Liu Liu,† Hang Yuan,† Tingting Fu,† Tao Wang,† Xiang Gao,§ Zhiping Zeng,§ Jun Zhu*,‡ and Yufen
Zhao*,†
†Department of Chemistry, College of Chemistry and Chemical Engineering, Key Laboratory for
Chemical Biology of Fujian Province, and Collaborative Innovation Center of Chemistry for
Energy Materials (iChEM), Xiamen University, Xiamen 361005, Fujian, China
‡State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key
Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, Fujian, China
§School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian, China
Email: jun.zhu@xmu.edu.cn; yfzhao@xmu.edu.cn
Table of Contents Graphic:
Abstract: Density functional theory (DFT) calculations have been carried out on Pdꢀcatalyzed
phosphorylꢀdirected orthoꢀolefination to probe the origin of the significant reactivity difference
between methyl hydrogen benzylphosphonates and dimethyl benzylphosphonates. The overall catalytic
cycle is found to include four basic steps: C−H bond activation, transmetalation, reductive elimination
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and recycling of catalyst, each of which is constituted from different steps. Our calculations reveal that
the hydroxy group of phosphoryl plays a crucial role almost in all steps, which can not only stabilize
the intermediates and transition states by intramolecular hydrogen bonds, but also act as a proton donor
so that the η1ꢀCH3COO− ligand could be protonated to form a neutral acetic acid for easy removal.
These findings explain why only the methyl hydrogen benzylphosphonates and methyl hydrogen
phenylphosphates were found to be suitable reaction partners. Our mechanistic findings are further
supported by theoretical prediction of Pdꢀcatalyzed orthoꢀolefination using methyl hydrogen
phenylphosphonate which is verified by experimental observations that the desired product was formed
in a moderate yield.
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1. INTRODUCTION
The transitionꢀmetalꢀcatalyzed crossꢀcoupling reactions such as Heck,1 Negishi2 and Suzuki–Miyaura3
reactions are very useful protocols for the creation of C−C and C−heteroatom bonds. These methods
have been extensively studied and some of them have proven to be exploited in the fine chemical
industrials, agrochemical and pharmaceutical.4 However, two disadvantages for these types of
transformations are poor atom economy and nonꢀgreen halogen byꢀproducts.5 Since 2000,
transitionꢀmetalꢀcatalyzed C−H bond activation reactions have attracted increasing attention owing to
the high efficiency and atom economy for C−C bond and C−heteroatom bond formation.6 Gratifyingly,
several distinct C−H functionalization strategies have been successfully applied in natural products
synthesis.7 To gain more insight into these important reaction mechanisms, a number of experimental8
and theoretical9 studies were carried out. The common acceptable mechanism involves four basic steps:
C−H activation, transmetalation, reductive elimination and recycling of catalyst (Scheme 1).
Recently, the directing groups such as carboxyl10 and hydroxyl11 have been widely utilized for
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transitionꢀmetalꢀcatalyzed ortho C−H activation reactions, providing a potentially useful procedure for
the construction of structurally sophisticated compounds. For instance, Kim and coꢀworkers reported a
phosphorylꢀ directed Pdꢀcatalyzed orthoꢀolefination (Scheme 2).12 It is very interesting to note that
methyl hydrogen benzylphosphonates (1a) and methyl hydrogen phenylphosphates (1b) were found to
be suitable reaction partners, whereas dimethyl benzylphosphonates (2a) and dimethyl
phenylphosphates (2b) as the substrates did not give orthoꢀolefination products under the same reaction
conditions.12 Although a plausible reaction mechanism was proposed by the authors,12b however, many
questions remain elusive, for instance, (i) How does each of the catalytic steps take place? (ii) What is
the barrier for each step? (iii) Why are methyl hydrogen benzylphosphonates and methyl hydrogen
phenylphosphates more reactive than dimethyl benzylphosphonates and dimethyl phenylphosphates?
(iv) Why does AgOAc improve the reaction significantly? Herein, our ongoing interest in
organophosphorus chemistry13 has led us to investigate the detailed reaction mechanisms on the
different reactivities of the substrates summarized by Scheme 2.
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Scheme 1. Common Acceptable Mechanism of Transitionꢀmetalꢀcatalyzed CꢀH Bond Activation
Reactions
Scheme 2. Phosphoryꢀrelated Directed Pdꢀcatalyzed orthoꢀOlefination.
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(0.1 equiv)
(3 equiv)
(2 equiv)
Pd(OAc)2
AgOAc
R'= Alkyl or Aryl
O
R'
O
P
OH
X
X
OR
OR
Moderate to
high yields
P
OH
8
9
1a
1b
: R= Me, X= CH2
: R= Me, X= O
R'
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O
P
OR
O
X
X
OR
OR
P
OR
No detected
2a
: R= Me, X= CH2
2b
: R= Me, X= O
R'
2. COMPUTATIONAL DETAILS
In the density functional theory (DFT) calculations, geometry optimizations and frequency calculations
were performed via the Gaussian 03 programs.14a DFT method B3PW9115 which has been chosen in
recent mechanistic studies on Pdꢀcatalysed reactions,16 with a mixed basis set employing 6ꢀ31+G(d)17
for C, H, O and LANL2DZ18 for P, Pd, Ag were used. Polarization functions were added for P (ξd =
0.387), Pd (ξf = 1.472) and Ag (ξf = 1.611) to the standard LANL2DZ basis set.19 Transition states were
examined by vibrational analysis and then submitted to intrinsic reaction coordinate (IRC) calculations
to determine two corresponding minima. Energies in solution (1,4ꢀdioxane) have been calculated by
means of single point calculations (IEFꢀPCM method with the Bondi radii)20 via the Gaussian 09
program14b with the B3PW91 method using SDD21 pseudoꢀpotential for the metal center and the
extended 6ꢀ311++G(2d,p)22 basis set for the other atoms. The gasꢀphase geometry was used for all of
the solution phase calculations. A similar treatment was also used in many recent computational
studies.23 The free energy correction from frequency calculation was added to the singleꢀpoint energy to
obtain the free energy in solution. All the solutionꢀphase free energies reported herein correspond to the
reference state of 1 mol/L, 298 K.
3. RESULTS AND DISCUSSION
3.1 C−H bond activation
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The model substrate methyl hydrogen benzylphosphonate (1a), dimethyl benzylphosphonate (2a),
styrene, catalyst Pd(OAc)2 and oxdant AgOAc were chosen. Relative free energies in solution
(1,4ꢀdioxane) are employed to analyze the reaction mechanism. Figure 1 depicts the C−H bond
activation step for Pd(II)ꢀcatalyzed orthoꢀolefination of methyl hydrogen benzylphosphonates (Figure
1a) and dimethyl benzylphosphonates (Figure 1b), respectively. In 2007, Yu and coꢀworkers reported
the first carbonyl directed Pdꢀcatalyzed orthoꢀC−H bond activation/C−C coupling reactions and
mechanistic rationalization of unusual kinetics in Pdꢀcatalyzed C–H olefination.24h,i Based on their
findings and previous proposed mechanisms,24 the reaction may start when 1a combines with the
Pd(OAc)2 catalyst, concomitant with η2→η1 hapticity change in the CH3COO− ligand. Three transition
states were identified for this transformation (Figure 2), because 1a has different Pꢀbonded oxygen
atoms, which can use their lone pairs to coordinate to the Pd center respectively. Our calculations show
that the most favorable process occurs when the oxygen atom of P=O attacks Pd center (TS1A). The
free energy of TS1A is lower than those of TS1C and TS1D by 5.0 kcal/mol and 6.9 kcal/mol,
respectively. In addition, natural bond orbital (NBO)26 analysis shows that negative charges of three
oxygens in 1a are ꢀ1.13 (P=O), ꢀ1.06 (P−O−H) and ꢀ0.88 (P−O−Me), respectively, indicating the
oxygen of P=O is more nucleophilic. Thus, TS1A was selected for the further study.
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Initially, model substrate methyl hydrogen benzylphosphonate (Figure 1a) binds to the Pd(OAc)2
catalyst to produce a complex IN1A by a hydrogen bond O6−HꢁꢁꢁO1 with a positive energy of 8.1
kcal/mol. Our calculations show that this complexation is a endergonic process and the major
contribution to the free energy comes from the entropy changes.27 From IN1A, a pentacoordinated
Pd(II) transition state TS1A is located with a distorted tetragonal pyramid structure. Then a
fourꢀcoordinated Pd(II) complex IN2A (0.7 kcal/mol) is formed, where the O5 uses its lone pair to
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coordinate to the Pd center. The overall barrier from IN0 to TS1A is 16.2 kcal/mol. Based on the
complexꢀinduced proximity effect proposed by Beak and Snieckus28 and the first C−H insertion
intermediate from simple carboxylic acids isolated by Yu8h, the substrate C7−C8 bond subsequently
coordinates to the Pd center to form IN3A via the TS2A transition state (activation barrier is 15.0
kcal/mol).
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In a similar way, model substrate dimethyl benzylphosphonate (Figure 1b) forms a complex IN1B
with the Pd(OAc)2. After several step, a fourꢀcoordinated Pd(II) complex IN3B with two η1ꢀCH3COO−
ligands is generated with a higher free energy of 24.3 kcal/mol than IN0. It is important to note that the
hydroxy group of phosphoryl can assist the first two steps. When dimethyl benzylphosphonate was
chosen as model substrate, the free energy of cooresponding transition states (TS1B and TS2B) are 8.0
kcal/mol and 14.3 kcal/mol higher than those of TS1A and TS2A, respectively, which can be mainly
attributed to the activation of the Pd−O1 bond and stabilizing the corresponding transition states by an
intramolecular hydrogen bond O6−HꢁꢁꢁO1. For instance, the Pd−O1 bond length (2.064 Å) in IN1A is
longer than that (2.053 Å) in IN1B. Furthermore, the Pd−C8 bond length (2.622 Å) in TS2B is much
shorter than that (2.741 Å) in TS2A, indicating IN2B requires more energies to reach TS2B. The
corresponding intermediate IN3A is more stable than IN3B by 15 kcal/mol. Interestingly, IN3A (9.3
kcal/mol) formed through TS2A is feathered by not only an η2ꢀcomplex, but also a spontaneous
hydrogen transfer from O6 to O1, forming an intramolecular hydrogen bond O6ꢁꢁꢁH−O1, which could
subsequently generate a more stable intermediate IN4A (6.6 kcal/mol relative to IN0) via the removal
of the neutral acetic acid.
The final step in C−H activation process of 1a is accomplished by forming a new intermediate
IN5A (ꢀ0.1 kcal/mol relative to IN0) via the TS4A structure. In TS4A, the bond lengths of Pd−C8,
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C8−H and H−O5 are 2.121, 1.345 and 1.368Å. In contrast to the process of 2a, intermediate IN3B
proceeds through a intramolecular sixꢀmembered transition state TS3B, which involves the cleavage of
the C8−H bond and the η1ꢀCH3COO−ꢀmediated hydrogen transfer, forming a new intermediate IN4B
(19.7 kcal/mol relative to IN0). After the removal of the neutral acetic acid, a more stable intermediate
IN5B is generated.
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Comparing the possible C−H bond activation pathways of the two substrates 1a and 2a, one can
realize that the hydroxy group of phosphoryl plays a key role in the first C−H activation step. It not
only stabilizes the intermediates and transition states by an intramolecular hydrogen bonds, but also
acts as a proton donor so that the η1ꢀCH3COO− ligand could be protonated to form a neutral acetic acid
for easy removal. Thus, the free energies of the intermediates and transition states of 1a (Figure 1a) are
much lower than those of 2a (Figure 1b). As a consequence, activation of the C−H bond in 1a is more
favorable than that in 2a both kinetically and thermodynamically.
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O
OR
P
OH
4
7
8
3
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3
O
O
O
6
1
O
3
OR
OR
(a)
Pd
O
O
5
Pd
O
O
P
P
Pd
O
5
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2
O
1
O
2
H
O
6
O
4
H
O
1
O
2
O
6
TS1A
16.2
IN0
0.0
IN1A
8.1
H
O
P
6
4
O
RO
3
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3
5
O
O
O
RO
Pd
Pd
7
O
O
2
P
5
O
4
7
8
8
H
O
O
6
1
IN5A
IN2A
0.
7
-0.1
RO
P
O
7
RO
P
OR
OR
6
H
O
6
5
HOAc
7
8
7
P
6
P
O5
O1
O5
Pd
H
8
O
O
O
O
6
5
7
O
2
8
H
Pd
O
1
O3
Pd
Pd
3
O
O
O
2
3
8
O
4
O
O
O
O
3
4
4
4
TS4A
25.7
TS2A
15.7
IN4A
6.6
IN3A
9.3
4
5
3
O
O
O
OR
RO
OR
P
OR
Pd
OR
7
7
8
O
(b)
P
P
6
O
5
O
5
4
7
8
2
6
8
O
1
OR
3
O
6
3
O
4
O
O1
O
1
O
3
OR
RO
TS1B
24.2
O
2
Pd
O
Pd
5
+
O
O
O
2
3
O
Pd
Pd
P
P
5
7
8
7
8
O
4
O
O
4
OR
O
RO
O
O
2
6
2
6
1
1
IN0
0.0
IN1B
IN2B
13.4
TS2B
30.0
13.6
6
6
RO
OR
OR
O
1
O
2
OR
7
HOAc
RO
RO
P
6
P
P
1
O
O
8
O
O
5
5
5
7
Pd
7
Pd
O
1
Pd
6
O
4
O
2
O
2
OR
O
1
8
8
O
O
RO
HO
3
4
P
O
3
O
5
IN3B
24.3
IN5B
1.8
2
IN4B
19.7
7
Pd
8
O
4
H
O
3
TS3B
29.6
Figure 1. Free energy profile for the C−H activation step for Pd(II)ꢀcatalyzed orthoꢀolefination of
methyl hydrogen benzylphosphonates (a) and dimethyl benzylphosphonates (b) (R = Me). The energies
are given in kcal/mol.
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Figure 2. The structures and relative free energies of three transition states with different oxygen atoms
binding to the Pd center.25 For clarity, the hydrogens of C−H are not shown. Bond lengths are given in
Å and energies in kcal/mol.
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3.2 Transmetalation and reductive elimination
The transmetalation and reductive elimination steps (Figures 3 and 4) start with the dissociation of the
η2ꢀCH3COO− ligand to create a vacant coordination site on Pd(II) and allow for the coordination of the
C−C double bond of styrene. IN5A can form two different η2ꢀcoordinated intermediates with styrene
depending on the orientation of the phenyl ring relative to the CH3COOH ligand (Figure 3, AꢀIN6A
and BꢀIN6A). Gratifyingly, the hydroxy of phosphoryl also plays a crucial role in η2→η1 hapticity
change in the CH3COO− ligand and stabilizing intermediates and transition states. For example, from
IN5A, the η2ꢀCH3COO− ligand dissociation and C−C double bond coordination give η2ꢀPd(II)
intermediate AꢀIN6A that is exothermic by ꢀ1.8 kcal/mol, concomitant with a hydrogen transfer
(O6−H→O3−H), forming an intramolecular hydrogen bond O6ꢁꢁꢁH−O3. The energetically favorable
intermediate AꢀIN6A proceeds via a threeꢀmembered transition state AꢀTS5A (activation barrier is
17.9 kcal/mol), leading to a complex AꢀIN7A. From AꢀIN7A, two possible reaction routes could be
located: (i) Direct hydrogen transfer from C9 to O6 through transition state AꢀTS6A with an activation
barrier of 8.6 kcal/mol. (ii) Hydrogen transfer from C9 to O3 through two transition states AꢀTS7A
(activation barrier of 9.0 kcal/mol for βꢀH elimination) and AꢀTS8A (activation barrier 3.3 kcal/mol),
respectively. Our calculations suggested that these two pathways may occur due to the similar
activation barrier, leading to an intermediate IN9A (ꢀ8.5 kcal/mol relative to IN0). Although path A is
energetically accessible under the experimental conditions (383 K),29 it is necessary to examine path B
(Figure 3) from unfavorable intermediate BꢀIN6A, because a more stable starting material
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(intermediate) may not lead to a more favorable transition state (CurtinꢀHammett Principle).30 From
BꢀIN6A, an η1ꢀCH3COO− transition state BꢀTS5A can be identified with an activation barrier of 19.0
kcal/mol, subsequently forming an unstable intermediate BꢀIN7A (16.9 kcal/mol relative to IN0). Next,
the reductive elimination takes place by 11.9 kcal/mol, leading to the formation of IN9A. Comparing
the two possible pathways, we found that the path B is unfaorable because it is too energyꢀdemanding.
For comparison of two model substrates, a similar pathway of dimethyl benzylphosphonate was
also located (Figure 4, Path C). The free energy of transtion state CꢀTS5B is computed to be 30.0
kcal/mol, which is 14.0 kcal/mol higher than that of AꢀTS5A. Then the C8−C9 bond formation gives
the intermediate CꢀIN7B. Sequentially, the hydrogen was transfered from the C9 atom to the O1 atom
via a sixꢀmembered transition state CꢀTS6B, leading to the formation of a more stable intermediate
IN9B. In addition, similar processes may take place from CꢀIN7B through two transition states
CꢀTS7B (23.5 kcal/mol) and CꢀTS8B (12.6 kcal/mol), respectively.
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In the transmetalation and reductive elimination steps, the activation barrier (17.6 kcal/mol) for
the rateꢀdeterming step of methyl hydrogen benzylphosphonate is much lower than that (28.2 kcal/mol)
of dimethyl benzylphosphonate. Moreover, the process of the IN5A→IN9A is more exothermic than
that of IN5B→IN9B. The methyl hydrogen benzylphosphonate is again favorable for this
transformation, in line with the experimental observations that dimethyl benzylphosphonate was
unreactive for the orthoꢀolefination reaction.
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OR
P
6O
H
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O
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5
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H
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Pd
O
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Ph
RO
O
H
A-TS6A
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P
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O
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O
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Pd
9
6
OH
P
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O
RO
O
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6
RO OH
RO
H
H
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6
Ph
Ph
P
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3
P
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P
5
H
O
3
O
4
O
O
A-TS5A
O
O
O
7
7
7
O
O
3
3
16.0
Pd
7
8
O
4
8
8
Pd
Pd
O
Path A
Pd
O
4
8
4
9
9
9
Ph
Ph
Ph
IN5A
-0.1
IN9A
-8.5
A-IN6A
-1.9
A-IN7A
2.9
RO
O
H
RO OH
6
H
O
6
6
RO
P
O
P
O
3
4
Ph
O
7
P
5
5
7
O
Path B
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3
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O
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H
7
O
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8
Pd
8
Pd
O
H
Ph
H
Ph
8
Pd
4
H
9
9
Ph
9
A-TS7A
11.9
A-TS8A
4.7
OR
A-IN8A
1.4
OR
P
6
H
O
P
6
O
7
O
5
H
O
7
5
8
4
O
4
Pd
9
8
Pd
O
IN9A
6
RO OH
Ph
OR
O
5O
HO
3
O
6
P
P
H
7
8
3
Ph
9
O
3
7
O
H
5
B-IN6A
B-IN7A
16.9
8
8.9
Pd
9
O
Pd
O
4
4
H
O
Ph
9
3
H
Ph
B-TS5A
27.9
B-TS6A
28.8
Figure 3. Free energy profile for the transmetalation and reductive elimination steps using methyl
hydrogen benzylphosphonate (1a) as model substrate. The free energies are given in kcal/mol.
Figure 4. Free energy profile for the transmetalation and reductive elimination steps using dimethyl
benzylphosphonate (2a) as model substrate. The free energies are given in kcal/mol.
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3.3 Recycling of catalyst
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Note that when methyl hydrogen benzylphosphonate was treated with ethyl acrylate (2 equiv) using
Pd(OAc)2 (10 mol %) and Ag(I) salts, the reaction was improved significantly.12 The yields of the
orthoꢀolefination product were changed with the oxidants as follows: AgOAc (2 equiv), 71%; Ag2CO3
(2 equiv), 32%; Ag2O (2 equiv), 57% and AgOAc (3 equiv), 95%. In order to investigate the role of
AgOAc in the reaction, we turn our attention to the recycling of Pd(OAc)2 catalyst step. As shown in
Figure 5, it starts with a more stable intermediate IN10A (ꢀ22.6 kcal/mol) via a removal of one
CH3COOH molecule from IN9A followed by a coordination with AgOAc. As experimental study31
showed that the Ag−Ag bond is relatively strong (bond dissociation energy is 38.3 kcal/mol), the
formation of Ag2 might be facile in the oxidation process. Indeed, when AgOAc was further added, a
relatively more stable intermediate IN11 (ꢀ30.7 kcal/mol) was formed. Then the recycling of the
catalyst Pd(OAc)2 was achieved by a transition state TS9. The barrier from IN11 to TS9 is +29.7
kcal/mol, in line with the experimental observation that this orthoꢀolefination reaction was carried out
at 110 °C.29 Finally, separation of Ag2 leads to regenerate the catalyst Pd(OAc)2 and Ag2 could build up
as the reaction proceeds,32 facilitating a forward shift in chemical equilibrium.
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Figure 5. Free energy profile for the recycling of catalyst step (R = Me). The free energies are given in
kcal/mol.
3.4 Theoretical prediction and experimental realization
Pdꢀcatalyzed C−H bond activation reactions involving a variety of substrates have been studied by
various groups and cyclopalladated compounds were proposed for the transformations.24 It is worth
noting that in our mechanistic study all cyclopalladated complexes have a sixꢀmembered ring.
Interestingly, several stable fiveꢀmemebered cyclopalladated complexes were prepared in the previous
studies.33,8h Can the fiveꢀmemebered cyclopalladated complexes be the intermediates or transition
states in Pdꢀcatalyzed orthoꢀolefination? To test this hypothesis, we first investigate the reaction
mechanism with methyl hydrogen phenylphosphonate (3) as the substrate theoretically. As shown in
Figure 6, the computed reaction barrier is comparable to that with 1a as the substrate. Thus the
substrate 3 is predicated to be reactive in in Pdꢀcatalyzed orthoꢀolefination.
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Figure 6. Free energy profile for the Pdꢀcatalyzed orthoꢀolefination using methyl hydrogen
phenylphosphonate (3). The energies are given in kcal/mol.
To verify this predication, we treated methyl hydrogen phenylphosphonate (3) (0.2 mmol) and
ethyl acrylate (0.4 mmol) with a mixture of Pd(OAc)2 (0.02 mmol) and AgOAc (0.6 mmol), in
o
1,4ꢀdioxane at 110 C for 24 h (Scheme 3). 31P NMR and ESIꢀMS analyses of the crude product
showed that the orthoꢀolefination product 4 was obtained, along with the 30% unchanged reactant. For
facile purifications, the crude product was methylated by TMSꢀdiazomethane, leading to the
methylated product 5 in 66% isolated yield. Not surprisingly, dimethyl phenylphosphonate did not
participate in the reaction since no coupled product could be detected in the crude reaction mixture.
Scheme 3. Pdꢀcatalyzed orthoꢀOlefination using Methyl Hydrogen Phenylphosphonate
O
P
O
10 mol % Pd(OAc)2
3 equiv. AgOAc
O
P
OMe
P
OMe
OMe
TMS-diazomethane
OH
OMe
1,4-dioxane, 110 oC
OH
r.t., 30 min
24 h
CO2Et
CO2Et
3
5
CO2Et
4
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4. CONCLUSION
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In summary, we have investigated the complete catalytic cycles of palladium(II)ꢀcatalyzed
phosphoryꢀdirected orthoꢀolefination by DFT calculations. Our calculation results reveal that the
hydroxy group of phosphoryl plays a crucial role almost in all steps, which can not only stabilize the
intermediates and transition states by an intramolecular hydrogen bond, but also act as a hydrogen
donor so that the η1ꢀCH3COO− ligand could be protonated to form a neutral acetic acid for easy
removal. These findings explain why only the methyl hydrogen benzylphosphonates and methyl
hydrogen phenylphosphates were found to be suitable reaction partners. Our mechanistic studies are
further supported by theoretical prediction of Pdꢀcatalyzed orthoꢀolefination using methyl hydrogen
phenylphosphonate (3) which is verified by experimental observations that the desired product was
formed in a moderate yield. These findings provide a useful guide to the design of more efficient
directing groups on Pdꢀcatalyzed orthoꢀolefination.
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5. EXPERIMENTAL SECTION
General Information. 31P, 1H and 13C NMR spectra were measured on 500M or 400M spectrometers.
1H NMR and 13C NMR were recorded using tetramethylsilane (TMS) in the solvent of CDCl3 as the
internal standard (1H NMR: TMS at 0.00 ppm, CHCl3 at 7.26 ppm; 13C NMR: CDCl3 at 77.0 ppm) and
85% H3PO4 as external standard for 31P NMR. All coupling constants (J values) were reported in Hertz
(Hz). HRMS spectra were recorded on a FTꢀMS apparatus.
Methyl hydrogen phenylphosphonate (3). Anhydrous methanol (0.20 mL, 5.0 mmol, 1.0 equiv) was
added slowly to an ice cooled solution of PhP(O)Cl2 (970 mg, 5.0 mmol, 1.0 equiv) in diethyl ether
(5.0 mL), followed by the subsequent addition of pyridine (0.40 mL, 5.0 mmol, 1.0 equiv). The white
precipitate of pyridineꢁHCl was filtered off and the filtrate concentrated in vacuo. The crude
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intermediate (PhP(O)(OMe)Cl), 1N NaOH (0.50 mL) was stirred in CH2Cl2:H2O (1:2 v/v, 10 mL)
under ambient temperature overnight. The reaction was then extensively extracted with CH2Cl2 (10 mL
× 5) and the combined organic extract was concentrated in vacuo. The crude residue was purified by
flash chromatography (CH2Cl2/acetone = 1:2) via a short silica plug to afford the desired product 334 in
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1
90% yield (774 mg). H NMR (500 MHz, CDCl3) δ: 7.77ꢀ7.87 (m, 2H), 7.51ꢀ7.58 (m, 1H), 7.39ꢀ7.47
(m, 2H), 3.71 (d, 3H, J = 11.4 Hz); 13C NMR (125 MHz, CDCl3) δ: 132.3 (d, J = 3.1 Hz), 131.4 (d, J =
10 Hz), 128.4 (d, J = 15.3 Hz), 128.2 (d, J = 192.7 Hz) and 52.4 (d, J = 5.6 Hz); 31P{H} NMR (203
MHz, CDCl3) δ: 20.9. ESIꢀMS: [M+H]+ m/z calcd for C7H10O3P+: 173.0, found: 173.0.
(E)ꢀethyl 3ꢀ(2ꢀ(dimethoxyphosphoryl)phenyl)acrylate (5). Methyl hydrogen phenylphosphonate 3
(35 mg, 0.2 mmol, 1.0 equiv), Pd(OAc)2 (4.5 mg, 10 mol %), AgOAc (100 mg, 0.6 mmol, 3.0 equiv),
ethyl acrylate (40 mg, 0.4 mmol, 2.0 equiv) and dry dioxane (2.0 mL) were mixed in a sealed vial. The
reaction mixture was stirred at 110 °C for 24 h. The mixture was then cooled to 0 °C and 2.0 N HCl
solution (1.0 mL) was added. The mixture was extracted with EtOAc (2 × 10 mL). The organic phase
was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to yield the crude
product, which was diluted with methanol (5.0 mL) and treated with TMSꢀCHN2 (0.50 mL, 2M in
hexane) at room temperature for 0.5 h. The mixture was evaporated under reduced pressure and
purified by silica gel flash column chromatography (hexane/ethyl acetate = 2:1) to afford product 5 in
66% yiled (38 mg). 1H NMR (400 MHz, CDCl3) δ: 8.35ꢀ8.25 (d, 1H, J = 15.8 Hz), 8.06ꢀ7.99 (m, 1H),
7.84ꢀ7.77 (m, 1H), 7.60ꢀ7.49 (m, 2H), 6.41ꢀ6.34 (d, 1H, J = 15.8), 4.32ꢀ4.24 (q, 2H, J = 7.2 Hz),
3.77ꢀ3.81 (d, 6H, J = 11.2 Hz), 1.36ꢀ1.32 (t, 3H, J = 7.2 Hz) ; 13C NMR (100 MHz, CDCl3) δ: 166.4,
142.5 (d, J = 4.7 Hz), 138.0, 134.6 (d, J = 9.4 Hz), 132.9 (d, J = 2.6 Hz), 131.9 (d, J = 9.6 Hz), 129.2 (d,
J = 14.7 Hz), 126.7 (d, J = 186.1 Hz), 121.5, 60.6, 52.6 (d, J = 6.0 Hz), 14.3; 31P{H} NMR (162 MHz,
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CDCl3) δ: 20.5. HRMS: [M+H]+ m/z calcd for C13H18O5P+: 285.08864, found: 285.08815.
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ASSOCIATED CONTENT
Supporting Information
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Copies of 1H and 13C NMR spectra for compounds 3, 5 and the cartesian coordinates for all the species.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
jun.zhu@xmu.edu.cn; yfzhao@xmu.edu.cn
Homepage: http://junzhu.chem8.org; http://chem.xmu.edu.cn/group/yfzhao/zhaoꢀhome.html
Notes
The authors declare no competing financial interest.
Acknowledgment. We acknowledge financial support from the National Basic Research Program of
China (2012CB821600, 2013CB910700 and 2011CB808504), the Chinese National Natural Science
Foundation (21305115, 21103142, 21172184, 21133007 and 81301888), the Program for New Century
Excellent Talents in University (NCETꢀ13ꢀ0511), the Program for Changjiang Scholars and Innovative
Research Team in University and the Fundamental Research Funds for the Central Universities
(2012121021). We are grateful to Prof. Dr. Sunggak Kim and Dr. Xiangjian Meng at Nanyang
Technological University for valuable discussions.
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(32) (a) The free energy change of 2Ag2 → Ag4 is ꢀ12.8 kcal/mol. (b) The formation of Ag metal can be detected
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