Mechanistic Studies on the Palladium-Catalyzed Cross Dehydrogenative Coupling of P(O)-H Compounds with Terminal Alkynes: Stereochemistry and Reactive Intermediates

Article abstract of DOI:10.1021/acs.organomet.5b00687

The mechanism of the palladium-catalyzed cross dehydrogenative coupling of P(O)-H compounds with terminal alkynes was studied. Successive ligand-exchange reactions of Pd(OAc)₂ with a hydrogen phosphoryl compound and a terminal alkyne take place

Full text of DOI:10.1021/acs.organomet.5b00687

Article
pubs.acs.org/Organometallics
Mechanistic Studies on the Palladium-Catalyzed Cross
Dehydrogenative Coupling of P(O)−H Compounds with Terminal
Alkynes: Stereochemistry and Reactive Intermediates
Jia Yang,† Tieqiao Chen,*,† Yongbo Zhou,† Shuang-Feng Yin,† and Li-Biao Han*,‡
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University,Changsha 410082, China
‡National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan
S
* Supporting Information
ABSTRACT: The mechanism of the palladium-catalyzed cross
dehydrogenative coupling of P(O)−H compounds with terminal
alkynes was studied. Successive ligand-exchange reactions of
Pd(OAc)2 with a hydrogen phosphoryl compound and a terminal
alkyne take place readily to replace the two acetates on palladium,
producing the corresponding (phosphoryl) (alkynyl)palladium
complexes, which upon heating decomposed to the corresponding
alkynylphosphorus compound. It is also confirmed that in the
stoichiometric reactions of the complexes, the configuration at
phosphorus is retained. On the basis of these stoichiometric
reactions, an efficient synthesis of P-chiral alkynylphosphoryl compounds via palladium-catalyzed stereoselective cross
dehydrogenative coupling of P-chiral P(O)−H compounds with terminal alkynes was developed. The key palladium complexes
and the stereochemistry of the chiral phosphorus compounds are all unambiguously determined by single-crystal X-ray analysis.
INTRODUCTION
Alkynylphosphoryl compounds are synthetically important
intermediates in organic synthesis.1 Some of these compounds
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Scheme 1. Known Methods for the Synthesis of
Alkynylphosphoryl Compounds
used as the substrates to produce the corresponding
alkynylphosphoryl compounds 1 efficiently.5 Herein we report
a detailed study on this reaction.
RESULTS AND DISCUSSION
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Facile Formation of trans-Pd[P(O)Z1Z2](OAc)(PEt3)2 via
Reactions of HP(O)Z1Z2 with Pd(OAc)2: Retention of
Configuration at Phosphorus. At room temperature, C6D6
(0.5 mL) was added to a mixture of (RP)-[(−)MenO]BnP(O)
H (2a, 0.1 mmol), PEt3 (0.2 mmol), and Pd(OAc)2 (0.1
mmol). The solids disappeared rapidly to give, first, a pale
yellow and then colorless transparent solution within 1 h. In 31P
NMR spectroscopy, the signal assigned to (RP)-[(−)MenO]-
BnP(O)H (δ 34.0) disappeared completely and two sets of new
signals appeared at δ 85.3 (t, J = 6.5 Hz, P(O)) and δ 19.7 (d,
PEt3), indicative of the formation of a new palladium complex,
trans-[(−)MenOBnP(O)]Pd(OAc)(PEt3)2, (SP)-3a (eq 2). No
other signals were observed on both 1H and 31P NMR
spectroscopies, showing this is a selective reaction. White
crystals of (SP)-3a suitable for X-ray analysis were obtained via
recrystallization from toluene−hexane at −30 °C. As shown in
are also of biological importance.2 As shown in Scheme 1,
traditionally, these compounds are prepared by the nucleophilic
substitution reactions of alkynyllithiums (or alkynylmagnesium
halides) with P(O)Cl compounds.3 In 2009, a copper-catalyzed
aerobic dehydrogenative coupling of terminal alkynes with
hydrogen phosphonates generating alkynylphsophonates was
disclosed.4 Despite its limitation at that time that only
(RO)2P(O)H was applicable to the reaction,4 this reaction
shows a totally different, clean approach to alkynylphosphoryl
compounds.
Recently, we communicated a Pd(OAc)2-mediated cross
dehydrogenative coupling of P(O)−H compounds with
terminal alkynes to prepare these alkynylphosphoryl com-
pounds 1 (eq 1). A great advantage of this reaction is that it
overcomes the substrate limitation problem of the above-
mentioned copper-catalyzed aerobic dehydrocoupling reaction,
and all of the three kinds of HP(O)Z1Z2 compounds 2 can be
Received: August 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b00687
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Figure 2. ORTEP drawing of (SP)-4a. Hydrogen atoms are omitted
for clarity. Selected bond lengths (Å) and angles (deg): P1−Pd =
2.3116(9), P2−Pd = 2.3357(10), P3−Pd = 2.3238(9), C3−Pd =
2.028(4), C3−C4 = 1.197(4), P1−C1 = 1.828(3), P1−O1 = 1.500(2),
P1−O2 = 1.621(2), P1−Pd−C3 = 177.63(11), P1−Pd−P2 =
97.95(3), P1−Pd−P3 = 89.80(3), P2−Pd−P3 = 171.38(4), Pd−
C3−C4 = 176.5(3), O1−P1−Pd = 119.05(10), O2−P1−Pd =
109.19(9), C1−P1−Pd = 105.88(12).
Table 1. Palladium-Catalyzed Stereoselective Cross
Dehydrogenative Coupling of Hydrogen Phosphoryl
Compounds with Terminal Alkynes: Retention of
Figure 1. ORTEP drawing of (SP)-3a. Hydrogen atoms are omitted
for clarity. Ellipsoids are drawn at 50% probability. Selected bond
lengths (Å) and angles (deg): P1−Pd = 2.331(10), P2−Pd = 2.357(9),
P3−Pd = 2.236(8), O3−Pd = 2.126(3), P3−C1 = 1.831(4), P3−O1 =
1.486(2), P3−O2 = 1.615(3), P3−Pd−O3 = 176.73(11), P3−Pd−P2
= 97.20(3), P3−Pd−P1 = 90.24(3), O1−P3−Pd = 119.02(10), O2−
P3−Pd = 102.23(9).
a
Configuration at Phosphorus
Scheme 2. Rapid Ligand Exchange of an Acetate on
a
Palladium with a Phosphoryl Group
a
Reaction conditions: 2 (0.1 mmol), Pd(OAc)2 (0.1 mmol), and PEt3
(0.2 mmol) were mixed in C6D6 (0.5 mL) at room temperature for 1
h.
a
Reaction conditions: 0.2 mmol of H-phosphinate, 0.2 mmol of
alkyne, 5 mol % Pd(OAc)2, 0.4 mmol of AgBF4, 1 mL of THF, 60 °C,
12 h. 0.6 mmol of Et3N, 120 °C, 1.5 h. 0.6 mmol of Et3N, 120 °C, 3
h.
Scheme 3. Facile Ligand Exchange of Complex 3 with
Phenylacetylene
b
c
a
The above reaction of Pd(OAc)2 with a P(O)−H compound
2 generating complex 3 is a general reaction. As shown in
Scheme 2, under similar reaction conditions, H-phosphonate
(EtO)2P(O)H (2b) and a five-membered H-pinacolatophosph-
onate (2c) reacted with Pd(OAc)2 smoothly to quantitatively
produce the corresponding phosphorylpalladium(II) complexes
3b and 3c, respectively. An H-phosphinate Ph(EtO)P(O)H
(2d) and a secondary phosphine oxide Ph2P(O)H (2e) also
underwent similar ligand-exchange reactions to afford the
phosphorylpalladium(II) complexes 3d and 3e, respectively
(Scheme 2).
a
Reaction conditions: 0.1 mmol of 3 and 0.1 mmol of phenylacetylene
dissolved in 0.5 mL of C6D6, room temperature, 24 h.
Reaction of Complex 3 with Phenylacetylene: A
Selective Ligand Exchange Reaction Generating
(Phosphoryl)(phenylethynyl)palladium 4. At room tem-
perature, an equivalent mixture of (SP)-3a and phenylacetylene
(0.05 mmol) was dissolved in C6D6 (Scheme 3). On 31P NMR
spectroscopy, after 10 min, two new signals at 101.6 (t, J = 15.7
Figure 1, the X-ray analysis confirms the trans geometry of the
palladium complex and the S configuration at phosphorus,
showing that the stereochemistry at phosphorus remains
unchanged during the ligand-exchange process.
B
DOI: 10.1021/acs.organomet.5b00687
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Hz) and 20.1 (broad) were observed. As described later, these
two signals are due to the formation of a new alkynyl-
(phosphoryl)palladium complex, (SP)-4a. As estimated from 1H
and 31P NMR spectroscopies, (SP)-3a was consumed in 24 h
and (SP)-4a was produced quantitatively. After removal of the
volatiles in vacuo, a white solid was obtained, which was
recrystallized from toluene−hexane at −30 °C to give single
crystals suitable for X-ray analysis. As depicted in Figure 2, X-
ray analysis clearly confirmed the structure of (SP)-4a, in which
the configuration of the phosphoryl group is also S geometry;
that is, the stereochemistry at phosphorus stays intact during
the ligand-exchange process.
1, entries 3 and 4). Similarly, (RP)-2a reacted with phenyl-
acetylene and 1-octyne to produce the corresponding (SP)-1a
and (SP)-1f in 56% and 87% yields, respectively (Table 1,
entries 5 and 6).7
MECHANISTIC DISCUSSION
On the basis of the stoichiometric reactions of the palladium
complexes (eqs 2 and 3 and Schemes 2 and 3) as described
■
Scheme 4. Mechanism for the Palladium-Catalyzed
Stereoselective Cross Dehydrogenative Coupling of P(O)−
H Bonds with Terminal Alkynes
Other complexes 3 also reacted with phenylacetylene to give
the corresponding complex 4 (Scheme 3). Compared to
complex 3a, under similar conditions, the reaction of 3c with
phenylacetylene proceeded slowly (24 h, 25% yield).
Fortunately, we found that by adding an equivalent of sodium
hydroxide, which neutralized the released acetic acid, the
reaction could complete in 24 h to give the corresponding
product 4b quantitatively. Under similar conditions, the
reaction of 3e with phenylacetylene took place readily.
However, although complex 4c could clearly be detected by
31P NMR spectroscopy, it was not stable at room temperature
and decomposed to the corresponding reductive elimination
product (diphenyl)(phenylethynyl)phosphine oxide (1g) even
in the presence of an excess amount of Et3P (Scheme 3).6
Stereoselective Reductive Elimination of Complex 4
Generating (Phenylethynyl)phosphoryl Compounds.
These complexes 4 are chemically labile. Thus, although (SP)-
4a is isolable at room temperature, at an elevated temperature,
a reductive elimination takes place readily to produce the
corresponding (phenylethynyl)phosphoryl compound (SP)-1a.
For example, by heating (SP)-4a (0.05 mmol in C6D6 (0.5
mL)) at 80 °C for 2 h, (SP)-1a was produced quantitatively (eq
3).7
above, it is reasonable to rationalize that this palladium-
catalyzed coupling takes place via a catalytic cycle involving (i)
a stepwise ligand exchange of Pd(OAc)2 with a P(O)−H
compound and an alkyne to generate an alkynyl(phosphoryl)
palladium intermediate 4, which then (ii) undergoes reductive
elimination to give the corresponding coupling product
alkynylphosphoryl compound 1. Subsequently, (iii) the
reduced zerovalent palladium is reoxidized by Ag(I) back to
Pd(II) to complete the catalytic cycle (Scheme 4). The
stereochemistry at phosphorus stays intact during these
transformations.
Palladium-Catalyzed Stereoselective Cross Dehydro-
genative Coupling of Hydrogen Phosphoryl Com-
pounds with Terminal Alkynes: Retention of Config-
uration at Phosphorus. On the basis of these stoichiometric
reactions (Schemes 2 and 3 and eqs 2 and 3), it is expected that
the palladium-catalyzed cross dehydrogenative coupling reac-
tion of a terminal alkyne with a hydrogen phosphoryl
compound 2 should proceed stereoselectively, providing an
efficient method for the stereoselective introduction of P-chiral
phosphoryl groups. This indeed is the case. P-Chiral organo-
phosphoryl compounds are of high significance in organic
synthesis, biochemistry, and pharmaceutical chemistry.8 How-
ever, methods for the preparation of a P-chiral alkynylphosporyl
compound are limited.9
Thus, mediated by a catalytic amount of Pd(OAc)2, the cross
dehydrogenative coupling reactions of (RP)-2f with phenyl-
acetylene and 1-octyne readily gave the corresponding (SP)-
alkynylphosphinates (SP)-1b and (SP)-1c in 48% and 65%
isolated yields, respectively (Table 1, entries 1 and 2). H-
Phosphinate (RP)-2g is also as reactive as (RP)-2f to react with
phenylacetylene and 1-octyne, producing the expected products
(SP)-1d and (SP)-1e in 58% and 80% yields, respectively (Table
SUMMARY
■
A ligand-exchange reaction takes place readily between
palladium acetate and a hydrogen phosphoryl compound
HP(O)Z1Z2 to produce the corresponding (phosphoryl)
palladium acetates. A successive ligand-exchange reaction also
readily takes place between these (phosphoryl)palladium
acetates with phenylacetylene to generate (phosphoryl)-
(alkynyl)palladium complexes, which upon heating produce
the corresponding alkynylphosphoryl compounds via reductive
elimination reactions. The stereochemistry at phosphorus is
retained in these reactions. On the basis of these mechanistic
studies, a palladium-catalyzed stereospecific cross dehydrogen-
ative coupling of P-chiral P(O)−H compounds with terminal
alkynes was developed, providing an efficient method to
prepare the valuable P-chiral alkynylphosphoryl compounds.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00687.
■
S
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DOI: 10.1021/acs.organomet.5b00687
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2776. (j) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293−
1314. (k) Shao, Z.; Peng, F. Angew. Chem., Int. Ed. 2010, 49, 9566−
9568. (l) Chen, T.; Zhang, J.-S.; Han, L.-B. Dalton Trans. 2015,
DOI: 10.1039/C5DT01896J.
General information, experimental procedures, character-
ization data, and copies of 1H, 13C, and 31P NMR spectra
for products (PDF)
CIF file for (SP)-3a (CIF)
CIF file for (SP)-4a (CIF)
CIF file for (RP)-1a (CIF)
(5) (a) Yang, J.; Chen, T.; Zhou, Y.; Yin, S.-F.; Han, L.-B. Chem.
Commun. 2015, 51, 3549−3551. For reports of similar Pd catalysts for
C(sp2)−H and C(sp3)−H cross dehydrogenative coupling with
phosphites, see: (b) Hou, C.; Ren, Y.; Lang, R.; Hu, X.; Xia, C.; Li,
F. Chem. Commun. 2012, 48, 5181−5183. (c) Feng, C.-G.; Ye, M.;
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: chentieqiao@hnu.edu.cn.
*E-mail: libiao-han@aist.go.jp.
■
Notes
(6) Its 31P NMR signal in the presence of an excess of Et3P (2 equiv):
δ 71.4 (t, J = 20.74 Hz, P(O)) and 17.4 (d, J = 20.74 Hz, PEt3).
(7) (SP)-1a is oily. We have synthesized (RP)-1a from the
substitution reaction of (−)MenOBnP(O)Cl with phenylacetynyl
lithium (for the procedure, see the SI). The structure of (RP)-1a was
confirmed by X-ray analysis and is shown in Figure 3.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Partial financial support from NFSC 21403062, 21373080,
HNNSF 2015JJ3039, and the Fundamental Research Funds for
the Central Universities (Hunan University) is gratefully
acknowledged. The authors also thank Prof. Dr. Xiaoyi Yi
from Central South University for X-ray analysis and Prof. Dr.
Zhan Lu from Zhejiang University for elemental analysis.
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D
DOI: 10.1021/acs.organomet.5b00687
Organometallics XXXX, XXX, XXX−XXX