Applications of α-phosphonovinyl tosylates in the synthesis of α-arylethenylphosphonates via suzuki-miyaura cross-coupling reactions

Article abstract of DOI:10.1021/ol503518h

It has been demonstrated for the first time that α-phosphonovinyl tosylates could efficiently couple with a range of arylboronic acids to access α-arylethenylphosphonates. The unprecedented procedure exhibits excellent functional group tolerance, giving the terminal vinylphosphonates in good to excellent isolated yields (60-99%) under mild reaction conditions.

Full text of DOI:10.1021/ol503518h

Letter
pubs.acs.org/OrgLett
Applications of α‑Phosphonovinyl Tosylates in the Synthesis of
α‑Arylethenylphosphonates via Suzuki−Miyaura Cross-Coupling
Reactions
Yewen Fang,*,† Li Zhang,‡ Jinjian Li,† Xiaoping Jin,*,§ Meijuan Yuan,‡ Ruifeng Li,*,‡ Rong Wu,†
and Jianghua Fang†
†School of Chemical Engineering, Ningbo University of Technology, No. 89 Cuibai Road, Ningbo 315016, China
‡College of Chemistry and Chemical Engineering, Taiyuan University of Technology, No. 79 West Yingze Street, Taiyuan 030024,
China
§Department of Biology and Pharmaceutical Sciences, Zhejiang Pharmaceutical College, No. 888 Yinxian Avenue East, Ningbo
315100, China
S
* Supporting Information
ABSTRACT: It has been demonstrated for the first time that α-phosphonovinyl tosylates could efficiently couple with a range of
arylboronic acids to access α-arylethenylphosphonates. The unprecedented procedure exhibits excellent functional group
tolerance, giving the terminal vinylphosphonates in good to excellent isolated yields (60−99%) under mild reaction conditions.
ross-coupling has been established as one of the preferred
methods for generating C−C bonds in synthetic
synthesis of α-arylethenylphosphonates with C−C bond
formation as the strategy. Moreover, α-phosphonovinyl
sulfonates have been less investigated, and there is only one
report about the applications of α-phosphonovinyl nonaflate 1
in Sonogashira cross-coupling reactions (Figure 1).15 Intrigued
C
chemistry.1 Within this broad family of transformations, the
Suzuki−Miyaura reaction2 is perhaps the most popular owing
to the low toxicity, air and water stability, functional group
compatibility, and commercial availability of the organoboron
compounds. In addition to the vast advancements of the
preparations of boron reagents3 and supporting ligands,4 the
development of pseudohalides as the alternative or comple-
mentary electrophiles for the C−C cross-coupling reactions
also received much attention.5 Among various pseudohalides,
alkyl,6 alkenyl,7 and aryl8 tosylates are indeed highly attractive
because they are easy to purify, thermally stable, and persistent
to hydrolysis. Moreover, the reactivity alkenyl/aryl tosylates
show good reactivity compared to corresponding bromides in
cross-coupling reactions.9
Figure 1. α-Phosphonovinyl nonaflate 1 and tosylate 2a.
with our continuing interest in cross-coupling reactions,16 we
became interested in the preparation of more economical α-
phosphonovinyl arylsulfonates 2 and their applications in
Suzuki−Miyaura cross-coupling reaction. Herein, we report for
the first time that α-phosphonovinyl arylsulfonates 2 could
efficiently couple with a set of aryl- and heteroarylboronic acids
to synthesize α-arylethenylphosphonates.
Terminal vinylphosphonates are a class of vinylphospho-
nates10 that exhibit a wide range of applications in organic
synthesis and medicinal and agricultural chemistry. Given the
interest in terminal vinylphosphonates and their applications as
reagents to prepare a host of useful molecules,11 there is a
significant demand for their synthesis. Despite the numerous
reported synthetic methods,12 procedures about transition-
metal-catalyzed synthesis of terminal vinylphosphonates are still
highly desirable.13 Presently, most of the protocols for the
synthesis of α-arylethenylphosphonates are based on metal-
catalyzed C−P bond formation.13 However, a mixture of α- and
β-alkenylphosphorus isomers is always produced via the well-
known metal-catalyzed hydrophosphorylation of terminal
alkynes. There is no specific procedure14 describing the
The current study began with the preparation of α-
phosphonovinyl arylsulfonates 2a−c using an adaptation of
the Dog
̆
an procedure.17 To our delight, α-phosphonovinyl
arylsulfonates 2 could be easily prepared by treatment of acetyl
phosphonates 3 with DBU and arylsulfonyl chlorides 4 in 74−
83% yields (Scheme 1). Importantly, 2 are highly crystalline
free-flowing solids.
Received: December 5, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503518h
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nucleophilic cross-coupling partner, the expected reaction could
proceed well in a 4:1 toluene and water mixture, giving 6a in
99% yield (entry 12). On the basis of these results, the
combination of 7 mol % of Pd(OAc)2, 15 mol % of S-Phos or
X-Phos, and 2.5 equiv of Cs2CO3 in toluene for 15 h emerged
as the best reaction conditions.
Scheme 1. Preparations of α-Phosphonovinyl Arylsulfonates
2a−c
With the optimized reaction conditions in hand, we next
tested the substrate scope of arylboronic acids. As indicated in
Scheme 2, electron-neutral, electron-donating, and electron-
withdrawing groups were suitable coupling partners in Suzuki−
Miyaura cross-coupling reactions. Surprisingly, sterically
hindered ortho-substituted (Me, OMe, and Cl) arylboronic
acids provided as high a yield as the less hindered meta- and
para-substituted arylboronic acids (6b−j). The present reaction
protocol was applicable to the coupling of halo-substituted
With the α-phosphonovinyl arylsulfonates 2 in hand, we set
out to optimize the reaction parameters. Using the reaction
between α-phosphonovinyl tosylate 2a and phenylboronic acid
5a as the template, a wide variety of ligands, bases, and solvents
were screened. First, screening of various phosphorus ligands
was carried out with Pd(OAc)2 as the palladium source and
toluene as the solvent at room temperature. As apparent from
Table 1, bidentate phosphine ligands rac-BINAP and DPE-
Scheme 2. Applications of α-Phosphonovinyl Arylsulfonates
a b
,
2a in Suzuki−Miyaura Cross-Coupling Reactions
Table 1. Optimization of α-Phosphonovinyl Tosylate 2a and
a
Phenylboronic Acid 5a
b
entry
ligand
base
solvent
toluene
yield (%)
1
DPE-Phos
rac-BINAP
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
trace
<10
36
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
3
4
t-Bu3P·HBF4
X-Phos
S-Phos
45
5
98
6
99
7
S-Phos
98
8
S-Phos
K2CO3
79
9
S-Phos
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
43
10
11
S-Phos
42
S-Phos
CH3CN
toluene:H2O
14
c,d
12
S-Phos
99
a
Reaction conditions: 2a (0.3 mmol), 5a (0.6 mmol), Pd(OAc)2 (7.0
mol %), ligand (15.0 mol %), base (2.5 equiv), solvent (2.0 mL), room
b
c
temperature, 15 h. Isolated yield. Used toluene/H2O (4:1, 0.15 M)
d
as the solvent. Potassium phenyltrifluoroborate (0.6 mmol) was used.
DPE-Phos: bis(2-diphenylphosphinophenyl)ether. rac-BINAP: rac-
2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. X-Phos: 2-(dicyclohexyl-
phosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl. S-Phos: 2-dicyclohexyl-
phosphinohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl.
Phos showed very poor reactivity (entries 1 and 2).
Interestingly, using the simple PPh3 ligand afforded the desired
coupled product in 36% isolated yield (entry 3). Encouraged by
this result, the subsequent reaction optimization focused on the
monophosphine ligands (entries 4−6). Gratifyingly, with
Buchwald’s S-Phos or X-Phos as the ligand (entries 5 and 6),
full conversion and nearly quantitative yield could be achieved.
Indeed, we decided to use two different ligands, S-Phos and X-
Phos, because they were often complementary in their
reactivity under Pd-catalyzed Suzuki−Miyaura cross-coupling
reaction conditions.18 In the next step of the screening
procedure, different bases were examined for the ability to
promote the cross-coupling of the model substrates. Cs2CO3
and K3PO4 displayed similar results, and excellent yields could
be obtained (entries 6 and 7). However, the use of K2CO3 and
Na2CO3 resulted in a drop in the yield (entries 8 and 9). THF
and CH3CN were observed to be ineffective solvents (entries
10 and 11). Interestingly, with potassium trifluoroborate as the
a
Reaction conditions: 2a (0.3 mmol), 5 (0.6 mmol), Pd(OAc)2 (7.0
mol %), S-Phos (15.0 mol %), Cs2CO3 (2.5 equiv), toluene (2.0 mL),
room temperature, 15−20 h. Isolated yield. The reaction was carried
out at 60 °C. X-Phos (15 mol %) used as the supporting ligand.
b
c
d
B
DOI: 10.1021/ol503518h
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Letter
arylboronic acids, including substrates bearing fluoro, chloro,
and bromo groups (6h−l). Of particular note, 3-bromophe-
nylboronic acid showed inferior reactivity compared to the
corresponding 3-chlorophenylboronic acid, and a higher
temperature (60 °C) was required. Additionally, 3,5-dimethyl-
phenylboronic acid, 3,4-dimethoxyphenylboronic acid, and 4-
biphenylboronic acid all underwent the reaction to deliver the
expected coupled products 6m−o in excellent yields (86−
95%). Satisfyingly, the base-sensitive cyano and hydroxyl
groups were well-tolerated under these conditions, affording
the coupled products 6p and 6q in moderate yields. As far as
the size of aryl group is concerned, 1- and 2-naphthalenebor-
onic acids with larger aryl moieties also worked uneventfully to
afford 6r and 6s in excellent isolated yields. Likewise,
heteroaromatic 3-thienylboronic acid was also a good cross-
coupling partner to give 6t in 89% yield.
reaction conditions, great functional group tolerance, and easily
accessible starting materials can make this reaction a method of
choice for the synthesis of α-arylethenylphosphonates.
Extensions of the application of the α-phosphonovinyl tosylates
in C−C bond formation reactions are currently being pursued
and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures and characterization data for
the prepared compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: fang@nbut.edu.cn.
*E-mail: xiaop.jin@gmail.com.
*E-mail: rfli@tyut.edu.cn.
To expand the substrate scope further, we next tested the
feasibility of the replacement of 2a (Scheme 3). Indeed, under
Notes
Scheme 3. C−C Cross-Coupling Reactions of α-
Phosphonovinyl Tosylates 2b and 2c
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21202090), the Zhejiang Provincial
Natural Science Foundation of China (Nos. LY12B02001 and
LQ13B010004), the Qianjiang Talents Project (B) (No.
2013R10076), and the Ningbo Natural Science Foundation
(Nos. 2011A610123 and 2012A610123).
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