Suzuki-Miyaura cross-coupling of α-phosphoryloxy enol ethers with arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2008.04.116

The Suzuki-Miyaura cross-coupling reaction of cyclic ketene acetal phosphates with arylboronic acids was found to be a convenient and highly efficient method for the construction of aryl vinyl ethers. A wide variety of differentially substituted electron-poor and electron-rich arylboronic acids smoothly underwent the coupling process to provide the desired dihydropyrans in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.04.116

Tetrahedron Letters 49 (2008) 4142–4144
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Suzuki–Miyaura cross-coupling of a-phosphoryloxy enol ethers
with arylboronic acids
*
Lee Pedzisa , Ian W. Vaughn , Rongson Pongdee
Otis A. and Margaret T. Barnes Science Center, Laboratory for Natural Products Chemistry, Department of Chemistry and Biochemistry, The Colorado College,
14 East Cache La Poudre, Colorado Springs, CO 80903, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The Suzuki–Miyaura cross-coupling reaction of cyclic ketene acetal phosphates with arylboronic acids
was found to be a convenient and highly efficient method for the construction of aryl vinyl ethers. A wide
variety of differentially substituted electron-poor and electron-rich arylboronic acids smoothly under-
went the coupling process to provide the desired dihydropyrans in moderate to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 13 March 2008
Revised 11 April 2008
Accepted 22 April 2008
Available online 24 April 2008
This Letter is dedicated to Professor Hung-
wen Liu on the occasion of his 55th birthday
Transition-metal mediated cross-coupling reactions have
emerged as powerful synthetic tools for the construction of a
myriad of carbon–carbon bonds.1 Of the various methodologies
available, most require the use of alkenyl or aryl halides or
trifluoromethanesulfonates as coupling partners. In particular,
the functionalization of lactone substrates have relied heavily upon
the formation of cyclic ketene acetal triflates for further derivitiza-
tion. However, these intermediates often exhibit instability upon
prolonged storage in addition to suffering from poor yields in their
formation and in the subsequent coupling event.2
Recently, the development of enol and cyclic ketene acetal
phosphates has emerged as attractive and more practical method-
ologies for the functionalization of lactam and lactone intermedi-
ates.3 Nicolaou has illustrated the synthetic utility of cyclic
ketene acetal phosphates in Stille cross-coupling reactions during
his elegant synthesis of brevetoxin A,3e a causative agent of the
red tide phenomena.4–6 Additionally, Sasaki has demonstrated
the efficiency of ketene acetal phosphates as coupling partners in
B-alkyl Suzuki–Miyaura cross-coupling processes in the total
synthesis of polycyclic ether secondary metabolites.3f,h,j,l–n
During the course of our research program aimed at the total
synthesis and biological evaluation of structurally complex natural
products, we required the synthesis of an aryl vinyl ether function-
ality. While there are methodologies available for the construction
of this prevalent architectural motif,7 we viewed the possibility of
performing a Suzuki–Miyaura cross-coupling reaction employing
cyclic ketene acetal phosphates with arylboronic acids as a mild
and robust method that would also greatly expand the scope of
this underutilized synthetic intermediate. To our knowledge, this
methodology has not been explored and we now wish to report
our early findings regarding this process.
With this in mind, we undertook our exploration into the
application of cyclic ketene acetal phosphates in the Suzuki–
Miyaura cross-coupling reaction with arylboronic acids by treating
d-valerolactone (1) with diphenylphosphoryl chloride followed by
the addition of lithium bis(trimethylsilyl)amide (LHMDS) accord-
ing to the procedure of Occhiato and Prandi as illustrated in
Scheme 1.3i
Next, to study the feasibility of our proposed methodology, we
initially surveyed several palladium catalysts. As can be seen
from Table 1 (entries 1–5), we explored the use of Pd(Ph3P)4,
Cl2Pd(Ph3P)2, Cl2Pd(dppf)ÁCH2Cl2, [allylPdCl]2, and Pd2dba3ÁCHCl3.
Tetrakis(triphenyl)phosphine palladium(0) was clearly the supe-
rior catalyst cleanly producing the desired coupled product 4a in
over eighty percent yield without the production of any side prod-
ucts. We then focused our attention on examining the effects of
various organic solvents and temperatures (entries 6–8) on the
outcome of the reaction. Our findings indicated that both N,N-
dimethylformamide (DMF, entry 1) and 1-methyl-2-pyrrolidinone
(NMP, entry 8) were the most efficient at facilitating the Suzuki–
Miyaura cross-coupling reaction of ketene acetal phosphate 2 with
3-nitrophenylboronic acid (3a). Further investigation (entry 9)
aimed at using DMF as our reaction solvent revealed that the prod-
uct yield could be increased by changing the base to potassium
* Corresponding author. Tel.: +1 719 389 6746; fax: +1 719 389 6182.
E-mail address: rongson.pongdee@coloradocollege.edu (R. Pongdee).
These authors contributed equally to this work.
Scheme 1. Synthesis of cyclic ketene acetal phosphate.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.116

L. Pedzisa et al. / Tetrahedron Letters 49 (2008) 4142–4144
4143
Table 1
Table 2
Optimization of Suzuki–Miyaura cross-coupling reaction between cyclic ketene acetal
Coupling reaction of cyclic ketene acetal phosphate 2 with electron-poor arylboronic
phosphate 2 with 3-nitrophenylboronic acid (3a)
acids 3a–h
Entrya
1
Boronic acid
Product
Yield (%)
88
Entrya
Catalyst
Solvent
DMF
T (°C)
Yield (%)
1
2
3
4
5
6
7
8
9b
Pd(Ph3P)4
50
82
33
27
<5
No Rxn
75
74
84
88
2
3
4
5
80
70
81
83
CI2Pd(Ph3P)2
CI2Pd(dppf)ÁCH2CI2
[allylPdCI]2
Pd2dba3ÁCHCI3
Pd(Ph3P)4
THF
1,4-Dioxane
NMP
65
100
50
DMF
50
a
All reactions were performed with 10 mol % of illustrated Pd source, 2.0 equiv of
ketene acetal phosphate, 2.0 equiv of triethylamine, and 2.0 equiv of Na2CO3 (2.0 M)
in the indicated solvent at the temperature listed.
b
Pd(Ph3P)4 loading was reduced to 5 mol %. K3PO4 was used as base.
phosphate (K3PO4) from sodium carbonate (Na2CO3). Furthermore,
reducing the catalyst loading from ten to five mole percent had
negligible impact on the overall efficiency of the coupling process.
Having established the optimal reaction conditions, we em-
barked on a systematic study regarding the substrate scope. We
were interested in exploring the functional group compatibility
as well as the positioning of both electron-withdrawing (EWG)
and electron-donating (EDG) groups on the arylboronic acid cou-
pling partners. As illustrated in Table 2, the reaction is tolerant of
a wide range of EWG’s including nitro (NO2, entries 1 and 2), cyano
(CN, entries 3 and 4), ester (CO2CH3, entry 5), ketone (CH3CO, entry
6), aldehyde (CHO, entry 7), and trifluoromethyl (CF3, entry 8)
functional groups. Furthermore, both meta- and para-substituted
electron-withdrawing groups performed well under the reaction
conditions affording the desired dihydropyrans in excellent yields.
However, the use of ortho-substituted electron-withdrawing
groups proved somewhat problematic. While 2-formylphenylbo-
ronic acid (3g) furnished the desired dihydropyran 4g in a moder-
ate, yet synthetically viable yield (Table 2, entry 7), the use of
alternative arylboronic acids bearing ortho-EWG’s such as NO2,
CN, CO2CH3, and CF3 failed to produce any of the anticipated prod-
ucts. A possible explanation for the poor reactivity of ortho-EWG’s
in the cross-coupling reaction could be chelation of the Lewis basic
heteroatoms to the palladium intermediate. This chelation may be
retarding the rate of the subsequent reductive elimination step to
the point that alternative reaction pathways are occurring leading
to decomposition of the starting material.8 It is worth mentioning
that we were unable to find a solitary report in the chemical liter-
ature detailing the Suzuki–Miyaura cross-coupling reaction of
cyclic ketene acetal phosphates or the structurally analogous a-
phosphoryloxy enecarbamates with electron-poor arylboronic acid
coupling partners.9 Taking this into account, our methodology has
significantly expanded the scope of this process and should allow
for the incorporation of a wide-range of arylboronic acids in vari-
ous medicinal chemistry applications involving the preparation
of aryl vinyl ethers.
6
7
79b
58
8
67
a
All reactions were performed with 5 mol % of Pd(Ph3P)4, 2.0 equiv of ketene
acetal phosphate, 2.0 equiv of triethylamine, and 3.0 equiv of K3PO4 (3.0 M) in DMF
at 50 °C.
b
Na2CO3 was used as base.
alkyl groups (CH3, entry 4), as well as protected aniline (NHBoc,
entry 5) and thio (SCH3, entry 6) substituents. In addition, extremely
electron-rich arylboronic acids such as 2,4-dimethoxyphenyl-
boronic acid (3k), substrates that oftentimes require elevated tem-
peratures and result in poor conversions in palladium-mediated
cross-coupling processes, also afforded the desired substituted
dihydropyran 4k in 88% yield, a demonstration of the overall
robustness of this process. Interestingly, we found that the inclu-
sion of triethylamine (Et3N) in the reaction mixture was crucial
to obtain high yields for electron-rich arylboronic acids. When
reactions were conducted in the absence of triethylamine, product
yields were approximately 20% lower compared to those with tri-
ethylamine. Our belief is that the presence of Et3N in the reaction
mixture is sequestering adventitious acid that may have resulted
in protodeborylation of the arylboronic acid starting material.10
In summary, we have developed a mild and efficient methodol-
ogy for the construction of aryl vinyl ethers employing the Suzuki–
Next, we turned our attention toward defining the substrate
scope for arylboronic acids bearing electron-donating groups. As
outlined in Table 3, electron-rich arylboronic acids generally fared
well furnishing the desired coupled products in modest to excel-
lent yields depending on the nature of the functional group
employed. The reaction is tolerant of ethers (OCH3, entries 1–4),

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L. Pedzisa et al. / Tetrahedron Letters 49 (2008) 4142–4144
Table 3
administered by The Colorado College. I.W.V. thanks the donors
of the Frank H.J. Figge Memorial Endowment Fund for a summer
undergraduate research stipend. High-resolution mass spectro-
metry analyses were performed by Dr. Shane E. Tichy of the Labo-
Coupling reaction of cyclic ketene acetal phosphate 2 with electron-rich arylboronic
acids 3i–n
Entrya
1
Boronic acid
Product
Yield (%)
74
ratory for Biological Mass Spectrometry at Texas
University.
A and M
Supplementary data
Experimental procedures and compound characterization for
compounds 4a–4n. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/j.tetlet.
2008.04.116.
2
3
86
88
References and notes
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a
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Miyaura cross-coupling reaction between cyclic ketene acetal
phosphates with arylboronic acids. The reaction is tolerant of both
electron-poor and electron-rich arylboronic acids as well as a
variety of aromatic substitution patterns. We believe that this
methodology will find broad use in the design and development
of natural and unnatural compounds requiring this structural
feature. Our own application of this methodology within the
context of complex natural products synthesis will be presented
in due course.
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reported in modest to poor yields. See: Ref. 3b,k.
Acknowledgments
10. A similar tactic was employed during the total synthesis of macrolactin A in
which the use of Hunig’s base (i-Pr2NEt) was found to suppress the
protodestannylation of a vinylstannane involved in a Stille cross-coupling
reaction: Smith, A. B., III.; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935.
Generous financial support from The Colorado College and the
American Philosophical Society is gratefully acknowledged. L.P. is
the recipient of a Student-Faculty Collaborative Venture Grant