Recyclable polystyrene-supported siloxane-transfer agent for palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/ol5007086

The rational design, synthesis, and validation of a significantly improved insoluble polymer-supported siloxane-transfer agent has been achieved that permits efficient palladium-catalyzed cross-coupling reactions. The cross-linked polystyrene support facilitates product purification with excellent siloxane recycling. Drawbacks of a previous polymer-supported siloxane-transfer agent, relating to reaction efficiency and polymer stability after repeated cycles, have been addressed.

Full text of DOI:10.1021/ol5007086

Letter
pubs.acs.org/OrgLett
Recyclable Polystyrene-Supported Siloxane-Transfer Agent for
Palladium-Catalyzed Cross-Coupling Reactions
Minh H. Nguyen and Amos B. Smith, III*
Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: The rational design, synthesis, and validation of a
significantly improved insoluble polymer-supported siloxane-transfer
agent has been achieved that permits efficient palladium-catalyzed
cross-coupling reactions. The cross-linked polystyrene support
facilitates product purification with excellent siloxane recycling.
Drawbacks of a previous polymer-supported siloxane-transfer agent,
relating to reaction efficiency and polymer stability after repeated
cycles, have been addressed.
alladium-catalyzed cross-coupling reactions (CCRs) of
organometallic reagents with electrophiles are among the
resulting from fast lithium−halogen exchange. Although the
reported transfer agents 1 proved highly effective in CCRs,
recovery of these congeners following the desired trans-
formation via either chromatographic separation or acid−base
extraction via inclusion of a Brønsted base in the transfer agent
in some cases proved less than optimal. The development of an
effective polymer-supported siloxane transfer agent (PSTA)
would simplify both product purification and siloxane recycling,
facilitating use of the siloxane tactic by the scientific community
and further advancing the siloxane based bond forming
process9 for a variety of applications (e.g., coating of siloxane
polymer in flow microreactors).
P
most important transformations in organic synthesis for the
construction of natural products, biologically active com-
pounds, and diverse functional materials.1 Recently, we
reported a highly atom-efficient process for intermolecular
cross-coupling of aryl- and alkenylorganolithiums with aryl and
alkenyl iodides exploiting a new class of silicon reagents, termed
siloxane-transfer agents (cf. compound 1, Scheme 1).2 This
Scheme 1. CCRs Employing Siloxane-Transfer Agent
Recently, we reported a soluble polynorbornene-supported
siloxane-transfer agent10 (PSTA-I, Scheme 2) employing the
ring-opening metathesis polymerization (ROMP) technique.
While this polymer proved effective in mediating palladium-
catalyzed cross-coupling reactions, there was a decrease in
reaction efficiency after repeated cycles in conjunction with
reagent-induced increase in the polymer dispersity. In recent
years, the trend emphasized in synthetic organic chemistry has
Scheme 2. Design of Second-Generation PSTA
tactic permits the direct use of readily available organolithium
reagents in cross-coupling reactions and, in turn, eliminates the
need for additional synthetic manipulations and/or the
isolation of suitable nucleophilic coupling partners (i.e., Suzuki
organoborons,3 Negishi organozincs,4 Stille organotins,5 and
Hiyama/Denmark organosilicons6). Importantly, the use of
siloxane-transfer agents offers a solution to the intrinsic
limitation of Murahashi CCR7 and the recent Feringa protocol8
where slow addition of the organolithium reagent is required to
avoid the competing formation of homocoupled products
Received: March 6, 2014
Published: March 24, 2014
© 2014 American Chemical Society
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Letter
been harmonization with the environment and reaction
efficiency; thus, recent work has been aimed at developing
new solid supports that could be recycled indefinitely with no
loss in reaction efficiency. Herein, we report the rational design,
synthesis, and validation of a second-generation polymer-
supported siloxane-transfer agent for efficient Pd-catalyzed
cross-coupling reactions with excellent recyclability.
Scheme 3. Synthesis of Second-Generation PSTA
Attention was first directed toward the design of a more
effective solid support for the transfer agent (Scheme 2).
During our study employing PSTA-I we observed, in repeated
Pd-catalyzed cross-coupling cycles, an increase in the number
average molecular weight and higher polydispersity index of the
recovered polymer as determined by gel permeation
chromatography. This result is likely due to polymer cross-
linking, in which the oxyanion (alkoxide 1a, Scheme 1) formed
in solution after the addition of the organolithium attacks a
nearby silicon atom of another siloxane unit on a different
polymer chain. We thus reasoned that we could suppress this
process by attaching the transfer agent onto an insoluble
support, thus eliminating the interaction between the freely
moving polymer chains in solution. Furthermore, the use of a
co-monomer would place the siloxane units further away from
each other, minimizing the undesired behavior. Removal of the
unsaturation in the polymer chain, given the possible
vulnerability of the olefinic backbone to chemical degradation,
was also viewed as desirable. Finally, a longer linker connecting
the siloxane unit to the polymer backbone would likely reduce
any steric effect caused by the bulky polymer backbone. On the
basic of these considerations, we decided to employ a cross-
linked polystyrene polymer (Scheme 2) as an insoluble support
for the design of a second-generation PSTA.
polymer was then reused five additional times, providing
excellent yield of the desired cross-coupling product 10, with
no loss in reaction efficiency after repeated cycles (Scheme 4).
We began the synthesis of the designed cross-linked
polystyrene-supported transfer agent via treatment of commer-
cially available 2-bromobenzaldehyde with allylmagnesium
chloride to furnish benzylic alcohol 3 (95%), which upon
lithiation with n-BuLi, followed by anion capture with
Me2SiHCl and treatment with H2O, led to siloxane 4 in 45%
yield (Scheme 3). Siloxane 4 was then converted to aryl
bromide 5 in 85% yield by hydroboration with 9-BBN, followed
by reaction with p-dibromobenzene in the presence of the
palladium catalyst Pd(dppf)Cl2.11 In turn, 5 was converted
smoothly to styrene 6 via Suzuki reaction12 employing
potassium vinyltrifluoroborate under Pd-catalyzed cross-cou-
pling condition. Suspension copolymerization13 of 6, styrene,
and the flexible tetrahydrofuran-based cross-linker 7 (in a molar
ratio of 12:87:1, respectively) was then achieved with benzoyl
peroxide to provide polystyrene-supported siloxane transfer
agent PSTA-II as well-defined beads.14 From the design
perspective, the employed cross-linker 7 contains a highly
stable phenyl ether linkage, leading to a gel-type resin that
exhibits excellent swelling properties.15 The siloxane loading of
PSTA-II was reasoned to be nearly identical to the silicon
loading (1.5 mmol/g), the latter indicated by elemental
analysis.
Scheme 4. Recyclability of PSTA-II Using the Same
Nucleophile and Electrophile
a
a
Siloxane loading was 1.5 mmol/g
We next explored the possibility of repeated recycling of
PSTA-II in cross-coupling reactions with different nucleophiles
and electrophiles (Scheme 5). 4-tert-Butylphenyllithium was
cross-coupled with 4-iodoanisole to provide the desired product
10b in 95% isolated yield. The recovered polymer was then
employed in the second cross-coupling reaction between
phenyllithium and 4-iodoanisole, furnishing the desired product
10 in 97% isolated yield. Pleasingly, the first cross-coupling
product 10b was not detected in the second cycle,
demonstrating the ability to reuse PSTA-II with a different
nucleophilic coupling partner without cross-contamination.
The recovered polymer above was then recycled successfully
in a sequence of eight cross-coupling reactions employing
different nucleophilic and electrophilic coupling partnerts for a
total of nine iterations (Scheme 5).17 Cross-coupling between
arylorganolithium reagents and aryl or alkenyl iodides
proceeded smoothly to provide the CCR products in excellent
yields. Electron-rich and electron-deficient substrates were well
tolerated; even an azaheterocycle proceeded well (entry 7).
To evaluate PSTA-II as a viable cross-coupling transfer
agent, we employed conditions similar to those previously
reported for PSTA-I.10 Pleasingly, PSTA-II efficiently mediated
the palladium-catalyzed cross-coupling reaction between
phenyllithium and 4-iodoanisole, furnishing the cross-coupling
product 10 in 96% isolated yield, importantly with no evidence
of homocoupling.16 Following the coupling reaction, the
polymer was removed from the product by simple filtration.
After several washings with organic solvents, the recovered
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cross-linked polystyrene support significantly simplifies product
purification and permits excellent siloxane polymer reuse with
diverse nucleophiles and electrophiles, rendering this tactic a
powerful new tool in organic synthesis that could provide
“greener” and more sustainable chemical processes. Studies to
expand the application of polymer-supported siloxane-transfer
agent in other bond-forming processes continue in our
laboratory.
Scheme 5. Recyclability of PSTA-II Using Multiple
Nucleophiles and Electrophiles
ab
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: smithab@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH through Grant No.
GM-29028. We also thank Bruno Melillo, Stephen P. Brown,
and Dr. Rakesh Kohli at Department of Chemistry, University
of Pennsylvania, for helpful suggestions on polymer selection,
polymer handling, and assistance with HRMS, respectively.
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