Polymer-supported siloxane transfer agents for Pd-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/ol402047d

The design, synthesis, and validation of a ring-opening metathesis polymerization (ROMP) polymer supporting siloxane transfer agents have been achieved that permit efficient palladium-catalyzed cross-coupling reactions. The solubility properties of the polymer facilitate not only product purification but also polymer recycling without significant loss of cross-coupling activity.

Full text of DOI:10.1021/ol402047d

ORGANIC
LETTERS
2013
Vol. 15, No. 16
4258–4261
Polymer-Supported Siloxane Transfer
Agents for Pd-Catalyzed Cross-Coupling
Reactions
Minh H. Nguyen and Amos B. Smith, III*
Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States
smithab@sas.upenn.edu
Received July 19, 2013
ABSTRACT
The design, synthesis, and validation of a ring-opening metathesis polymerization (ROMP) polymer supporting siloxane transfer agents have been
achieved that permit efficient palladium-catalyzed cross-coupling reactions. The solubility properties of the polymer facilitate not only product
purification but also polymer recycling without significant loss of cross-coupling activity.
Palladium-catalyzed cross-coupling reactions (CCRs)
of organometallic reagents with electrophiles is one of
the most important reactions utilized for the construction
of both simple and complex structures involving CꢀC
and Cꢀheteroatom bond formation.1 Recently we reported
a highly atom-efficient process for intermolecular cross-
coupling of aryl and alkenyl organolithiums with aryl and
alkenyl iodides exploiting a siloxane transfer agent
(Scheme 1).2 In this tactic readily available organolithium
reagents serve as the nucleophilic coupling partners, elim-
inating the need for stoichiometric toxic metals (e.g., zinc
and tin as used in Negishi3 and Stille4 CCRs, respectively),
as well as the manipulation and purification steps required
by the Hiyama,5 Denmark,6 and Suzuki7 CCRs to access
the nucleophilic coupling partners. Importantly, the use of
siloxane transfer agents holds promise for a solution to the
intrinsic limitation of Murahashi8 and the recent Feringa9
cross-coupling protocols where slow addition of the organ-
olithium is required to avoid homocoupled products
resulting from competitive lithiumꢀhalogen exchange.
Although siloxane 1 proved highly effective in CCRs,
recovery of 1 via flash chromatography in some cases
proved lessthanoptimal (i.e., streaking). This shortcoming
(1) (a) Metal-catalyzed Cross-coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Seechurn, C. C. J.;
Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012,
51, 5062.
(2) Smith, A. B., III; Hoye, A. T.; Martinez-Solorio, D.; Kim, W.-S.;
Tong, R. J. Am. Chem. Soc. 2012, 134, 4533.
(3) (a) Negishi, E.; Baba, S. Chem. Commun. 1976, 596. (b) Baba, S.;
Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729. Reviews: (c) Negishi, E.
Acc. Chem. Res. 1982, 15, 340. (d) Negishi, E.; Hu, Q.; Huang, Z.; Qian,
M.; Wang, G. Aldrichimica Acta 2005, 38, 71.
(6) (a) Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821.
(b) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876.
Reviews: (c) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(d) Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486.
(7) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979,
20, 3437. (b) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun.
1979, 866. Reviews: (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (d) Suzuki, A.; Yamamoto, Y. Chem. Lett. 2011, 40, 894.
(8) (a) Murahashi, S.-I.; Tanba, Y.; Yamamura, M.; Moritani, I.
Tetrahedron Lett. 1974, 15, 3749. (b) Murahashi, S.-I.; Tanba, Y.;
Yamamura, M.; Yoshimura, N. J. Org. Chem. 1978, 43, 4099. (c)
Murahashi, S.-I. J. Organomet. Chem. 2002, 653, 27.
(4) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. (b)
Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992. Reviews: (c)
Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (d) Mitchell, T. N.
Synthesis 1992, 803.
(5) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. (b)
Hatanaka, Y.; Hiyama, T. Synlett 1991, 845. (c) Hiyama, T.; Hatanaka,
T. Pure Appl. Chem. 1994, 66, 1471. (d) Hiyama, T. J. Organomet. Chem.
2002, 653, 58. (e) Nakao, Y.; Imanaka, H.; Sahoo, A. K.; Yada, A.;
Hiyama, T. J. Am. Chem. Soc. 2005, 127, 6952. (f) Nakao, Y.; Takeda,
M.; Matsumoto, T.; Hiyama, T. Angew. Chem., Int. Ed. 2010, 49, 4447.
(g) Chen, J.; Tanaka, M.; Sahoo, A. K.; Takeda, M.; Yada, A.; Nakao,
Y.; Hiyama, T. Bull. Chem. Soc. Jpn. 2010, 83, 554. (h) Nakao, Y.;
Hiyama, T. Chem. Soc. Rev. 2011, 40, 4893. (i) Tang, S.; Takeda, M.;
Nakao, Y.; Hiyama, T. Chem. Commun. 2011, 47, 307.
(9) Giannerini, M.; Fananas-Mastral, M.; Feringa, B. L. Nat. Chem.
2013, 5, 667.
r
10.1021/ol402047d
Published on Web 07/31/2013
2013 American Chemical Society

Scheme 1. CCRs Using Siloxane Transfer Agent
Scheme 2. Synthesis of PSTA
was recently addressed by careful redesign with incoporation
of Brønsted bases.10 Nonetheless, the development of a solid-
supported siloxane transfer agent would further simplify
both product purification and siloxane recycle, facilitating
use of the siloxane tactic by the chemical community.11
Ring-opening metathesis polymerization (ROMP), a
powerful method among living polymerization techniques,
permits access to a wide range of polymers with unique
architectures, reactivities, and physical properties (i.e.,
solubility).12 One of the most common monomers em-
ployed in the ROMP protocol comprise norbornene and
derivatives thereof, due to both their high ROMP activity
and ease of incorporation of diverse functional groups.13
Herein, we report the design, synthesis, and validation of a
readily recyclable ROMP polymer-supported siloxane
transfer agent (PSTA) for efficient Pd-catalyzed CCRs.
From the outset, we envisioned the ideal polymer to be
soluble in THF, the optimal CCR solvent, and insoluble
upon addition of a more polar solvent (ca. CH3CN or
H2O) to permit facile recovery of both the CCR product
and polymer. Withthese considerationsin mind, treatment
of commercially available 5-norbornene-2-carboxalde-
hyde (a mixture of endo- and exo-isomers) with PhMgBr
furnished benzylic alcohol 3 (94%), which upon ortho-
lithiation with n-BuLi, followed by anion capture with
Me2SiHCl and treatment with H2O, led to a mixture of
benzyl alcohol 3b and siloxane 4 (1H NMR), which in turn
was treated with catalytic KOtBu14 tocompleteconversion
to the desired siloxane monomer 4 (Scheme 2). Polymeriza-
tion of 4 (ROMP) was then achieved in 96% yield with the
first generation Grubbs catalyst.15 Pleasingly, the conver-
sion of 2 to PSTA-I200 can be achieved on multigram scale.
The residual Ru was removed by treatment with an aqueous
solution of P(CH2OH)3.16 Precipitation via dropwise addi-
tion of the concentrated reaction mixture into CH3CN
afforded the desired polymer-supported siloxane transfer
agent PSTA-I200 as a white solid. Given that the polymer
was obtained in near quantitative yield, without use of cross-
linking units or copolymerization agents, the siloxane load-
ing of the polymer was reasoned to be nearly identical to the
molarity of the monomer, namely 3.9 mmol/g, with each
polymer chain having a relative length of 200-mers, the
latter based on the ratio of monomer 4 to the Grubbs
catalyst (200:1). Importantly, PSTA-I200 is soluble in most
organic solvents and insoluble in CH3CN and H2O.
To evaluate PSTA-I200 as a viable CCR transfer agent,
we employed conditions similar to those previously reported
for solution CCRs.2 As illustrated in Table 1 (entry 1),
the use of 2.0 equiv of PSTA-I200 at a concentration of
15 mg/mL led to cross-coupling product 6 with PhLi and
4-iodoanisole. A significant amount of starting aryl iodide
however remained, in conjunction with formation of a
small amount of homocoupled product 7. Increasing the
equivalents of PhLi and PSTA-I200 to 2.5 and 3.0, respec-
tively, withthe polymer concentration at 15mg/mL greatly
improved the efficiency of the process, providing 6 as the
major product (entry 2). Lowering the polymer concentra-
tion to 10 mg/mL led to complete conversion of 5 within
2 h, furnishing 6 in 98% isolated yield (entry 3). Attempts
to reduce the amount of either PhLi or the siloxane
polymer required to consume the starting aryl halide,
without leading to homocoupled products, proved unsuc-
cessful (entries 4ꢀ6). Finally, inefficient cross-coupling in
conjunction with significant homocoupled product re-
sulted in the absence of PSTA-I200 (entry 7). The latter is
characteristic of the early Murahashi CCR of aryl lithiums
with aryl halides promoted by Pd catalysis.8
(10) Martinez-Solorio, D.; Hoye, A. T.; Nguyen, M. H.; Smith, A. B.,
III. Org. Lett. 2013, 15, 2454.
(11) For reviews on the use of polymer supports in Pd-catalyzed
CCRs, see: (a) Franzen, R. Can. J. Chem. 2000, 78, 957. (b) Brase, S.;
Kirchhoff, J. H.; Kobberling, J. Tetrahedron 2003, 59, 885. (c) Ljungdahl,
N.; Bromfield, K.; Kann, N. Top. Curr. Chem. 2007, 278, 89. (d) Carrera,
N.; Albeniz, A. C. Eur. J. Inorg. Chem. 2011, 2347.
(12) (a) Herisson, J. L.; Chauvin, Y. Makromol. Chem. 1971, 141,
161. (b) Murdzek, J. S.; Shrock, R. R. Macromolecules 1987, 20, 2640.
(c) Grubbs, R. H.; Tumas, W. Science 1989, 243, 4893. Reviews: (d)
Bielawski, C. W.; Grubbs, R. H. Prog. Polym. Sci. 2007, 32, 1. (e) Hilf,
S.; Kilbinger, A. F. M. Nat. Chem. 2009, 1, 537.
(13) Barrett, A. G. M.; Hopkins, B. T.; Kobberling, J. Chem. Rev.
2002, 102, 3301.
Having identified the optimal conditions for CCR with
PSTA-I200, we examinedthe effect of the polymer structure
ꢀ
vis-a-vis the ability to serve as a transfer agent for CCRs
(Table 2). By varying the amount of Grubbs catalyst
during the ROMP process, we could readily adjust the
number of repeating siloxane units on each polymer chain.
To date siloxane transfer agent PSTA-I200 provides the
best results (entry 1). Reducing the relative length of
polymer chain to 20-mer led to significant homocoupling
(entry 2). Moreover, enlarging the two substituents on the
Si atom from methyl to ethyl, unlike that reported for the
corresponding monomer under solution phase CCRs,10
(14) Weickgenannt, A.; Oestreich, M. Chem.;Asian J. 2009, 4, 406.
(15) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
(16) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137.
Org. Lett., Vol. 15, No. 16, 2013
4259

Table 1. Optimization of CCR Employing PSTAa
Table 2. StructureꢀActivity Studyof SiloxanePolymers in CCRa
equiv
equiv
concd
1H NMR resultsb
entry
1
siloxane polymer
time 1H NMR resultsb (6:5:7)
entry PhLi STA-I200
STA-I200
time
(6:5:7)
100:nd:<1c
80:nd:20
1:99:nd
1c
2d
3e
4
1.5
2.5
2.5
1.5
2.0
2.0
2.5
2.0
3.0
3.0
3.0
3.0
2.5
ꢀ
15 mg/mL 25 h
15 mg/mL 15 h
10 mg/mL 2 h
10 mg/mL 15 h
10 mg/mL 2 h
10 mg/mL 2 h
57:40:3
90:5:5
PSTA-I200: R = Me, n = 200, 2 h
unsaturated backbone
2
3
4
PSTA-I20: R = Me, n = 20,
2 h
100:nd:<1
84:11:5
72:18:<1
88:9:3
unsaturated backbone
PSTA-II200: R = Et, n = 200, 50 h
5
unsaturated backbone
6
7f
PSTA-II20: R = Et, n = 20,
20 h
42:33:25
6:94:nd
ꢀ
2 h
14:77:9
unsaturated backbone
a All reactions were performed on 0.3 mmol scale. b Determined by
1H NMR analysis of the reaction mixture following an aqueous workup,
extraction with Et2O, and polymer removal via precipitation in CH3CN.
c Part of recovered polymer remained insoluble in THF. d Small amount
of the recovered polymer remained insoluble in THF; 82% yield of 6.
e Polymer was recovered quantitatively and reuseable; 98% yield of 6.
f Reaction was run in the absence of siloxane polymer.
5d PSTA-I0200: R = Me, n = 200, 20 h
saturated backbone
PSTA-I020: R = Me, n = 20, 2 h
6
83:nd:17
saturated backbone
a All reactions were performed on 0.3 mmol scale. b Determined by
1H NMR analysis of the reaction mixture following an aqueous workup,
extraction with Et2O, and polymer removal via precipitation in CH3CN.
c 98% yield of 6. d The insoluble polymer was stirred heterogeneously in
reaction mixture. nd = not detected.
eliminates near completely the ability of the polymer to serve
as a transfer agent, presumably due to increased steric bulk
at Si (entries 3 and 4). We also explored the effect of the
unsaturation in the polymer chain, given the possible vulner-
ability of the polymer backbone to chemical degradation. To
this end, we prepared the corresponding saturated polymer
via a modified tandem ROMP-hydrogenation protocol.17
Not surprisingly, the saturated 200-mer was not soluble in
any organic solvents and only yielded trace amounts of cross-
coupling products after 20 h in THF (entry 5). The saturated
20-mer, on the other-hand, displayed similar solubility
profiles to the unsaturated polymers. Attempts to use this
polymer in CCRs, although resulting in complete consump-
tion of starting aryl halide within 2 h, led to significant
homocoupling (entry 6), a result very similar to that obtained
when employing the unsaturated 20-mer (entry 2).
We next explored the scope of Pd-catalyzed CCRs
employing PSTA-I200 (Table 3). Cross-coupling between
aryl organolithiums and aryl or alkenyl iodides readily
provided the CCR products in excellent yields (entries 1, 2,
3, and 6). Electron-rich and -deficient substrates were well
tolerated in the CCRs; even azaheterocycle proceeded well
(entry 3). Cross-coupling between PhLi and the electron-
rich p-methoxyphenyl bromide however proved ineffective
(entry 4), but electron-deficient p-cyanophenyl bromide pro-
ceeded smoothly in excellent yield with PhLi (entry 5).
Equally successful, use of alkenyl organolithium reagents as
the nucleophilic partner proceeded in good yield with reten-
tion of the alkene geometry (entries 7ꢀ9). In all cases,
the reaction mixtures were quenched with saturated aqueous
NH4Cl, followed by extraction with Et2O. The resultant
organic solution was then concentrated, the siloxane poly-
mer precipitated with CH3CN, and then the polymer re-
moved from the product by filtration. Importantly, the
CCRs employing PSTA-I200 are as rapid and high-yielding
as those employing the originally reported siloxane transfer
agent (1) in solution,2,10 of course, with the added advantage
of product isolation.
Attention was next directed toward the structural stability
of PSTA-I200 upon CCRs. We first examined the ability of
PSTA-I200 to retain CCR activity through multiple cycles,
using the same nucleophile for each transformation (Table 4).
Here, PhLi and 4-idodoanisole were used for each experi-
ment. After a 2 h reaction time, the polymer was removed
from the reaction products as described above and employed
in the subsequent run. The ratio of the products in each cycle
was determined by 1H NMR. Pleasingly, the polymer can be
reused for at least 3 cycles, providing excellent to good yields
of the desired cross-coupling product. In all cases, the poly-
mer was recovered in near quantitative yield. We however
noticed a small decrease in CCR efficiency after each cycle.
The small decrease of CCR efficiency led us to explore
the molecular weight (MW) of the polymer both before
and after several CCR cycles. We observed an increase in
the number average molecular weight (Mn) and higher
polydispersity index (PDI) of the recovered polymer de-
termined by gel permeation chromatography (Table 4,18).
Although unconfirmed, we reason that the increase in the
Mn is likely due to polymer cross-linking, in which the
(17) Drouin, S. D.; Zamanian, F.; Fogg, D. E. Organometallics 2001,
20, 24.
(18) See Supporting Information for plotted Gel Permeation Chro-
matograms of recovered polymers.
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Org. Lett., Vol. 15, No. 16, 2013

Table 3. Substrate-Scope Study of CCR Employing PSTA
Table 4. Recyclability of Polymer Using the Same Nucleophile
isolated
1H NMR results
cycle yield of 6
polymer recovereda
(6:5:7)
0
(Mn = 63500, PDI = 1.2)
1st
98%
91%
81%
98% (Mn = 73000, PDI = 1.6)
99% (Mn = 104400, PDI = 2.3)
99% (Mn = 94600, PDI = 2.6)
100:nd:<1
97:nd:3
86:11:3
2nd
3rd
a Poly(methyl methacrylate) standards were used to determine Mn
and PDI values. nd = not detected.
Table 5. Recyclability of Polymer Using Multiple Nucleophiles
a Isolated yield. b After polymer removal, the product mixture was
treated with TBAF to remove the silyl group prior to purification.
oxyanion formed after the addition of PhLi attacks a
nearby silicon atom of another siloxane unit on a different
polymer chain. The fact that the recovered polymer ap-
peared to have an increased hardness, in conjunction with
a small decrease in solubility in organic solvents after each
a Determined by 1H NMR analysis of the reaction mixture following
an aqueous workup, extraction with Et2O, and polymer removal.
activity through multiple cycles. The ability to simplify
product purification, coupled with a high level of atom
economy, mild reaction conditions, and an operationally
convenient protocol, furtheradvancessiloxane basedCCR
and renders this tactic an example of Green Chemistry.
Furthermore, the validation of a solid-supported transfer
agent holds promise for a variety of applications (e.g.,
coating of siloxane polymer in flow microreactors). Studies
to determine the effect of polymer structure on reactivity,
with the possibility of designing a polymer that can be
recycled indefinitely, continue in our laboratory.
1
cycle, supports this hypothesis. The H NMR and IR of
PSTA-I200 however did not reveal a significant difference.
A similar increase in MW of the recovered polymer was
also observed when the saturated polymer (PSTA-I020) was
employed in iterative cycles (see Supporting Information),
eliminating the unsaturation in the polymer backbone as
being responsible for the increase in Mn.
Finally, we explored the possibility of cross-contamina-
tion of the nucleophile in the CCR product, upon repeated
recycling of PSTA-I200 (Table 5). Even with an excess of
vinyl lithium (2.5 equiv) employed in the first CCR cycle,
only a trace amount (4%) of the first cross-coupling
product was formed in the second cycle when PhLi was
employed as the second nucleophile. The crossover vinyl
contaminant was further reduced in the third cycle with
PhLi, demonstrating the ability to reuse the PSTA in
multiple cycles with different nucleophilic coupling part-
ners without significant cross-contamination.
Acknowledgment. Financial support was provided by
the NIH through Grant CA-19033. We thank Professor
Virgil Percec, Dr. Nga H. Nguyen, and Dr. Rakesh Kohli
at the University of Pennsylvania for helpful discussions,
assistance with GPC, and HRMS, respectively.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed and validated a soluble
ROMP polymer-supported siloxane transfer agent for use
in Pd-catalyzed CCRs. Importantly, the ROMP-generated
polymer can be recovered in a simple and efficient manner,
with the recovered polymer retaining near complete CCR
The authors declare no competing financial interest.
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