Design, Synthesis, and Application of Polymer-Supported Silicon-Transfer Agents for Cross-Coupling Reactions with Organolithium Reagents

Article abstract of DOI:10.1021/acs.joc.7b02004

The initial design, synthesis, and validation of polymer-supported siloxane transfer agents have been achieved that permit the direct use of organolithium reagents in the palladium-catalyzed cross-coupling reactions. Through rational design, two generations of polymer support were developed that significantly simplify product purification and the transfer agent recycling.

Full text of DOI:10.1021/acs.joc.7b02004

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Article
Design, Synthesis and Application of Polymer-Supported Silicon Transfer
Agents for Cross-Coupling Reactions with Organolithium Reagents
Minh H. Nguyen, Kevin T. O'Brien, and Amos B Smith, III
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02004 • Publication Date (Web): 20 Sep 2017
Downloaded from http://pubs.acs.org on September 22, 2017
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Design, Synthesis and Application of Polymer-Supported Silicon Transfer Agents for
Cross-Coupling Reactions with Organolithium Reagents
Minh H. Nguyen, Kevin T. O’Brien and Amos B. Smith, III*
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Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell
Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United
States
smithab@sas.upenn.edu
Abstract
The initial design, synthesis and validation of polymerꢀsupported siloxane transfer agents
have been achieved that permit the direct use of organolithium reagents in the palladiumꢀ
catalyzed crossꢀcoupling reactions. Through rational design, two generations of polymer support
were developed that significantly simplify product purification and the transfer agent recycling.
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Introduction
Over the past 50 years, palladiumꢀcatalyzed crossꢀcoupling reactions (CCRs) of
organometallic or mainꢀgroup reagents with organic halides have revolutionized the method by
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which (sp )carbonꢀ(sp )carbon bonds are constructed, permitting facile preparation of diverse,
structurally complex molecules for the development of biologically active compounds as well as
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functional materials. Organolithium reagents are cheap and either commercially available or
readily accessible through lithiumꢀhalogen exchange or via direct metalation. Not surprisingly,
organolithium reagents are thus among the most commonly used highly reactive reagents in
organic synthesis, and in turn comprised one of the earliest organometallic reagents to be
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exploited in crossꢀcoupling reactions (i.e., the Murahashi CCR). Organolithiums in the Pdꢀ
catalyzed crossꢀcoupling reactions however have some limitations, including in some cases low
yields, narrow substrate scope due to the very high reactivity, and competitive formation of
homoꢀcoupled products. To overcome these issues, organolithium reagents are frequently
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converted to other less reactive organometallic reagents (e.g., organozincs, organoborons,
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organotins and organosilicons ) to be employed in CCR. A potentially concise and efficient
method taking advantage of the direct use of organolithiums in CCR would be to eliminate the
need for extra manipulations and purification steps required to generate the requisite
organometallic reagents, as well as, to avoid the heavy metal and/or main group waste streams
often observed in traditional crossꢀcoupling reactions (Scheme 1).
Scheme 1. The Waste Problem in Traditional Palladium-
Catalyzed Cross-Coupling Reactions (CCR)
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In connection with the evolution of Anion Relay Chemistry (ARC), we recently
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demonstrated that siloxane 1 and analogues thereof comprise competent recoverable siliconꢀ
based transfer agents for efficient palladiumꢀcatalyzed intermolecular crossꢀcoupling reactions of
aryl and alkenyl organolithium reagents at ambient temperature and pressure (Scheme 2). This
tactic offers the solution to the intrinsic limitation of the Murahashi and importantly recent
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2
,9
Feringa crossꢀcoupling protocols of organolithiums, which are not compatible with substrates
bearing sensitive functional groups such as nitriles or carbonyl functionalities (i.e., ketones,
aldehyde and/or esters). Given that the siloxaneꢀbased transfer agents are fully regenerated
following the CCRs, the siloxaneꢀbased method comprises an effective atomꢀeconomical
approach for the construction of CꢀC bonds. The recovery of these transfer agents via either
chromatographic separation or acidꢀbase extraction, the latter by incorporation of a Brønsted
8b
base in the siloxane transfer structure, however in some cases has proven less than optimal. The
development of solidꢀsupported transfer agents hold the promise of significantly simplifying
product purification, and thereby providing an attractive and practical method for recycling of
transfer agents, further advancing the siloxaneꢀbased crossꢀcoupling tactic (e.g., a polymer with
attached siloxane transfer agents in flow reactors). We therefore recently undertook the
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incorporation of siloxane transfer agents onto readily recyclable polymer supports. Herein we
record a full account on the rational design, synthesis,
Scheme 2. Cross-Coupling Reactions of Organolithiums
Mediated by Siloxane Transfer Agent
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and validation of polymerꢀsupported silicon reagents for palladiumꢀcatalyzed crossꢀcoupling
reactions of organolithiums.
Results And Discussion
A. First-Generation Design, Synthesis and Validation of Polymer-Supported Siloxane
Transfer Agents for Cross-Coupling Reactions. At the outset, we set two goals for the
development of an effective polymerꢀsupported siloxane transfer agents: (A) the synthesis of the
polymer must be short, scalable, and inexpensive; and (B) the designed polymer preferably
soluble in THF, the optimal reaction solvent for the crossꢀcoupling reactions, and then upon
addition of a more polar solvent become insoluble after completion of the crossꢀcoupling
reaction to permit facile removal of the polymer from the desired products. On the basis of these
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considerations, we chose to employ ringꢀopening metathesis polymerization (ROMP) to
construct a polymeric siloxane transfer agent. To this end, the ROMP monomer was constructed
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via treatment of commercially available 5ꢀnorborneneꢀ2ꢀcarboxaldehyde with PhMgCl to
furnish benzylic alcohol 3, which upon orthoꢀlithiation with nꢀBuLi, followed by capture of the
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3
desired anion with Me SiHCl, and ringꢀclosure promoted by KOtBu leading to the slow
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evolution of hydrogen gas (Caution should be exercised!) led to siloxane 4 containing the desired
norbornene moiety (Scheme 3). Ringꢀopening metathesis polymerization of 4 was then smoothly
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achieved with the first generation Grubbs catalyst to provide the polynorborneneꢀsupported
transfer agent PNTA-I . Importantly, this short, efficient, and costꢀeffective route permits
200
preparation of the polymer on multiꢀgram scale. The resulting polymer proved soluble in most
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organic solvents and insoluble in H O and MeCN, which we took advantage of in the CCR
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purification process. Given that PNTA-I200 was produced in near quantitative yield employing
the living polymerization technique, the
Scheme 3. Synthesis of Polynorbornene-Supported
Transfer Agent
siloxane loading was reasoned to be nearly identical to the molarity of the monomer (3.9
mmol/g); each polymer chains containing an average of 200 monomer units based on the ratio of
monomer 4 to the Grubbs catalyst employed in the polymerization process.
Pleasingly, PNTA-I200 proved to be a viable transfer agent in crossꢀcoupling reactions
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employing conditions similar to those reported for the small molecule transfer agents (Table 1).
For example, use of 2.0 equiv of the siloxane polymer at a concentration of 15 mg/mL permitted
crossꢀcoupling between phenyllithium and 4ꢀiodoanisole to furnish the desired product 6, albeit
with the formation of a small amount of undesired homocoupled product 7 (entry 1). An increase
in product yield was observed upon increasing the equivalence of PhLi and PNTA-I200 to 2.5 and
3.0, respectively (entry 2). Particularly pleasing, the crossꢀcoupling efficiency was greatly
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improved by lowering the polymer concentration to 10 mg/mL, leading to complete conversion
of aryl iodide 5 within 2 h at room temperature to furnish product 6 in 98% isolated yield (entry
3). Attempts to reduce the amount of PhLi or the siloxane loading, while maintaining the
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efficiency of the process, provided no enhancement (entries 4ꢀ6). As expected, and consistent
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with Murahashi’s observation, a control experiment in the absence of siloxane polymer resulted
in inefficient crossꢀcoupling in conjunction with significant formation of undesired homocoupled
product (entry 7).
a
Table 1. Optimization of CCR Employing PNTA
1
b
equiv
PhLi
equiv
PNTA
concd
PNTA
H-NMR results
(6 : 5 : 7)
entry
time
c
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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
15 mg/mL
10 mg/mL
10 mg/mL
10 mg/mL
10 mg/mL
ꢀꢀꢀ
25 h
15 h
2 h
57 : 40 : 3
90 : 5 : 5
100 : nd : <1
84 : 11 : 5
72 : 18 : <1
88 : 9 : 3
14 : 77 : 9
d
2
e
3
4
5
6
15 h
2 h
2 h
f
7
2 h
a
All reactions were performed on 0.3 mmol scale using 3 mol %
2
, 4 mol % dpca, 10 mol % CuI. Determined by HꢀNMR analysis
b
1
PdCl
of the reaction mixture following an aqueous workup, extraction with
c
Et O and polymer removal via precipitation in CH CN. Part of the
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3
d
recovered polymer remained insoluble in THF. Small amount of the
recovered polymer remained insoluble in THF; 82% yield of 6.
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Polymer was recovered quantitatively and reꢀuseable; 98% yield of 6.
f
Reaction was run in the absence of siloxane polymer.
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Having developed both an effective synthetic tactic for polymer construction and
identification of optimal crossꢀcoupling conditions employing the siloxane polymer PNTA-I200,
we examined the effect of polymer structure on reactivity, visꢀàꢀvis the ability to serve as a
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transfer agent. To this end, a series of polymer analogues were synthesized and employed in the
crossꢀcoupling reaction between PhLi and 4ꢀiodoanisole (Table 2). Reducing the relative length
of polymer chain
a
Table 2. Structure-Activity of Siloxane Polymer in Cross-Coupling Reactions
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b
1
b
entry
siloxane polymer
time
H-NMR results
6 : 5 : 7)
entry
siloxane polymer
time
H-NMR results
(6 : 5 : 7)
(
c
1
2 h
100 : nd : <1
80 : nd : 20
1 : 99 : nd
4
20 h
42 : 33 : 25
6 : 94 : nd
83 : nd : 17
PNTA-I200
PNTA-II20
PNTA-I’200
PNTA-I’20
d
2
2 h
5
20 h
PNTA-I20
3
50 h
6
2 h
PNTA-II200
a
All reactions were performed on 0.3 mmol scale using 2.5 equiv PhLi, 3.0 equiv siloxane polymer, 3 mol % PdCl
2
, 4 mol % dpca, 10 mol %
b
1
CuI. Determined by HꢀNMR analysis of the reaction mixture following an aqueous workup, extraction with Et
precipitation in CH
2
O and polymer removal via
CN. 98% yield of 6. The insoluble polymer was stirred heterogeneously in reaction mixture. nd = not detected.
c
d
3
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to 20ꢀmer units by employing a higher Grubbs catalyst loading in the ROMP process led to
competing homocoupled product formation in the crossꢀcoupling process (entry 2). The
polymer’s ability to serve as a transfer agent also proved sensitive to the steric environment
around the silicon center, as a small increase in the steric bulk by changing the substituents on
the silicon atom on the transfer groups from methyl to ethyl resulted in an unproductive crossꢀ
coupling processes (entries 3 and 4). To explore the effect of the unsaturation present in the
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polymer chain, a tandem ROMPꢀhydrogenation protocol was developed to access polymers
with a saturated backbone. Interestingly, while the saturated 20ꢀmer displays physical and crossꢀ
coupling properties similar to those of the unsaturated analogue (i.e., complete conversion with
significant homocoupling, entry 6), the saturated 200ꢀmer proved insoluble in most organic
solvents and yielded only a trace amount of desired product (entry 5). Best results in this series,
with regard to the polymer physical properties (i.e., solubility), ease of handling, and crossꢀ
coupling efficiency were obtained with the unsaturated 200ꢀmer possessing dimethyl substituents
on silicon (i.e., PNTA-I , entry 1).
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To illustrate the utility and scope of the polynorbornene support, a series of crossꢀcoupling
reactions were carried out employing PNTA-I200 as the transfer agent (Table 3). Aryllithiums
underwent effective coupling with various aryl and alkenyl iodides to provide the CCR products
in excellent yield (entries 1,2,3, and 6). While the crossꢀcoupling reaction was also effective with
the electronꢀdeficient pꢀcyanophenyl bromide, reaction employing the electronꢀrich pꢀ
methoxyphenyl bromide proved ineffective (entries 4 and 5). Alkenyl lithiums were also well
tolerated in the crossꢀcoupling reactions, proceeding in good yield with retention of the alkene
geometry (entries 7ꢀ9). In all cases, the polymer was conveniently removed from the crossꢀ
coupling product mixture via precipitation in MeCN followed by filtration. Importantly, crossꢀ
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coupling reactions employing PNTA-I200 are as rapid and highꢀyielding as those employing the
small molecule transfer agents, with the added advantage of simple product isolation.
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Table 3. Validation of Polynorbornene Support across a
Series of Cross-Coupling Reactions
a
1
2
b
entry
R -Li
R -X
product
yield
1
PhLi
PhLi
PhLi
PhLi
PhLi
OMe 98%
5
6
2
3
91%
93%
7%
5
a
6a
6b
6
5b
c
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5
c
c
CN
5
89%
5d
5e
6a
6c
6
7
98%
71%
70%
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c
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All reactions were run with 2.5 equiv R Li, 3.0 equiv siloxane polymer, 3
b
c
2
mol % PdCl , 4 mol % dpca, 10 mol % CuI. Isolated yield. 12ꢀ24 h reaction
time. After polymer removal, the product mixture was treated with TBAF to
remove the silyl group.
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Attention was next directed toward the possibility of repeated recycling of the
polynorborneneꢀsupported transfer agent. We first examined the ability of PNTA-I200 to retain
crossꢀcoupling activity in multiple reactions employing the same coupling partners. As illustrated
in Table 4, PhLi and 4ꢀiodoanisole were employed for each experiment. The reaction was
quenched after a 2 h reaction time to remove the excess lithium reagent. The siloxane polymer
was then removed from
Table 4. Recyclability of Polynorbornene-Supported
Transfer Agent in Cross-Coupling Reactions Employing
the Same Coupling Partnerts
a
1
isolated
yield of 6
b
H-NMR Results
(6 : 5 : 7)
cycle
polymer recovered
0
(M = 63500, PDI = 1.2)
n
st
1
2
3
98%
91%
81%
98% (M = 73000, PDI = 1.6)
= 104400, PDI = 2.3)
= 94600, PDI = 2.6)
n
100 : nd : <1
97 : nd : 3
86 : 11 : 3
nd
99% (M
99% (M
n
rd
n
a
All reactions were run with 2.5 equiv PhLi, 3.0 equiv siloxane polymer,
b
1
2
.0 equiv 5, 3 mol % PdCl , 4 mol % dpca, 10 mol % CuI. Poly(methyl
methacrylate) standards were used to determine M and PDI values. nd = not
n
detected.
the reaction products via precipitation in MeCN and employed in the subsequent run. Pleasingly,
the polymer was recovered in near quantitative yield and reused for three cycles, furnishing the
1
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desired crossꢀcoupling product in good to excellent yields. However, a small decrease in crossꢀ
coupling efficiency was observed after each cycle, in conjunction with an increase in the number
average molecular weight (M ) and polydispersity index (PDI) of the recovered polymer as
n
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determined by gel permeation chromatography (Figure 1). We reason that a change in the
polymer structure after successive crossꢀcoupling reactions was likely due to crossꢀlinking of the
polymers. As depicted in Scheme 4, addition of PhLi into the polymer solution in the siloxane
activation step is envisioned to generate alkoxide intermediates. During the course of the
reaction, an oxyanion could then attack a silicon atom of a nearby siloxane unit (either remaining
intact after the activation step or regenerated after the crossꢀcoupling step) residing on a different
polymer chain, resulting in crossꢀlinking of the polymer. The higher degree of crossꢀlinking, the
less efficient the
Figure 1. Gel Permeation Chromatogram of Recovered
PNTA-I200 after Successive Cross-Coupling Reaction
Scheme 4. Polymer Cross-linking that Leads to Decrease in Reaction Efficiency after Repeated Cycles
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recovered polymer would be in mediating the crossꢀcoupling process. The observation that the
recovered polymer appeared to have an increase in hardness, in conjunction with a small
decrease in solubility in organic solvents after each cycle, supports this hypothesis. An increase
in M was also observed in repeated crossꢀcoupling reactions employing the saturated polymer
n
’
2
(
PNTA-I , Table 2), thus suggesting that the olefinic backbone is not responsible for the
0
increase in molecular weight.
We next performed a series of experiments to explore repeated recycling of the
polynorbornene support in crossꢀcoupling reactions employing different coupling partners, with
particular attention paid to crossꢀcontamination of the nucleophile in the subsequent crossꢀ
coupling products (Table 5). In the first experiment, two different nucleophilic coupling partners
were employed in two
Table 5. Recyclability of Polynorbornene-Supported Transfer Agent in Cross-Coupling Reactions Employing
a
Different Nucleophilic Coupling Partnerts
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A. Using the same electrophilic coupling partner
1
cycle
nucleophile
electrophile
H-NMR ratio of cross-coupling products
st
1
I CN
1
00
nd
2
I
CN
CN
9
6
7
4
3
rd
3
I
9
B. Using different electrophilic coupling partners
1
cycle
nucleophile
electrophile
H-NMR ratio of cross-coupling products
st
1
1
00
2nd
9
4
6
nd
a
1
2
All reactions were run with 2.5 equiv R Li, 3.0 equiv siloxane polymer, 1.0 equiv R X , 3 mol % PdCl
2
, 4 mol % dpca, 10 mol % CuI. nd =
not detected.
successive crossꢀcoupling reactions employing the same electrophilic coupling partner. Analysis
1
of HꢀNMR of the product mixture revealed a small amount of the first crossꢀcoupling product
(4%) in the second cycle; this crossꢀover contaminant remained present in the third cycle, albeit
in a minor amount (Table 5A). In the second experiment, the crossꢀover contamination of the
nucleophile was also observed in repeated crossꢀcoupling reactions employing different
nucleophiles and electrophiles (Table 5B). These results clearly demonstrate nucleophile
scrambling due to the incomplete reform of the siloxane moiety following quenching of the
16
reaction mixture, leading to nucleophile carryover when the crossꢀcoupling partners are
changed in subsequent reactions.
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In summary, we successfully validated the use of ringꢀopening metathesis polymerization to
incorporate an effective transfer agent onto a readily recoverable polynorbornene support that
significantly simplifies product purification and transfer agent recycle. However, while this
soluble linear polymer support proved effective in mediating the palladiumꢀcatalyzed crossꢀ
coupling reactions, we observed a decrease in reaction efficiency in conjunction with nucleophile
crossꢀcontamination after repeated reuse of the polymerꢀsupported transfer agent.
0
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B. A Second-Generation Design, Synthesis and Validation of Polymer-Supported
Siloxane Transfer Agents for Cross-Coupling Reactions. Attention was next directed toward
the design of a more effective solid support with improved recycling properties (i.e., less crossꢀ
contamination). We began by addressing the issue of polymer crossꢀlinking that we reasoned
accounted for the drop in reaction efficiency. We hypothesized that we could suppress this
process by restricting the polymer chain mobility and subsequently restrain the interaction of the
reactive sites on the polymer chain via use of a more rigid, crossꢀlinked, insoluble polymeric
network. Towards this end, use of an inert coꢀmonomer in the polymerization process would
place the siloxane units further away from each other, minimizing the undesired crossꢀlinking
behavior. Another factor considered in the design was removal of the unsaturation element in the
polymer chain, given the possible vulnerability of the olefinic backbone to chemical and thermal
degradation. Based on our previous observation that steric hindrance at the silicon atom leads to
inefficient reactivity, use of a spacer between the siloxane moiety and the polymer matrix was
also considered to reduce any steric effect induced by a bulky polymer backbone (Scheme 5). On
the basis of this logic, crossꢀlinked polystyrene polymers emerged as suitable solid supports for
the transfer agent.
nd
Scheme 5. Design of 2 Generation Polymer-Supported
Transfer Agent
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To test this hypothesis, we first directed our effort at strategies to attach the transfer agent
onto commercially available crossꢀlinked polystyrene resin beads. However, all attempts to
install the siloxane moiety onto a polystyrene resin via nucleophilic substitution reactions proved
unsuccessful, presumably due to undesired reactions at the silicon atom (Scheme 6). The use of a
crossꢀcoupling strategy employing 14 to functionalize the commercial resin beads also proved
unsatisfactory as less than 10% of siloxane moiety was incorporated into the polystyrene resin
16.
Scheme 6. Unsuccessful Attempts to Immobilize Transfer
Agent onto Commercially Available Resin Beads
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6
We next turned to polymeric immobilization of the transfer agent, with a “bottomꢀup” tactic
by first construction of a siloxane monomer (20, Scheme 7) having a styrene moiety which could
then be subjected to coꢀpolymerization with styrene and a suitable crossꢀlinker to provide the
desired crossꢀlinked polystyreneꢀsupported transfer agent. In this way we would have excellent
0
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1
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Synthesis of Polystyrene-Supported Siloxane
Transfer Agent
control of both the siloxane loading and the swelling properties of the polymer, the latter simply
a matter of mixing the monomer and the crossꢀlinker of choice in the appropriate ratio. Again,
we focused on simplicity for the polymer synthesis.
We began with the synthesis of the siloxane monomer 20 via treatment of commercially
available 2ꢀbromobenzaldehyde 17 with allylmagnesium chloride to furnish benzylic alcohol 18,
which was converted to siloxane 14 (Scheme 6) employing a oneꢀpot, three step reaction
sequence involving lithiation with nꢀBuLi, followed by anion capture with Me SiHCl, and ring
2
closure upon addition of H O leading to the evolution of hydrogen gas (Caution should be
2
exercised!). Hydroboration with 9ꢀBBN followed by a Suzuki Pdꢀcatalyzed crossꢀcoupling
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reaction with pꢀdibromobenzene smoothly provided aryl bromide 19 in 85% yield. In turn, 19
was converted to siloxane monomer 20 via a second Suzuki crossꢀcoupling reaction employing
1
8
19
vinyltrifloroborate.
Suspension coꢀpolymerization
of 20, with styrene and the
10
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tetrahydrofuranꢀderived crossꢀlinker 21 (in a molar ratio of 12:87:1, respectively) was then
smoothly achieved with benzoyl peroxide to provide the 1% crossꢀlinked polystyreneꢀsupported
transfer agent PSTA-I as wellꢀdefined beads. Selection of the highly flexible crossꢀlinker 14 in
the polymerization process led to a gelꢀtype resin that exhibits excellent swelling properties in
2
0
THF, which again is the reaction solvent for many crossꢀcoupling reactions. The siloxane
loading of PSTA-I (1.5 mmol/g) was reasoned to be nearly identical to the silicon loading, the
latter determined by elemental analysis.
We next evaluated PSTA-I as a viable transfer agent employing similar conditions as
developed for the polynorborneneꢀsupported transfer agent (Scheme 8). Pleasingly, PSTA-I
efficiently mediated the palladiumꢀcatalyzed crossꢀcoupling reaction between PhLi and 4ꢀ
iodoanisole, furnishing the desired crossꢀcoupling product 6 in 96% yield without observation of
Scheme 8. Recyclability of the Polystyrene Support in
Cross-Coupling Reaction Employing the Same Nucleophile
a
and Electrophile
a
All reactions were run with 2.5 equiv PhLi, 3.0 equiv siloxane polymer,
2
1.0 equiv of 5, 3 mol % PdCl , 4 mol % dpca, 10 mol % CuI. Siloxane loading
was 1.5 mmol/g.
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5
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5
5
6
the homoꢀcoupling product. Best results were again obtained employing 2.5 equiv of the lithium
reagent and 3.0 equiv of the siloxane polymer. Importantly, the crossꢀcoupling efficiency
remained the same after six crossꢀcoupling iterations employing the same batch of polymer,
thereby demonstrating a significant improvement of the designed polystyrene support compared
to the polynorbornene support. Also noteworthy was the ease of transfer agent recovery, as the
polymer could be readily removed from the product mixture via simple filtration, followed by
washing with organic solvents and drying under vacuum before being employed in the next
crossꢀcoupling cycle.
0
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9
0
With PSTA in hand, we next explored the use of the new polymer support in repeated crossꢀ
coupling reactions employing different nucleophiles and electrophiles. As shown in Table 6, a
single batch of siloxane polymer efficiently mediated a total of ten crossꢀcoupling reactions,
furnishing the desired crossꢀcoupling products with no evidence of homocoupled products.
Importantly, crossꢀcoupling reactions employing recycled PSTA-I proved as high yielding as
those employing the freshly made PNTA-I . Equally significant, no nucleophile crossꢀ
2
00
contamination was detected across this series of reactions. Moreover, substrates containing
highly sensitive functional groups such as nitriles and ketones were well tolerated in cross-
21
coupling reactions mediated by PSTA-I, demonstrating the unique advantage of this protocol
2,9
compared to other reported cross-coupling methods employing organolithium reagents as the
nucleophilic coupling partners.
Table 6. Recyclability of PSTA-I in Reactions Employing
a
Multiple Cross-Coupling Partners
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1
2
b
#
run
R -Li
R -X
product
yield
st
1
95%
97%
90%
74%
8
d
5
6f
6
nd
2
PhLi
5
rd
3
8
a
5e
5
6c
6d
6f
6a
th
4
8
b
th
c
5
72%
92%
8
e
5e
th
I
CN
CN
6
PhLi
PhLi
5
a
th
7
91%
5
5
b
d
6b
th
8
PhLi
PhLi
PhLi
CN
85%
82%
68%
6a
6h
th
9
5f
th
1
0
5
g
6h
a
1
All reactions were run with 2.5 equiv R Li, 3.0 equiv siloxane polymer, 3
, 4 mol % dpca, 10 mol % CuI. Siloxane loading was 0.74
mol % PdCl
2
b
c
mmol/g. Isolated yield. After polymer removal, the product mixture was
treated with TBAF to remove the silyl group.
Having showcased the recyclability of PSTA-I, we next expanded the scope of this efficient
siloxane polymer in the palladiumꢀcatalyzed crossꢀcoupling reactions, with a focus on substrates
containing heteroatoms (Table 7). To this end, electrophilic coupling partners comprising
imidazole and all regioisomers of iodopyridine proceeded efficiently. Also noteworthy,
trifluoromethyl groups were well tolerated both in electrophilic and nucleophilic coupling
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partners (6k and 6r). A variety of heteroaryl and hindered aryl lithiums were suitable to the
crossꢀcoupling conditions. We were particularly interested in crossꢀcoupling reactions of 2ꢀ
substituted heterocycles, given the inherently unstable and/or challengingꢀtoꢀaccess 2ꢀ
0
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heterocyclic crossꢀcoupling surrogates. Gratifyingly, use of PSTA-I permits direct crossꢀ
coupling of 2ꢀlithiopyridine (8g), thus alleviating the need for preconstruction of 2ꢀpyridyl Nꢀ
2
3
methylꢀiminodiacetic acid (MIDA) boronates. Furthermore, crossꢀcouplings of 2ꢀthienyllithium
and 2ꢀbenzofuryllithium were successful, providing good yield of desired products (6n and 6q),
with the latter accessed via a direct orthoꢀlithiation/crossꢀcoupling sequence of benzofuran.
Importantly, a single batch of polymer was employed and recycled in near quantitative yield
following each reaction in this series of experiments.
Table 7. Expanded Substrate-Scope of Pd-Catalyzed
a
Cross-Coupling Reactions Employing Recycled PSTA-I
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b
#
run
R -Li
R -X
product
yield
st
1
77%
81%
92%
PhLi
PhLi
5
h
6i
6j
nd
2
10
11
12
13
14
15
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5i
rd
3
PhLi
PhLi
PhLi
5
j
6k
6l
th
4
84%
88%
5k
th
5
5
l
6m
6n
6o
th
6
71%
89%
8
f
5
th
7
8
g
5
th
8
64%
8h
8i
5
5
5
6p
O
th
9
OMe 73%
6q
6r
th
10
7
9%
8j
a
1
All reactions were run with 2.5 equiv R Li, 3.0 equiv siloxane polymer, 3
, 4 mol % dpca, 10 mol % CuI. Siloxane loading was 0.57
mmol/g. Isolated yield.
mol % PdCl
2
b
A proposed reaction mechanism for the siloxaneꢀmediated crossꢀcoupling reaction of
0
I
organolithium reagents under catalytic amounts of Pd and Cu is illustrated in Scheme 9.
Addition of organolithium to the transfer agent during the siloxane activation step generates an
6
alkoxide intermediate, presumably in an equilibrium with a pentavalent siliconate complex.
2
4
I
Transmetalation from silicon to copper furnishes the arylꢀCu species and in turn regenerates
the
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Scheme 9. Proposed Reaction Mechanism
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transfer agent. A second transmetalation step from copper to palladium results in the ligated
diarylpalladium(II) complex, which undergoes reductive elimination to provide the coupled
0
I
products, and the resulting Pd then reꢀenters the catalytic cycle. A catalytic amount of Cu is
required and serves as a molecular transport or shuttle between two transmetallation processes,
i.e., first accepting nucleophile from activated transfer agent and then donating nucleophile to
palladium center.
As part of an effort to expand the siloxane transfer agent tactic, we demonstrated that the
polymerꢀsupported transfer agent could be employed to mediate carbonꢀnitrogen bond formation,
2
5
as recently demonstrated with monomeric siloxane transfer agents. A preliminary example is
showed in Scheme 10 in which PNTA-I200 was used in the copperꢀcatalyzed, electrophilic
amination of PhLi to generate the desired aniline 16. This protocol featured a chromatographyꢀ
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free purification strategy in which the desired amination product was purified by acidꢀbased
extraction and the polymer was recovered via precipitation in MeCN and reused for two
additional cycles.
10
11
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Scheme 10. Electrophilic Amination of Organolithium
Mediated by Polymer-Supported Transfer Agent
a
Ph
200
O
Si
PNTA-I200
cycle yield
BzO
N
1st
92%
0%
71%
1
5
nd
PhLi
Ph N
2
3
8
THF, –78 °C to rt, 3 h
CuI, dpca
THF, rt, 2 h
rd
16
a
All reactions were run with 2.5 equiv PhLi, 3.0 equiv siloxane polymer,
1
.0 equiv 15, 10 mol % CuI, 10 mol % dpca.
Summary
The initial rational design, synthesis, and validation of two generations of polymerꢀsupported
transfer agents for use in the palladiumꢀcatalyzed crossꢀcoupling reactions of organolithiums has
been achieved. The polymer supports greatly simplify product purification, provide a practical
method for transfer agent recovery, and maintain the efficiency of the crossꢀcoupling process
through multiple cycles. The mild reaction conditions and high functional group tolerance in
conjunction with the operationally convenient protocol provided by the solid supports further
advance the siloxane based transfer tactic in crossꢀcoupling reactions of organolithiums. Studies
to improve the design of polymer bound transfer agent to reduce the required equivalents of
lithium reagents and to expand the concept of polymerꢀsupported siloxaneꢀtransfer agent in other
bondꢀforming processes as well as to explore the possibility of coating of siloxane polymer in
flow microꢀreactors continue in our laboratory.
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Experimental Section
Materials and Methods. All moistureꢀsensitive reactions were performed using syringeꢀ
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septum cap techniques under an inert atmosphere of N . All glassware was flame dried or dried
2
in an oven (140 ° C) for at least 4 h prior to use. Reactions were magnetically stirred unless
otherwise stated. Tetrahydrofuran (THF), dichloromethane (CH Cl ) and diethyl ether (Et O)
2
2
2
were dried by passage through alumina in a solvent purification system. Unless otherwise
stated, solvents and reagents were used as received. Analytical thin layer chromatography
was performed on preꢀcoated silica gel plates (particle size 40ꢀ55 micron, 230ꢀ400 mesh).
Column chromatography was performed using silica gel (40ꢀ63 micron particle size, 230ꢀ300
mesh) and compressed air pressure with commercial grade solvents. Yields refer to
chromatographically and spectroscopically pure compounds, unless otherwise stated. NMR
1
13
spectra were recorded at 500 MHz/125 MHz ( H NMR/ C NMR) on a 500 MHz spectrometer
at 300 K. Chemical shifts are reported in parts per million with the residual solvent peak as
1
an internal standard. H NMR spectra are tabulated as follows: chemical shift, multiplicity
(s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet of doublets, ddd= doublet of doublet of
doublets, dddd= doublet of doublet of doublet of doublets, dt= doublet of triplets,
1 3
m=multiplet, b=broad), coupling constant and integration. C NMR spectra are tabulated by
observed peak. Melting points were determined using a capillar melting point apparatus and are
uncorrected. Infrared spectra were measured on a FT/IR plus spectrometer. Highꢀresolution
mass spectra (HRMS) were measured on a LCꢀTOF mass spectrometer. GPC analysis of the
polymer samples were done on a highꢀperformance liquid chromatography (HPLC), equipped
o
with a column oven (30 C), an integration data station, a UVꢀvis detector (254 nm), a refractive
2
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index detector, and three gel columns (500 Å, 5 µm; 1000 Å, 5 µm; and 10 Å, 5 µm). THF
(
HPLC grade) was used as eluent at a flow rate of 1 mL/min. The numberꢀaverage (M ) and
n
weightꢀaverage (M ) molecular weights of polymer samples were determined with poly(methyl
w
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methacrylate) (PMMA) standards. Elemental analysis of Si was determined via inductively
2
6
coupled plasma optical emission spectrometry (ICPꢀOES). Compound 5e
and the
2
6
27
corresponding vinyl iodides of 8b and 8d were prepared according to previously reported
procedures. Caution: organolithium reagents, especially alkyl lithium reagents such as nꢀBuLi
and tꢀBuLi are corrosive, flammable, and pyrophoric. Careful planning prior to execution of
experiments and proper personal protective equipment are needed to safely handle organolithium
reagents in the laboratory.
Preparation of water-washed silica gel for column chromatography (where specified). Silica
gel was suspended in deionized H O and the slurry mixture was then packed into a prepared
2
column. The obtained H Oꢀwashed silica gel packed column was then rinsed with 2 column
2
volumes of acetone, 1 column volume of EtOAc and 2 column volumes of hexanes,
successively.
Synthesis and Cross-Coupling Reactions of Polynorbornene-supported Transfer
Agents.
Norborn-5-en-2-yl-phenol-methanol (3). PhMgBr (3.0 M in Et O, 17.55 mL, 52.64 mmol)
2
was added slowly to a vigorously stirred solution of aldehyde 2 (95% purity, mixture of endoꢀ
o
and exoꢀisomers) (5.36 g, 41.68 mmol) in 200 mL Et O at 0 C. The obtained solution was stirred
2
at rt for 15 h, and was quenched with saturated aqueous NH Cl (50 mL). The organic layer was
4
collected and the aqueous layer was extracted with Et O (2 x 50 mL). The combined organic
2
layers were washed with brine, dried with MgSO , and concentrated in vacuo. The crude product
4
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was purified by flash chromatography on silica gel (5 – 30% Et O/Hexanes) to afford the desired
2
1
alcohol 3 as a mixture of diastereomers in a 1 : 1 : 3.7 : 3.7 ratio by H NMR spectroscopy (7.87
o
g, 39.3 mmol, 94%): colorless solid (M.P. = 50 – 53 C); R 0.2 (20% Et O in Hexanes); IR
f
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2
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–1
(
neat, cm ) 3376, 3060, 3029, 2967, 2939, 2869, 1603, 1494, 1454, 1335, 1068, 1015, 758, 719,
1
700; H NMR (500 MHz, CDCl ) δ 7.41 – 7.23 (m, 4 H), 6.27 – 6.22 (m, 0.77 H, vinyl proton),
3
6.20 – 6.14 (m, 0.51 H, vinyl proton), 6.10 – 6.04 (m, 0.22 H, vinyl proton), 6.00 – 5.94 (m, 0.50
H, vinyl proton), 4.41 (d, J = 9.5 Hz, 0.11 H, benzylic proton), 4.36 (d, J = 10.1 Hz, 0.11 H,
benzylic proton), 4.03 (d, J = 10.1 Hz, 0.39 H, benzylic proton), 3.98 (d, J = 10.1 Hz, 0.39 H,
benzylic proton), 3.16 (bs, 0.39 H, allylic proton), 3.10 (bs, 0.11 H, allylic proton), 2.92 (bs, 0.11
H, allylic proton), 2.88 (bs, 0.39 H, allylic proton), 2.77 (bs, 0.11 H, allylic proton), 2.75 (bs,
0.39 H, allylic proton), 2.52 – 2.42 (m, 0.80 H), 2.31 (bs, 0.39 H, allylic proton), 2.26 (bs, 0.11
13
H, allylic proton), 2.05 – 1.98 (m, 0.43 H), 1.87 – 0.88 (m, 4.37 H), 0.52 – 0.45 (m, 0.40 H); C
NMR (125 MHz, CDCl ) δ 144.6, 144.5, 144.3, 144.2, 138.1, 138.1, 137.3, 137.1, 136.8, 136.8,
3
1
32.8, 132.4, 128.7, 128.6, 128.6, 128.3, 127.9, 127.9, 127.8, 127.0, 126.8, 126.5, 126.0, 80.0,
9.5, 79.3, 78.6, 49.9, 49.5, 48.1, 47.2, 46.9, 46.9, 45.7, 45.3, 44.9, 44.5, 44.4, 43.7, 43.0, 42.5,
7
+
+
42.3, 42.0, 30.9, 30.3, 30.1, 29.5; HRMS (CI ) m/z (M+H) : Calcd for C H O: 201.1279,
1
4
17
found: 201.1277.
-(Bicyclo[2.2.1]hept-5-en-2-yl)-1,1-dimethyl-1,3-dihydrobenzo[c][1,2]oxasilole (4). To a
3
stirred solution of alcohol 3 (7.71 g, 38.55 mmol) in hexanes (125 mL, dried over MgSO ) and
4
o
Et O (100 mL) at 0 C was added nꢀBuLi (2.3 M in hexanes, 36.9 mL, 84.87 mmol) dropwise.
2
The solution was stirred at rt for 1 h, at which time reflux condenser was attached and the
o
o
solution was heated to reflux at 70 C for 21 h. The solution was then cooled to –78 C and
Me SiHCl (9.22 ml, 84.87 mmol) was added dropwise. The solution was stirred and warmed to
2
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rt. After 29 h, the reaction mixture was quenched by addition of deionized H O (100 mL) and
2
stirred for 16 h. Note slow evolution of hydrogen gas (caution!). The organic layer was collected
and the aqueous layer was extracted with hexanes (2 x 50 mL). The combined organic layers
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were washed with brine, dried with MgSO , and concentrated in vacuo. The crude product was
4
then taken up in THF (150 mL), and KOtBu (0.65 g, 5.79 mmol) was divided into 3 portions and
added to the stirred solution sequentially, each portion after 1 h. The mixture was stirred for a
total of 4 h, followed by addition of d.i. H O (50 mL), and the resulting mixture was stirred for
2
another 30 min. The organic layer was collected and the aqueous layer was extracted with
Hexanes (2 x 50 mL). The combined organic layers were washed with brine, dried with MgSO4,
o
and concentrated in vacuo. Kugelrohr distillation (110 – 160 C, 0.025 mmHg), followed by
flash chromatography on waterꢀwashed silica gel (0 – 0.5% Et O/Hexanes) afforded the desired
2
1
siloxane 4 as a mixture of diastereomers in a 1 : 1.5 : 3.4 : 4.9 ratio by H NMR spectroscopy
–
1
(
3.97 g, 15.51 mmol, 40%): colorless oil; R 0.5 (5% Et O in Hexanes); IR (neat, cm ) 3058,
f 2
1
2
962, 1594, 1445, 1254, 1028, 873, 823, 787, 748; H NMR (500 MHz, CDCl ) δ 7.59 – 7.52
3
(m, 0.88 H), 7.44 – 7.20 (m, 3.12 H), 6.30 – 6.14 (m, 1.70 H, vinyl proton), 6.08 – 6.03 (m, 0.30
H, vinyl proton), 5.41 (d, J = 4.0 Hz, 0.14 H, benzylic proton), 5.25 (d, J = 5.5 Hz, 0.09 H,
benzylic proton), 4.65 (d, J = 9.7 Hz, 0.46 H, benzylic proton), 4.55 (d, J = 10.3 Hz, 0.31 H,
benzylic proton), 3.18 (bs, 0.32 H, allylic proton), 2.97 (bs, 0.45 H, allylic proton), 2.90 (bs, 0.19
H, allylic proton), 2.87 – 2.80 (m, 0.74 H, allylic proton), 2.76 (bs, 0.18 H, allylic proton), 2.58
(bs, 0.12 H, allylic proton), 2.15 – 2.06 (m, 0.80 H), 1.95 – 1.67 (m, 1.43 H), 1.48 – 1.12 (m,
1
3
2
1
1
.77 H), 0.45 – 0.31 (m, 6 H); C NMR (125 MHz, CDCl ) δ 154.2, 153.5, 153.3, 138.1, 138.0,
3
37.8, 137.5, 137.5, 137.0, 136.1, 136.0, 135.9, 135.8, 133.5, 132.5, 131.2, 131.0, 130.9, 130.0,
29.7, 129.3, 129.2, 127.1, 127.0, 127.0, 126.9, 123.2, 122.8, 122.7, 122.5, 85.9, 85.3, 84.3, 84.0,
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9.8, 49.3, 49.0, 48.3, 47.1, 46.3, 46.2, 46.2, 46.0, 45.6, 44.7, 43.1, 42.6, 42.3, 42.2, 41.6, 30.0,
+
+
29.8, 29.8, 27.0, 1.8, 1.8, 1.6, 1.2, 1.0, 1.0, 0.8, 0.7; HRMS (CI ) m/z (M+H) : Calcd for
C H OSi: 257.1362, found: 257.1357.
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-(Bicyclo[2.2.1]hept-5-en-2-yl)-1,1-dimethyl-1,3-dihydrobenzo[c][1,2]oxasilole (4b). To a
stirred solution alcohol 3 (7.78 g, 38.89 mmol) in hexanes (125 mL, dried over MgSO ) and Et O
4
2
o
(100 mL) at 0 C was added nꢀBuLi (2.3 M in hexanes, 37.2 mL, 85.56 mmol) dropwise. The
solution was stirred at rt for 1 h, at which time reflux condenser was attached and the solution
o
o
was heated to reflux at 70 C for 21 h. The solution was then cooled to –78 C and Et SiCl (7.56
2
2
mL, 50.56 mmol) was added dropwise. The solution was stirred and warmed up to rt. After 21 h,
the reaction mixture was quenched by addition of d.i. H O (50 mL) and stirred for 15 min. The
2
organic layer was collected and the aqueous layer was extracted with hexanes (2 x 50 mL). The
combined organic layers were washed with brine, dried with MgSO , and concentrated in vacuo.
4
o
Kugelrohr distillation (120 – 150 C, 0.025 mmHg), followed by flash chromatography on silica
gel (0 – 1% Et O/Hexanes) afforded the desired siloxane 4b as a mixture of diastereomers in a 1
2
1
:
1 : 1.8 : 4.8 ratio by H NMR spectroscopy (1.49 g, 5.25 mmol, 13%): colorless oil; R 0.55 (5%
f
–
1
1
Et O in Hexanes); IR (neat, cm ) 3056, 2957, 1460, 1443, 1019, 962, 853, 741, 715; H NMR
2
(500 MHz, CDCl ) δ 7.59 – 7.51 (m, 0.93 H), 7.44 – 7.34 (m, 1.36 H), 7.34 – 7.23 (m, 1.71 H),
3
6
.31 – 6.15 (m, 1.67 H, vinyl proton), 6.09 – 6.03 (m, 0.33 H, vinyl proton), 5.37 (d, J = 4.4 Hz,
.12 H, benzylic proton), 5.20 (d, J = 6.5 Hz, 0.12 H, benzylic proton), 4.63 (d, J = 10.1 Hz, 0.55
0
H, benzylic proton), 4.55 (d, J = 10.5 Hz, 0.21 H, benzylic proton), 3.20 (bs, 0.21 H, allylic
proton), 3.00 (bs, 0.56 H, allylic proton), 2.92 (bs, 0.21 H, allylic proton), 2.87 – 2.81 (m, 0.77
H, allylic proton), 2.78 – 2.72 (m, 0.25 H, allylic proton), 2.15 – 2.05 (m, 0.79 H), 1.94 – 1.79
13
(m, 1.17 H), 1.52 – 0.71 (m, 13.04 H); C NMR (125 MHz, CDCl ) δ 154.9, 154.3, 153.9,
3
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38.15, 137.8, 137.7, 137.5, 137.4, 136.9, 134.1, 134.1, 134.0, 133.9, 133.6, 132.5, 131.8, 131.8,
31.6, 131.5, 129.6, 129.3, 129.2, 126.9, 126.8, 126.8, 126.7, 123.1, 122.8, 122.7, 122.4, 86.1,
5.5, 84.7, 84.2, 49.7, 49.4, 48.9, 48.2, 47.4, 46.2, 46.1, 46.1, 46.0, 45.6, 44.6, 43.3, 42.6, 42.4,
10
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+
2.1, 41.6, 30.1, 30.0, 30.0, 29.8, 27.0, 7.6, 7.4, 7.1, 7.1, 7.0, 6.9, 6.6, 6.5; HRMS (CI ) m/z
+
(M+H) : Calcd for C H OSi: 285.1675, found: 285.1664.
1
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st
General procedure A: ring opening metathesis polymerization (ROMP). Grubbs catalyst (1
generation) was dissolved in 0.5 mL DCM and stirred for 30 min. The catalyst solution was then
cannulated into another flask containing siloxane monomer in 1 mL DCM (rinsed with 2 x 0.5
mL DCM). Under a flowing stream of N the obtained solution was stirred at rt for 16 h, at
2
,
which time reflux condenser was attached, another 1 mL DCM was added and the solution was
o
heated to reflux at 50 C for 19 h. The obtained mixture was cooled to rt, diluted with 1 mL
DCM, followed by addition of ethyl vinyl ether (2 mL). The solution was then heated to reflux
for another 2 h. The solution was then cooled to rt, diluted with 1 mL DCM, followed by
addition of a solution of tris(hydroxymethyl)phosphine in d.i. H O (2 mL) and Et N (freshly
2
3
distilled, 0.1 mL). The obtained mixture was stirred vigorously for 30 min. The resultant organic
layer was collected and the aqueous layer was extracted with DCM (2 x 5 mL). The combined
organic layers were washed with brine, dried with MgSO , and concentrated in vacuo. The
4
obtained solid was then dissolved in 1 mL DCM and precipitated via dropwise addition into a
vigorously stirred solution of CH CN (250 mL). The precipitate was filtered and concentrated in
3
vacuo to afford the desired polymer.
Siloxane Polymer PNTA-I . Following general procedure A, ROMP of siloxane monomer 4
2
00
(
0.256 g, 1.0 mmol) using first generation Grubbs catalyst (4.1 mg, 5.0 µmol, 0.5 mol %) and
tris(hydroxymethyl)phosphine (120 mg, 1.0 mmol) afforded siloxane polymer PNTA-I200 (0.245
2
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