Development and Application of a Recyclable High-Load Magnetic Co/C Hybrid ROMP-Derived Benzenesulfonyl Chloride Reagent and Utility of Corresponding Analogues

Article abstract of DOI:10.1021/acs.orglett.7b00792

The development and application of high-load, recyclable magnetic Co/C hybrid ROMP-derived benzenesulfonyl chloride and analogues is reported. The regeneration and utility of these reagents in the methylation/alkylation of various carboxylic acids is demonstrated via efficient retrieval of the magnetic reagent with a neodymium magnet. Additional reactions employing the analogue sulfonic acid and in situ generated magnetic benzenesulfonyl azide are also reported.

Full text of DOI:10.1021/acs.orglett.7b00792

Letter
pubs.acs.org/OrgLett
Development and Application of a Recyclable High-Load Magnetic
Co/C Hybrid ROMP-Derived Benzenesulfonyl Chloride Reagent and
Utility of Corresponding Analogues
Saqib Faisal,†,‡ Qin Zang,†,‡ Pradip K. Maity,†,‡ Agnes Brandhofer,†,‡,∥ Patrick C. Kearney,§
Oliver Reiser,∥ Robert N. Grass,⊥ Diana Stoianova,# and Paul R. Hanson*,†,‡
†Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, United States
‡The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), 2034 Becker Drive, Delbert
M. Shankel Structural Biology Center, Lawrence, Kansas 66047, United States
§HD Sciences, Kansas City, Missouri 66103, United States
∥Institute for Organic Chemistry, University of Regensburg, Universitatsstrasse 31, 93053 Regensburg, Germany
⊥Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg
̈
1-5/10, 8093 Zurich, Switzerland
̈
#Materia, Inc., 60 North San Gabriel Boulevard, Pasadena, California 91107, United States
S
* Supporting Information
ABSTRACT: The development and application of high-load, recyclable magnetic Co/C hybrid ROMP-derived benzenesulfonyl
chloride and analogues is reported. The regeneration and utility of these reagents in the methylation/alkylation of various
carboxylic acids is demonstrated via efficient retrieval of the magnetic reagent with a neodymium magnet. Additional reactions
employing the analogue sulfonic acid and in situ generated magnetic benzenesulfonyl azide are also reported.
he growing demand for recyclable materials has resulted in
an increasing need for the development of sustainable
Barrett,4 Buchmeiser,5 Bolm,6 and others7 has demonstrated
ring-opening metathesis polymerization (ROMP)8 as a viable
technology for grafting oligomers onto a variety of surfaces. In
this area, our group has reported ROMP-derived soluble, high-
load, oligomeric reagents and scavengers through the use of
norbornene-tagged (NB-tagged) monomers.9 In addition, recent
developments in our laboratories have demonstrated advance-
ments in grafting high load oligomeric reagents and scavengers
T
technologies in the production of chemical entities.1 Recovery
and recycling of expensive or toxic reagents in a more sustainable
manner is an important area in minimizing environmental
impact. Among many technologies being developed toward this
goal, the use of magnetically supported reagents has emerged as a
viable method of recovery due to their innate physical properties,
including advantageous means of isolation and recyclability.2
Despite ongoing developments for magnetic reagents and key
advances in this area, noted limitations in load levels, physical
properties (swelling, accessibility, etc.), ease of synthesis, and
reuse are continued challenges to be met.
10
onto SiO2 and magnetic Co/C surfaces3,11 for application in
facilitated synthesis and sequestration protocols. Our interest in
this area has led to efforts aimed at the development of
methylation/alkylation reactions using magnetic reagents.
Common methylating reagents, such as dimethyl sulfate,
methyl iodide, and diazomethane, are extensively used in organic
The synthesis of hybrid materials, which combine the
properties of Co/C magnetic nanoparticles developed by
Stark, Grass, and co-workers3 with a high-load functionalized
material,3b−d is a powerful means to address the limitations in the
area of immobilized reagents. In this regard, pioneering work by
Received: March 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00792
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Organic Letters
Letter
and medicinal chemistry but have undesirable physical character-
istics that pose potential safety issues when used for routine
synthesis, such as toxicity, carcinogenicity, and an explosive
nature.12 Alternative, safe, bench-stable, polymer-supported, and
recyclable methylating or alkylating reagents represent a
potentially more viable platform with enhanced safety/toxicity
profiles for routine synthetic transformations.13 In this regard,
herein we report the first example of high-load magnetic Co/C-
ROMP-derived oligomeric benzenesulfonate ester (Co/C-
OBSEn) and the in situ use of benzenesulfonyl chloride (Co/
C-OBSCn)/ROH as efficient methylating/alkylating reagents for
various carboxylic acids.
Figure 1. Methylation of various carboxylic acids utilizing magnetic Co/
C-OBSEn.
To synthesize the magnetic version of oligomeric benzenesul-
fonate ester Co/C-OBSEn, we first synthesized NB-tagged
benzenesulfonyl chloride monomer 1 utilizing our previously
reported procedure14 (Scheme 1). The synthesis of Co/C-NB 5
sulfonate ester. In this regard, grafting of NB-tagged
benzenesulfonyl chloride 1 was successfully achieved on a
gram scale by using the aforementioned ROMP protocol, which
afforded hybrid ROMP-derived magnetic benzenesulfonyl
chloride NPs Co/C-OBSCn 8 (Scheme 2).
Scheme 1. Magnetic Co/C Hybrid ROMP Benzenesulfonate
Ester NPs (Co/C-OBSEn)
Scheme 2. Synthesis of Hybrid Magnetic Co/C-ROMP
Benzenesulfonyl Chloride NPs Co/C-OBSCn
Images of the hybrid material were next taken using
transmission electron microscopy (TEM) to observe and
evaluate the grafting of the corresponding NB-tagged monomers
onto the surface of the Co/C-nanoparticles (Figure 2). The
is achieved by the utilization of a Cu(I)-catalyzed alkyne/azide
cycloaddition reaction using commercially available Co/C-azide
3 and propargylated bicycle[2.2.1]hept-5-en-2-ylmethanol 4
(Scheme 1). This NB-tagged magnetic linker (Co/C-NB) 5
has been established as a suitable precursor for the surface-
initiated ROMP of various NB-tagged monomers.11
The NB-tagged benzenesulfonate ester monomer 2 was
synthesized by grinding NB-tagged sulfonyl chloride 1 in wet
MeOH, which afforded compound 2 in excellent yield and high
purity without the need to perform column chromatography
(Scheme 1).15 Subsequent surface-initiated ROMP11 of NB-
tagged sulfonate monomer 2 using the Grubbs second-
generation catalyst [G-II, C848, (IMesH2) (PCy3) (Cl2)-Ru =
CHPh] afforded the desired ROMPgel grafted onto the surface
of the Co/C nanobeads. More than 95% of monomer was
incorporated into the hybrid material, resulting in magnetic NPs
with a load of 2.10−2.18 mmol/g. To utilize this magnetic Co/C-
OBSEn, initial studies were focused on the methylation of simple
carboxylic acid substrates. The reagent Co/C-OBSEn 6 was
successfully utilized for methylation of various carboxylic acids
7a−e (Figure 1), which afforded excellent yield (88−95%) and
purity after retrieval of the spent magnetic reagent using a
neodymium magnet and filtration through a Celite SPE to
remove insoluble base.
Figure 2. TEM Images of Co/C-NB, Co/C-OBSEn, and Co/C-OBSCn.
grafted ROMP polymer (light gray areas) is clearly attached
around the Co/C NPs (dark area), and individual particles can be
seen. The lack of large cohesive particles may indicate lack of
cross-linking. This observation is substantiated by the fact that
the experimental load values are similar to the theoretical loads,
indicating that the majority of active sites were available and most
likely not cross-linked.
Direct methylations of carboxylic acids were successfully
achieved via utilization of the magnetic reagent Co/C-OBSCn 8
in the presence of an excess of MeOH (6−10 equiv). Various
simple aromatic and aliphatic carboxylic acids were subjected to
methylation, which afforded the majority of products 9a−h in
excellent yields and purity (Table 1). In addition, chemoselective
methylation of a carboxylic acid group was observed in the
presence of a phenolic hydroxyl group (entry 4).
Efforts were next focused on the synthesis of magnetic
benzenesulfonyl chloride, Co/C-OBSCn, which could subse-
quently be used for in situ direct alkylations of a carboxylic acid in
the presence of alcohols without preparation/isolation of the
B
DOI: 10.1021/acs.orglett.7b00792
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Organic Letters
Letter
Table 1. Methylation of Various Carboxylic Acids Utilizing
Magnetic Co/C-OBSCn
Figure 3. Regeneration of Co/C-ROMP benzenesulfonic acid NP (Co/
C-OBSAn) byproduct.
possible that the grafted ROMP gel provides additional
protection of the core magnetic nanoparticles.
We further utilized the magnetic benzenesulfonic acid Co/C-
OBSAn 11 in acid-catalyzed coupling reactions of indole with
methyl vinyl ketone (MVK) as well as for the alcoholysis of
exocarbic anhydride at room temperature (Scheme 3).18 Again,
the spent magnetic sulfonic acid was recovered by external
magnet and the coupling products were isolated in 85−90%
yield.
Considering the wide applications of esterification reactions,16
we next directed our attention to further explore the scope of
magnetic Co/C-OBSCn reagent for the alkylation of carboxylic
acids with various alcohols. Toward this goal, reaction of
carboxylic acids with deuterated MeOH was successfully
achieved in <90% yield and purity (10a and 10b, Table 2). In
Scheme 3. Acid-Catalyzed Reactions Using Co/C
Benzenesulfonic Acid NPs (Co/C-OBSAn)
Table 2. Alkylation of Carboxylic Acids Utilizing Magnetic
(Co/C-OBSCn)
Recently sulfonyl azides have been utilized in a variety of
transformations to generate various useful scaffolds.19 Previously,
our group has reported the in situ use of a soluble oligomeric
benzenesulfonyl azide and facile application of diazo-transfer
reactions.14 As a result, we generated the magnetic version of
benzenesulfonyl azide and utilized it in diazo-transfer reactions
(Scheme 4). Magnetic decantation of the magnetic sulfonamide
Scheme 4. Synthesis and Utilization of Co/C Benzenesulfonyl
Azide NPs (Co/C-OBSAzn)
addition, alkylation in the presence of different alcohols afforded
the desired alkylated ester (10c−g) in 72−82% yield. In all cases,
the spent reagent was quantitatively retrieved by magnetic
decantation of the reaction mixture.
Our next goal was to regenerate Co/C-OBSCn 8 from the
corresponding magnetic NP sulfonic acid salts, Co/C-OBSAn 11,
being formed in the course of the reaction. To achieve this goal,
the spent reagent was treated with SOCl2 in toluene in the
presence of a catalytic amount of DMF, which successfully
afforded magnetic sulfonyl chloride NPs, Co/C-OBSCn
8
17 formed in the course of the reaction allowed us to further treat
the reaction mixture with Rh2(OAc)4 in the same pot, which
afforded a 1:1 mixture of dihydrofuran19c and α-haloenones20 in
90% overall yields.
In conclusion, we have demonstrated the utilization of high-
load magnetic Co/C ROMP-derived oligomeric benzenesulfo-
nate ester Co/C-OBSEn and benzenesulfonyl chloride Co/C-
(Figure 3), without significant loss of magnetic material. Multiple
esterifications/regenerations (up to 10×) were successfully
achieved without any loss in performance using the same
protocol. It was observed that the Co/C magnetic nanoparticles
survived the acidic environment of the regeneration process,
which has also been shown in a previous report.17 It is also
C
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Organic Letters
Letter
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OBSCn as efficient methylating/alkylating reagents for a variety
of carboxylic acids. These alkylations were achieved by simple
magnetic decantation followed by Celite filtration of the reaction
mixture to remove insoluble base to derive alkylated products
without the use of chromatographic purification, which makes
this method suitable for automated parallel synthesis. The spent
reagent, i.e., magnetic benzenesulfonic acid Co/C-OBSAn has
been successfully regenerated and reused multiple times without
appreciable loss of magnetic material. Current efforts are
focusing on further utilization of these magnetic reagents in
parallel synthesis and in one-pot protocols.
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ASSOCIATED CONTENT
■
S
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00792.
Full experimental details, copies of spectral data (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: phanson@ku.edu.
ORCID
Oliver Reiser: 0000-0003-1430-573X
Robert N. Grass: 0000-0001-6968-0823
Paul R. Hanson: 0000-0001-5356-0069
A.; Samarakoon, T. B.; Faisal, S.; Kurtz, R. D.; Long, T. R.; Schatz, A.;
̈
Notes
Flynn, D. L.; Grass, R. N.; Stark, W. J.; Reiser, O.; Hanson, P. R. Org.
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The authors declare the following competing financial
interest(s): P.R.H. is on the Scientific Advisory Board of Materia,
Inc.
ACKNOWLEDGMENTS
■
This research was made possible by the National Institute of
General Medical Sciences (NIH STTR R42GM112449), NIH
Center for Chemical Methodologies and Library Development at
the University of Kansas (P50 GM069663), and PITN-GA-
2012-290248_Magneticfun. We thank Materia, Inc., for
providing the metathesis catalyst.
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