Application of Silica-Supported Alkylating Reagents in a One-Pot, Sequential Protocol to Diverse Benzoxathiazepine 1,1-Dioxides

Article abstract of DOI:10.1021/acscombsci.6b00041

Applications of silica-ROMP reagents in a one-pot, sequential protocol have been developed for the synthesis of a variety of diverse benzoxathiazepine 1,1-dioxides. This protocol includes sulfonylation, intramolecular S_NAr, alkylation with silica-supported oligomeric benzyl (Si-OBP_n) and triazole (Si-OTP_n) phosphates, and intermolecular S_NAr addition with a number of secondary amines in one-pot to afford a variety of unique benzoxathiazepine 1,1-dioxides sultams in good to excellent yields.

Full text of DOI:10.1021/acscombsci.6b00041

Letter
pubs.acs.org/acscombsci
Application of Silica-Supported Alkylating Reagents in a One-Pot,
Sequential Protocol to Diverse Benzoxathiazepine 1,1-Dioxides
Saqib Faisal, Pradip K. Maity, Qin Zang, Thiwanka B. Samarakoon, Robert L. Sourk, 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
S
* Supporting Information
ABSTRACT: Applications of silica-ROMP reagents in a one-pot, sequential protocol have been developed for the synthesis of a
variety of diverse benzoxathiazepine 1,1-dioxides. This protocol includes sulfonylation, intramolecular SNAr, alkylation with silica-
supported oligomeric benzyl (Si-OBPn) and triazole (Si-OTPn) phosphates, and intermolecular SNAr addition with a number of
secondary amines in one-pot to afford a variety of unique benzoxathiazepine 1,1-dioxides sultams in good to excellent yields.
KEYWORDS: one-pot, Si-immobilized reagents, alkylation, SNAr, benzoxathiazepine 1,1-dioxides
ulticomponent reactions in one-pot processes are
supported reagents and scavengers is finding a suitable
Mefficient pathways to synthesize complex heterocyclic technology to install functional groups on the surface of silica.
scaffolds from simple building blocks.1 One-pot strategies
The use of ring-opening metathesis polymerization (ROMP) to
attach functional groups on Nb-tagged silica core, has proven to
enable the formation of multiple bonds and stereocenters in
one synthetic step, as well as reducing purification resources,
time and waste. This process minimizes the need of workup
and procedures for chromatographic separations of interme-
diary reactions. Among several literature reports, elegant
efficient efforts by Hayashi2 have demonstrated the power of
consecutive one-pot, sequential procedures to complete
multistep syntheses.
The utilization of immobilized reagents in one-pot protocols
can further integrate synthesis, diversification, and purification
into one parallel process to rapidly expand efforts in early stage
drug discovery.3 A number of technologies for immobilization
of reagents and catalysts have been developed, including those
based on polystyrene resins,4 Janda-gels and microporous
resins,5 soluble polyethylene glycol (PEG) polymers,6 mono-
lith,7 fluorous-tagging,8 and silica.9 In particular, silica-
supported reagents and scavengers have shown a number of
advantages that can exploited in synthesis, including (i)
elimination of the precipitation step, (ii) avoidance of
polymeric swelling, and (iii) providing a free-flowing solid
support for ease of handling. These features have inspired the
recent development of a number of silica-supported reagents
and catalysts.10 A critical part of developing successful silica-
be an efficient method for high-load functionality on cost-
effective and environmentally benign silica particles.11
A
number of ROMP-derived Si-supported reagents have been
developed in our group.12 To expand the applicability of our
recently developed silica-immobilized benzyl phosphate Si-
OBPn and triazole phosphate Si-OTPn reagents,13,14 we herein
report studies aimed at the use of Si-OBPn and Si-OTPn in one-
pot, sequential protocols for the facile synthesis of diverse
benzothiaoxazepine-1,1-dioxides.
Benzothiaoxazepine-1,1-dioxides are unique scaffolds,15 that
have shown a broad range of bioactivities, including inhibition
against a variety of enzymes.16 Substituted benzothiaoxazepine-
1,1-dioxides have shown activity as antipsychotic agents,17
modulators of histamine H3-recceptor,18 glucokinase activa-
tors,19 and modulators of AMPA receptors (Figure 1).20 The
current demand is to develop step-economical methods, which
can facilitate the synthesis of these biologically inspired sultams
in a desirable fashion. In light of our recent approaches for the
Received: March 23, 2016
Revised: May 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acscombsci.6b00041
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Figure 1. Biologically active benzothiaoxazepine-1,1-dioxide-containing sultams.
Scheme 1. Synthesis of Si-Supported Oligomeric Benzyl (Si-OBPn) and Triazole (Si-OTPn) Phosphates
Scheme 2. Synthesis of Benzothiaoxazepine-1,1-dioxides in a One-Pot, Sequential Protocol
synthesis of scaffolds containing benzothiaoxazepine-1,1-
difluoroarylsulfonyl chloride (4) as an attractive building block
for the generation of these scaffolds.
dioxides,21 herein, we further elaborate the importance of 2,4-
B
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Table 1. One-Pot Synthesis of Benzothiaoxazepine-1,1-dioxides Utilizing Various Si-OBP Reagents
The titled silica phosphate reagents, Si-OBPn and Si-OTPn,
were synthesized from norbornenyl-functionalized silica (Si−
Nb) 1 and Nb-tagged phosphate monomers 2a−2e using a
similar protocol reported in our previous work.12 Surface-
initiated polymerization of these monomers onto the surface of
silica was achieved using the Grubbs second-generation catalyst
(G-II) in toluene-CH2Cl2.22 Following the reported procedure,
the desired Si-ROMP benzylating Si-OBPn 3a−3c (n ≈ 50) and
triazolating Si-OTPn 3d−3e (n ≈ 50) reagents were furnished
as free-flowing solids on gram-scale.
With Si-OBPn reagents 3a−3c and (triazolyl)methylating
reagents Si-OTPn 3d−3e in hand, we directed our attention for
their utilization in the titled one-pot sequential process. Thus,
we planned to achieve sulfonylation, intramolecular nucleo-
philic aromatic substitution (IM-SNAr), alkylation (Si-OBPn
and Si-OTPn) and intermolecular SNAr reactions using the
same solvent (DMF) in an overall one-pot protocol. The
synthesis started with commercially available 2,4-difluoroben-
zenesulfonyl chloride (4), and a simple chiral amino alcohol 5
to achieve sulfonylation at room temperature using Et3N in
DMF. The resulting sulfonamide 6 next underwent facile IM-
SNAr cyclization using microwave conditions at 140 °C in the
same pot to furnish benzothiaoxazepine-1,1-dioxide 7 (Scheme
2). Further diversification of 7 was achieved through use of Si-
OBPn and Si-OTPn for benzylation and (triazolyl)methylation,
respectively. Successful benzylations using Si-OBPn 3a of the
corresponding cyclic sulfonamides were achieved in the same
pot by heating the reaction mixture to 80 °C for 10−12 h. The
final intermolecular SNAr reaction (150 °C under microwave
irradiation) with a variety of cyclic five- or six-membered
secondary/aromatic amines afforded diverse benzofused
sulfonamides 10a−10e in the same pot (Table 1, entry 1−5).
In the next stage, different variants of silica-immobilized
benzylating reagents 3b−3c were employed in similar one-pot
procedures, and the desired N-benyzlated benzoxathiazepine
1,1-dioxides 10f−10j were achieved after the final intermo-
lecular SNAr reactions (DMF, 150 °C under microwave
irradiation), again using a variety of cyclic five-membered
secondary/aromatic amines (Table 1, entry 6−10).
We next studied diversifications via sulfonamide N-
(triazolyl)methylation utilizing Si−OTP reagents 3d−3e as
summarized in Table 2. These efforts were driven by the
biological importance of 1,2,3-triazole-containing scaffolds,23 as
well as their effective mimicry of trans-amide bonds due to
similarity in size, planarity, dipole and H-bonding capabilities.24
To consider the biological importance of benzoxathiazepine
1,1-dioxides, we planned to design a small library of diverse N-
(triazolyl)methylated benzoxathiazepine 1,1-dioxides deriva-
C
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Table 2. One-Pot Synthesis of Benzofused Sultams Utilizing Variable Si-OTP Reagents
tives using a similar one-pot protocol as described above.25
ASSOCIATED CONTENT
■
Subsequent intermolecular SNAr reaction in the same pot using
various cyclic amines afforded the desired N-(triazolyl)-
methylated benzoxathiazepine 1,1-dioxides 11a−11e in high
yield, 70−92% over four sequential steps, representing average
yields of 91.5−98% per reaction (av/rxn) (Table 2).
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.6b00041.
Experimental details and NMR spectral data for new
compounds (PDF)
The one-pot, sequential protocol employing Si-alkylating
reagents 3a−3e highlights the importance of our recently
developed silica-immobilized reagents, which allow for facile
direct N-benzylation or N-(triazolyl)methylation. Overall,
grafting of Nb-tagged silica particles with functionalized Nb-
tagged phosphate monomers using ROM polymerization
efficiently yields high-load, hybrid Si-immobilized oligomeric
benzyl (Si-OBPn) and triazole phosphates (Si-OTPn). We have
now demonstrated applications of these Si-ROMP reagents in
the diversification of core scaffolds to achieve the synthesis of a
variety of unique benzoxathiazepine 1,1-dioxides in a one-pot,
sequential protocol. Efforts to expand the scope of these
reagents to various drug-related molecules, and improvement in
synthesis and scale-up are continued for application in diversity-
oriented synthesis.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: phanson@ku.edu.
Notes
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 R42GM097896) and
NIH Center for Chemical Methodologies and Library
Development at the University of Kansas (P50 GM069663).
We thank Materia, Inc., for providing the metathesis catalyst.
D
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(25) It should be noted that the typical manner of installing a triazole
group requires a two-step protocol, such as the alkylation of propargyl
bromide (a severe lachrymator), followed by a click reaction with a
corresponding azide. The developed Si-alkylating reagent avoids the
use of these toxic reagents and provides a more modular way of
installing a triazole group onto the complex-substrates in a one-pot
protocol. Moreover, the developed Si-alkylating reagents are free
flowing solids, bench stable and can be stored for longer time at room
temperature and successfully utilized for alkylation reactions in a one-
pot protocol. In addition, once made they can be shipped under safer
conditions as compared to the corresponding benzyl bromides.
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DOI: 10.1021/acscombsci.6b00041
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