Intramolecular monomer-on-monomer (MoM) Mitsunobu cyclization for the synthesis of benzofused thiadiazepine-dioxides

Article abstract of DOI:10.1039/c1cc14807a

The utilization of a monomer-on-monomer (MoM) intramolecular Mitsunobu cyclization reaction employing norbornenyl-tagged (Nb-tagged) reagents is reported for the synthesis of benzofused thiadiazepine-dioxides. Facile purification was achieved via ring-ope

Full text of DOI:10.1039/c1cc14807a

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Intramolecular monomer-on-monomer (MoM) Mitsunobu cyclization for
the synthesis of benzofused thiadiazepine-dioxidesw
Pradip K. Maity,a Quirin M. Kainz,ab Saqib Faisal,ac Alan Rolfe,a
Thiwanka. B. Samarakoon,a Fatima Z. Basha,c Oliver Reiser*b and Paul R. Hanson*a
Received 4th August 2011, Accepted 21st September 2011
DOI: 10.1039/c1cc14807a
The utilization of a monomer-on-monomer (MoM) intramolecular
Mitsunobu cyclization reaction employing norbornenyl-tagged
(Nb-tagged) reagents is reported for the synthesis of benzofused
thiadiazepine-dioxides. Facile purification was achieved via ring-
opening metathesis (ROM) polymerization initiated by one of
three metathesis catalyst methods: (i) free metathesis catalyst,
(ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated
catalyst-armed Co/C magnetic nanoparticles.
Scheme 1 Catalyst-armed Silica- and Co/C magnetic nanoparticles.
The ongoing effort in the search for new pharmacophores and
small molecular probes is a key feature of modern drug
discovery. The Mitsunobu reaction and its variants1 represent
separation of the desired product from unwanted Mitsunobu
by-products.5
Methods developed within our group for facile purification-
versatile synthetic methods which are pivotal to accessing
small molecules for drug discovery.2 The Mitsunobu reaction
free Mitsunobu protocols have focused on the application of a
is a mild and effective method for the conversion of alcohols
polymer-on-polymer (PoP) Mitsunobu protocol, employing
into a variety of functionality through the formation of C–C,
ROMP-derived oligomeric triphenylphosphine (OTPP) and
C–O, C–N and C–S bonds, including the ability to invert the
stereochemistry of stereogenic carbinol-bearing centers. A formal
oligomeric benzylethyl azodicarboxylate (OBEAD) reagents,6
as well as a monomer-on-monomer (MoM) Mitsunobu protocol,
‘‘redox’’ reaction, the Mitsunobu reaction is promoted under
utilizing norborneneyl-tagged (Nb-tagged) PPh3 and BEAD
reagents.7 In the latter case, facile sequestration of the excess
usually triphenylphosphine (PPh3) and an azodicarboxylate,
relatively mild conditions by a combination of a tertiary phosphine,
and spent reagents was achieved via ring-opening metathesis
(ROM) polymerization initiated by any one of three methods
usually diethyl or diisopropyl ester (DEAD or DIAD). Such is
the scope of the Mitsunobu reaction, its application has played
a pivotal role in the synthesis of natural products,3 and
bioactive small molecules.4 Despite these powerful attributes,
the Mitsunobu reaction suffers from the need for tedious
purifications to isolate the desired product, an operational
disadvantage in both high-throughput chemistry and natural
product synthesis. Addressing this issue, several variants of the
Mitsunobu reaction have been developed which include tagged,
immobilized and water-soluble reagents that allow for facile
utilizing Grubbs catalyst [(IMesH2)(PCy3)(Cl)2RuQCHPh,
cat-B]:8 (i) free catalyst in solution, (ii) surface-initiated
catalyst-armed silica,9,10 or (iii) surface-initiated catalyst-armed
carbon-coated (Co/C) magnetic nanoparticles (Nps) (Scheme 1).7,11
The intramolecular Mitsunobu reaction has been widely
utilized as a cyclization protocol for the synthesis of hetero-
cyclic molecules.12 Building on these reports, we herein report
the synthesis of benzofused thiadiazepine-dioxides via an
intramolecular 7-membered MoM Mitsunobu cyclization
reaction, whereby facile purification was achieved utilizing
ROMP sequestration initiated by free metathesis catalyst or
catalyst-armed particle surfaces (Scheme 2).
a Department of Chemistry, University of Kansas, 1251 Wescoe Hall
Drive, Lawrence, KS, 66045 and The University of Kansas Center
for Chemical Methodologies and Library Development
(KU-CMLD), 2034 Becker Drive, Delbert M. Shankel Structural
Biology Center, Lawrence, KS 66047. E-mail: phanson@ku.edu
b Institute for Organic Chemistry, University of Regensburg,
The synthesis of benzofused thiadiazepine-dioxides 3a and 3b
was investigated utilizing the intramolecular MoM Mitsunobu
cyclization with the readily prepared Nb-tagged PPh3 (Nb-TPP)
and DEAD (Nb-BEAD) reagents.6 The corresponding hydroxy-
benzylsulfonamide starting materials 2a and 2b were rapidly
generated via a microwave-assisted SNAr protocol (Scheme 3).13
With sulfonamides 2a–b in hand, the application of MoM
cyclization reaction was investigated utilizing Nb-TPP and
Universitatsstr. 31, D-93053 Regensburg, Germany.
¨
E-mail: Oliver.Reiser@chemie.uni-regensburg.de
c H. E. J. Research Institute of Chemistry, International Center for
Chemical and Biological Science, University of Karachi, Karachi,
Pakistan
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc14807a
c
12524 Chem. Commun., 2011, 47, 12524–12526
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Table 1 Intramolecular MoM Mitsunobu-Sequestration
Entry Sequestration
Comp. Method Yield (%) Crude Purity (%)a
1b
2b
3c
4c
5d
6d
Cat-B
Cat-B
Co/C Nb-tagged 3a
Co/C Nb-tagged 3b
Si Nb-tagged
Si Nb-tagged
3a
3b
A
A
B
B
C
C
85
88
87
81
89
84
495%
495%
495%
495%
495%
495%
3a
3b
Scheme 2 Synthesis of benzofused thiadiazepine-dioxides via a intra-
molecular MoM Mitsunobu cyclization.
a
b
Purity determined by 1H NMR. Isolated via precipitation in Et2O.
Isolated via magnetic decantation and filtration through Silica SPE.
Isolated via filtration through Celites SPE.
c
d
crude purity (Table 1, entries 1–2). Purification was followed
by TLC analysis, whereby the typical Mitsunobu multispot
crude reaction mixture was reduced to a single spot after
utilizing this polymerization sequestration protocol. Despite
this success, the need for precipitation of the crude reaction
mixture to remove the polymerized reagents/spent reagents
was deemed not ideal for a high-throughput appproach.
Therefore, alternative syntheses of benzofused thiadiazepine-
dioxides 3a and 3b were investigated utilizing a catalyst-armed
surface generated from either Nb-tagged Co/C magnetic particles,
or Nb-tagged silica particles.
Scheme 3 Synthesis of hydroxy-benzylsulfonamides 2a–b via micro-
wave-assisted SNAr.
Nb-BEAD (Table 1). Initially, purification was achieved by
phase switching of all Nb-tagged species in solution (mono-
meric reagents and spent reagents) by addition of free metathesis
catalyst [(IMesH2)(PCy3)(Cl)2RuQCHPh, cat-B] (Method A) to
induce ROM polymerization. The ROM polymerization event
was followed by precipitation to produce the desired benzofused
thiadiazepine-dioxides 3a and 3b in good yield and excellent
After polymerization sequestration of excess reagents/spent
reagents on the surface of the magnetic Co/C beads [Method B],
3a and 3b could be obtained in reasonable crude purity by
collecting the nanobeads with an external magnet, decanting the
Scheme 4 Synthesis of benzofused thiadiazepine-dioxides. (3c–3f: Method A; 3g–3j: Method B; 3k–3n: Method C).
c
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Chem. Commun., 2011, 47, 12524–12526 12525

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solution and evaporating the solvent (Table 1, entries 3–4).
Noteworthy, this work-up procedure is carried out within a
few seconds, being an operational advantage to conventional
filtration techniques. However, to further improve the product
purity the solution was filtered over a silica SPE. As an
alternative method, the sequestration by Nb-tagged silica
particles [Method C] was applied to generate 3a and 3b in
comparable yields and purities with simple filtration through
Celites SPE to isolate the desired product, avoiding the need
for precipitation (Table 1, entries 5–6). Building on these results,
substrate scope was evaluated across all three purification
sequestration protocols A–C for the synthesis of 3c–3n via
MoM Mitsunobu cyclization (Scheme 4). Thus, benzofused
thiadiazepine-dioxides 3c–3f were generated with free cat-B
[Method A], compounds 3g–3j via Nb-tagged Co/C magnetic
particles [Method B] and benzofused thiadiazepine-dioxides
3k–3n utilizing Nb-tagged SiO2 particles [Method C].
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In conclusion, we have demonstrated the application of a MoM
intramolecular Mitsunobu cyclization for the synthesis of bi- and
tri-cyclic benzofused thiadiazepine-dioxides. Facile purification of
crude reaction mixtures was achieved via ROM polymerization
sequestration of excess reagents/spent reagents. This was
accomplished initially utilizing free metathesis catalyst Cat-B,
followed by precipitation. The method was further optimized
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We gratefully acknowledge the National Institute of General
Medical Science (Center in Chemical Methodologies and
Library Development at the University of Kansas, KU-CMLD,
NIH P50 GM069663 and NIH-STTR R41 GM076765) with
additional funds from the State of Kansas, the International
Doktorandenkolleg NANOCAT (Elitenetzwerk Bayern), the
Deutsche Forschungsgemeinschaft (Re 948/8-1, ‘‘GLOBUCAT’’),
the Bayer-Science and Education foundation, and the EU-Atlantis
program CPTUSA-2006-4560 for funding this research. We thank
Materia Inc. for providing metathesis catalyst.
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12526 Chem. Commun., 2011, 47, 12524–12526
This journal is The Royal Society of Chemistry 2011