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. Author manuscript; available in PMC: 2012 Jun 14.
Published in final edited form as: Chem Commun (Camb). 2011 Oct 26;47(46):12524–12526. doi: 10.1039/c1cc14807a

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

Pradip K Maity a, Quirin M Kainz a,b, Saqib Faisal a,c, Alan Rolfe a, Thiwanka B Samarakoon a, Fatima Z Basha c, Oliver Reiser b,✉, Paul R Hanson a,✉
PMCID: PMC3271939  NIHMSID: NIHMS340005  PMID: 22027744

Abstract

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.

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 versatile synthetic methods which are pivotal to accessing small molecules for drug discovery.2 The Mitsunobu reaction is a mild and effective method for the conversion of alcohols into a variety of functionality through the formation of C–C, C–O, C–N and C–S bonds, including the ability to invert the stereochemistry of stereogenic carbinol-bearing centers. A formal “redox” reaction, the Mitsunobu reaction is promoted under relatively mild conditions by a combination of a tertiary phosphine, usually triphenylphosphine (PPh3) and an azodicarboxylate, 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 prodcut 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 separation of the desired product from unwanted Mitsunobu by-products.5

Methods developed within our group for facile purification-free Mitsunobu protocols have focused on the application of a polymer-on-polymer (PoP) Mitsunobu protocol, employing ROMP-derived oligomeric triphenylphosphine (OTPP) and oligomeric benzylethyl azodicarboxylate (OBEAD) reagents,6 as well as a monomer-on-monomer (MoM)Mitsunobu protocol, employing norborneneyl-tagged (Nb-tagged) PPh3 and BEAD reagents.7 In the latter case, facile sequestration of the excess and spent reagents was achieved via ring-opening metathesis (ROM) polymerization initiated by any one of three methods utilizing Grubbs catalyst [(IMesH2)(PCy3)(Cl)2Ru=CHPh 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

Scheme 1.

Scheme 1

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Catalyst-armed Silica- and Co/C magnetic nanoparticles.

The intramolecular Mitsunobu reaction has been widely utilized as a cyclization protocol for the synthesis of heterocyclic 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).

Scheme 2.

Scheme 2

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Synthesis of benzofused thiadiazepine-dioxides via a intramolecular MoM Mitsunobu c/yclization.

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

Scheme 3.

Scheme 3

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Synthesis of hydroxy-benzylsulfonamides 2a–b via microwave- assisted SNAr.

With sulfonamides 2a–b in hand, the application of MoM cyclization reaction was investigated utilizing Nb-TPP and Nb-BEAD (Table 1). Initially, purification was achieved by phase switching of all Nb-tagged species in solution (monomeric reagents and spent reagents) by addition of free metathesis catalyst [(IMesH2)(PCy3)(Cl)2Ru=CHPh, 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 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.

Table 1.

Intramolecular MoM Mitsunobu-Sequestration

graphic file with name nihms340005u1.jpg
Entry Sequestration Comp. Method Yield (%) Crude Purity (%)a
1b Cat-B 3a A 85 >95%
2b Cat-B 3b A 88 >95%
3c Co/C Nb-tagged 3a B 87 >95%
4c Co/C Nb-tagged 3b B 81 >95%
5d Si Nb-Tagged 3a C 89 >95%
6d Si Nb-Tagged 3b C 84 >95%
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a

Purity determined by 1HNMR.

b

Isolated via precipitation in Et2O.

c

Isolated via magnetic decantation and filtration through Silica SPE.

d

Isolated via filtration through Celite® SPE.

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 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 Celite® 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 Silica particles [Method C].

Scheme 4.

Scheme 4

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Synthesis of benzofused thiadiazepine-dioxides. (3c–3f: Method A; 3g–3j: Method B; 3k–3n: Method C).

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 utilizing catalyst-armed surfaces generated from either Nb-tagged Si-particles or Nb-tagged Co/C magnetic nano-particles.

Supplementary Material

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Acknowledgments

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.

Footnotes

†

Electronic supplementary information (ESI) available. See DOI: 10.1039/c1cc14807a

Contributor Information

Oliver Reiser, Email: Oliver.Reiser@chemie.uni-regensburg.de.

Paul R. Hanson, Email: phanson@ku.edu.

Notes and references

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