A new access to substituted tetraethyl N-Boc 2-aminoethylidene-1,1-bisphosphonates and phosphonyl-substituted aza-Morita–Baylis–Hillman-type adducts

doi:10.1016/j.tet.2007.11.072

Tetrahedron

Volume 64, Issue 7, 11 February 2008, Pages 1233-1241

This paper is dedicated to Professor Andrzej Zwierzak on the occasion of his 75th birthday

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Abstract

A general one-pot synthesis of substituted 2-aminoethylidene-1,1-bisphosphonates has been developed. The protocol involves base-induced addition of sodium tetraethyl methylenebisphosphonate to N-Boc imines generated in situ from N-Boc-α-amidoalkyl-p-tolylsulfones by the action of sodium hydride. The direct and efficient conversion of the title compounds into aza-Morita–Baylis–Hillman-type adducts has been also elaborated.

Graphical abstract

Introduction

Geminal bisphosphonates are hydrolytically stable analogs of naturally occurring inorganic pyrophosphates and constitute an important class of biologically active compounds. A number of these compounds have found application in treatment of bone diseases such as Paget's disease, myeloma, bone metastases, and osteoporosis1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g) (Fig. 1). Recently, bisphosphonates have also been used as antiprotozoan1(f), 2, 2(a), 2(b), 2(c) agents and are found to stimulate human γδ T cells.3, 3(a), 3(b)

Current investigations prove that mevalonate pathway enzyme, farnesyl pyrophosphate synthase (FPPS), is a principal molecular target of the bisphosphonates action.4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f) Bioactivity of bisphosphonates is determined by the structure of the side-chain as well as the nature of the functional groups connected with the methylenebisphosphonate moiety. Among numerous bisphosphonates the nitrogen-containing derivatives (N-BPs) are shown to be the most potent compounds.^1a Increasing interest in the nitrogen-containing bisphosphonates resulted in the development of different strategies for their synthesis. The standard route to 2-aminoethylidene-1,1-bisphosphonates 6 exploits the Michael-type addition of amines2(a), 2(b), 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g) or amides6, 6(a), 6(b) to tetraethyl vinylidenebisphosphonate (5) by the method elaborated by Hutchinson and Thornton^5a (Scheme 1). The addition of nitrogen-containing nucleophiles to homologs of the above-mentioned Michael acceptor has not been hitherto reported.

Some N-BPs are also available via reductive (Pd/ammonium formate) ring-opening of N-(p-toluenesulfonyl)-2,2-(diethoxyphosphoryl)aziridine,^5f or by Curtius rearrangement of 2,2-bis(diethoxyphosphoryl)cyclopropanecarboxylic acid.⁷ Another well documented methodology, leading, however, only to 2-amino-1-hydroxyethylidene-1,1-bisphosphonate derivatives, is based on the reaction of the corresponding carboxylic acid with a mixture of phosphorus trichloride and phosphorous acid,2(a), 2(b), 4(e), 8 followed by hydrolysis. Alternatively, phosphorus oxychloride/phosphorous acid2(a), 4(b) or phosphorus trichloride/phosphoric acid^1e system can be applied. In turn, N-methyl and N,N-dimethyl analogs of 2-amino-1-hydroxyethylidene-1,1-bisphosphonate can be obtained via addition of dimethyl phosphite to 2-(N-phthaloylamino)acetylphosphonic acid dimethyl ester, followed by hydrolysis with hydrobromic acid and subsequent methylation with formic acid/formaldehyde.⁹

N-Boc-α-amidoalkyl-p-tolylsulfones can be considered as a stable and easy to handle equivalents of N-Boc imines. Therefore, nucleophilic additions to N-Boc imines generated in situ from the α-amidosulfones mentioned above by base-induced elimination have been recently the subject of extensive research.10, 10(a), 10(b), 10(c), 10(d), 10(e), 10(f)

Herein we report on the synthesis of novel β-functionalized bisphosphonates using N-Boc-α-amidoalkyl-p-tolylsulfones as imine precursors for the β-aminoalkylation of tetraethyl methylenebisphosphonate. To the best of our knowledge this approach to 2-aminoethylidene-1,1-bisphosphonate derivatives has not been hitherto reported.

Section snippets

Results and discussion

We established a new and efficient route to diethyl 2-substituted [2-tert-butoxycarbonylamino-1-(diethoxyphosphoryl)-ethyl]phosphonates 11 via addition of sodium tetraethyl methylenebisphosphonate (9) to N-Boc imines 10, both generated in situ from tetraethyl methylenebisphosphonate (7) and N-Boc-α-amidoalkyl-p-tolylsulfones 8, by the action of sodium hydride (Scheme 2).

As shown in Scheme 2, the reaction was performed by adding 7 (1 equiv) to the suspension of sodium hydride (2 equiv) in THF at

Conclusions

The protocol described here provides a new and operationally simple one-pot access to substituted N-Boc 2-aminoethylidene-1,1-bisphosphonate derivatives from easily available tetraethyl methylenebisphosphonate and N-Boc-α-amidoalkyl-p-tolylsulfones. The reaction is general and structurally diverse aminobisphosphonates have been thus obtained under mild conditions and in good yields. The title products are also versatile synthetic intermediates for further transformations, including selective

General

NMR spectra were recorded on a Bruker Avance DPX 250 instrument at 250.13 MHz for ¹H NMR, 62.90 MHz for ¹³C NMR, and 101.3 MHz for ³¹P NMR in CDCl₃ solution, using either tetramethylsilane as an internal or 85% H₃PO₄ as an external standard. Positive chemical shifts are downfield from external 85% H₃PO₄ for ³¹P NMR spectra. Chemical shifts (δ) are indicated in parts per million and coupling constants (J) in hertz. For ¹³C NMR spectra, the peak assignments were made with the assistance of CH-COSY

Acknowledgements

Financial support by a grant 1T 09A 054 30 (2006–2009) from the Ministry of Education and Science is gratefully acknowledged.

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A new access to substituted tetraethyl N-Boc 2-aminoethylidene-1,1-bisphosphonates and phosphonyl-substituted aza-Morita–Baylis–Hillman-type adducts

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General

Acknowledgements

J. Organomet. Chem.

Cancer

J. Med. Chem.

Breast Cancer Res.

J. Med. Chem.

J. Biol. Chem.

Phosphorus, Sulfur Silicon

Chem. Rev.

J. Med. Chem.

Synlett

Synthesis

Synth. Commun.

J. Chem. Soc., Perkin Trans. 1

Phosphorus, Sulfur Silicon

Tetrahedron

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Bone Miner. Res.

Bioorg. Med. Chem.

J. Med. Chem.

J. Organomet. Chem.

Bioorg. Med. Chem. Lett.

J. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Organomet. Chem.

Chem. Pharm. Bull.

Phosphorus, Sulfur Silicon

Chem. Pharm. Bull.

J. Med. Chem.

Synthesis

Synthesis

Eur. J. Med. Chem. Chim. Ther.

Helv. Chim. Acta

Synth. Commun.