Magnesium Ethoxide Promoted Conversion of Nitriles to Amidines and

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Magnesium Ethoxide Promoted Conversion of Nitriles to Amidines and Its Application in 5,6-Dihydroimidazobenzoxazepine Synthesis Michael E. Dalziel,* Julie A. Deichert, Diane E. Carrera,* Danial Beaudry, Chong Han, Haiming Zhang, and Remy Angelaud Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States S Supporting Information *

ABSTRACT: Magnesium ethoxide has been shown to be a mild, safe, and scalable alternative to trimethylaluminum for the direct addition of amines to aryl nitriles to access cyclic amidines. A variety of electronically diverse oxa-, thia-, and diazepine products were successfully synthesized in moderate to high yields. Further elaboration of these compounds to 5,6dihydroimidazobenzoxazepines, a privileged class of pharmacologically active heterocycles, highlights the utility of this method.

T

he amidine1,2 is a privileged chemical motif due to the ubiquity of this functional group in bioactive compounds and its role as a key intermediate in the synthesis of heterocycles.3 Amidines are found in a large number of pharmaceutical agents with applications ranging from the antipsychotic agent clozapine, calcium receptor (CaR) antagonists for the treatment of osteoporosis,4 and the DNA-RNA binding treatment for protozoan based infections diminazene5 (Figure 1). Due to their synthetic utility, many methods for the preparation of both aliphatic and aromatic amidines have been reported from nitrile, amide, thioamide,1,2 and even ynamide6 based starting materials. The most common protocol for the preparation of amidines from nitriles, the classic and modified Pinner7,8 reaction (Scheme 1, eq 1), proceeds through an imidate intermediate that is susceptible toward displacement with a nitrogen nucleophile. However, this approach suffers from slow

Scheme 1. Synthetic Strategies To Access Amidines from Nitriles

reaction rates due to the “proximity effect”2 when orthosubstituted aryl nitriles are used.9 More recently, Lewis acids have been employed to circumvent these issues by tuning the reactivity of the system, allowing for direct addition of the amine to a hindered nitrile and avoiding the imidate intermediate. The use of CuCl was shown to be effective for generating tertiary alkyl amidines; however, the scope of Received: March 13, 2018

Figure 1. Biologically active compounds containing amidines. © XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.8b00824 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Lewis Acid Mediated Intramolecular Amidine Cyclizationa,b

entry

Lewis acid (equiv)

solvent

convc (%)

yieldd (%)

1 2 3 4 5 6e 7f 8f 9f

AlMe3 (2.0) ZnCl2 (2.0) CuCl (2.0) MgCl2 (2.0) Mg(OMe)2 (2.0) Mg(OEt)2 (2.0) Mg(OEt)2 (2.0) Mg(OEt)2 (2.2) Mg(OEt)2 (2.5)

toluene EtOH EtOH EtOH MeOH toluene/MeOH 2-MeTHF/MeOH 2-MeTHF/MeOH 2-MeTHF/MeOH

100 0 8 0 90 86 85 94 90

20 0