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Synlett 2010(8): 1143-1169  
DOI: 10.1055/s-0029-1219820
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© Georg Thieme Verlag Stuttgart ˙ New York

Phosphonium- and Benzotriazolyloxy-Mediated Bond-Forming Reactions and Their Synthetic Applications

Tarek S. Mansoura, Sujata Bardhana, Zhao-Kui Wan*b
a Department of Chemistry, PharmaTherapeutics, Pfizer Inc., 401 Middletown Road, Pearl River, NY 10965, USA
b Department of Chemistry, PharmaTherapeutics, Pfizer Inc., 200 Cambridge Park Drive, Cambridge, MA 02140, USA
Fax: +1(617)6655682; e-Mail: Zhao-Kui.Wan@pfizer.com;
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Publication History

Received 23 October 2009
Publication Date:
15 April 2010 (online)

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Abstract

Phosphonium and benzotriazolyloxy (and related) intermediates are easily prepared by the reactions of cyclic amides and ureas with (1H-benzotriazol-1-yloxy)triaminophosphonium hexafluorophosphate related reagents. The former intermediates could also be made available using analogous phosphonium reagents prepared in situ or from commercial sources. These intermediates efficiently lead to carbon-nitrogen, carbon-oxygen, carbon-sulfur, and carbon-carbon bond formations through nucleophilic aromatic substitution reactions with various nucleophiles. A new ­reaction involving the generation of phenols in situ from arylboronic acids and oxygen under palladium(0) catalysis or with boronic acids and hydrogen peroxide is reviewed.

1 Introduction

2 Phosphonium-Mediated Nucleophilic Aromatic Substitution Reactions of Heterocyclic Systems

2.1 Phosphonium-Mediated Carbon-Nitrogen Bond Forming Reactions via Modified Appel Conditions

2.2 Phosphonium-Mediated Carbon-Nitrogen Bond Forming Reactions via Commercially Available Phosphonium Reagents

2.2.1 (1H-Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium Hexafluorophosphate as an Activating Agent

2.2.2 (1H-Benzotriazol-1-yloxy)tripyrrolidinylphosphonium Hexafluorophosphate and Bromotripyrrolidinylphosphonium Hexafluorophosphate as Activating Agents

2.2.3 Solvent and Base Effects

2.3 Reactivity of Various Phosphonium Reagents

2.4 Phosphonium-Mediated Carbon-Oxygen, Carbon-Sulfur, and Carbon-Carbon Bond Forming Reactions

3 Benzotriazolyloxy-Mediated and Related Bond-Forming Reactions of Heterocyclic Systems

4 Phosphonium-Mediated Reaction Mechanisms

4.1 Stepwise Pathways via Phosphonium and 1H-Benzotriazol-1-ol (or Pyridotriazol-1-ol) Adducts

4.2 1H-Benzotriazol-1-ol (or Pyridotriazol-1-ol) Adduct Independent Pathway

5 Palladium-Catalyzed Heteroaryl Ether Formation from Benzotriazolyloxy- or Pyridotriazolyloxy-Substituted Heterocycles with Arylboronic Acids

6 Unusual 1H-Benzotriazol-1-ol Adduct Rearrangement

7 A Tentative Protection and Amination Strategy Involving a 1H-Benzotriazol-1-ol Adduct

8 Conclusion and Outlook

Key words

phosphonium - benzotriazoles - nucleophilic aromatic substitutions - aryl ethers - aminations

20

Lee, J.; Wan, Z.-K.; Wilson, D.; Chenail, E. unpublished results.

48

These reactions were performed under dilute conditions (0.02 M) to avoid problems with product or substrate solubility.

49

Trace amounts of N 6-dimethylamino-2′,3′,5′-tri-O-acetyladenosine were occasionally observed, probably resulting from decomposition of DMF.

59

Wacharasinhdu, S.; Wan, Z.-K.; Mansour, T. S. unpublished results.

70

While the toxicity profile of hexamethylphosphoramide (HMPA) is well established, that for tris(N,N-tetra-methylene)phosphoric acid triamide (TTPT) has not been reported to the best of our knowledge. Because of the close structural relationship of these compounds, experienced medicinal chemists could easily assume similar toxic effects until TTPT is tested or clear SARs have been established. Therefore, the same precautions should be taken when handling these compounds! One of the shared health concerns is that both liquid chemicals might cause respiratory problems, despite the fact that both liquids have relatively high boiling points (HMPA: 230-232 ˚C at 740 mmHg; TTPT: 140-142 ˚C at 0.1 mmHg) and reasonable flash points (HMPA: 144 ˚C, closed cup; TTPT: 112.8 ˚C, closed cup. See Aldrich material safety data sheets for HMPA (product number 52730) and TTPT (product number 93404).