Electrogenerated hypervalent iodine compounds as mediators in organic synthesis

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Recent progress in the electrochemistry of hypervalent iodine compounds

Hypervalent iodine compounds constitute a well-established and broadly used reagent family in organic synthesis. As they are usually either used in stoichiometric quantities or generated in situ from an aryl iodide precursor using a terminal oxidant, the associated waste and separation problems pose major challenges en route to sustainable and scalable processes. In this regard, the use of inexpensive electric current as a traceless oxidant for the in-situ generation of hypervalent iodine has emerged as a promising alternative. This review summarizes the advances over the past 2 years, including improved electrolysis protocols, new synthetic applications, and concepts for enhancing the sustainability of the reactions.     

Oxidative rearrangement of alkenes using in situ generated hypervalent iodine(III)

A novel protocol for the oxidative rearrangement of alkenes using in situ generated hypervalent iodine(III) was developed. This approach uses inexpensive, readily available, and stable chemicals (PhI, mCPBA, and TsOH) giving rearrangement products in yields comparable to those obtained using the more expensive commercially available [hydroxy(tosyloxy)iodo]benzene [HTIB or Koser’s reagent]. Additionally, an alternative protocol for the synthesis of 1-methyl-2-tetralone through the one-step epoxidation/rearrangement of 4-methyl-1,2-dihydronaphthalene using mCPBA and TsOH was developed.     

A novel and direct synthesis of chroman derivatives using a hypervalent iodine(III) reagent

The direct aromatic carbon-oxygen bond-formation reaction was described and the novel and simple synthetic method for chroman derivatives involving aromatic cation radical intermediates was developed using the hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA).     

Stereoselective total synthesis of (±)-α-vetispirene, (±)-hinesol, and (±)-β-vetivone based on a Claisen rearrangement

The stereoselective total syntheses of (±)-α-vetispirene, (±)-hinesol, and (±)-β-vetivone were accomplished based on a Claisen rearrangement in an alkenyl bicyclic dihydropyran system. The most striking feature of this approach is that the Claisen rearrangement of bicyclic dihydropyran proceeds stereoselectively to provide a multi-functionalized spiro[4.5]decane, which is an efficient precursor for the synthesis of the vetivane sesquiterpenes.     

Hypervalent iodine(III)-mediated tandem oxidative reactions: application for the synthesis of bioactive polyspirocyclohexa-2,5-dienones

In 2002, we reported the first total syntheses of potent antimalarial natural products, the aculeatins, employing the concept of tandem oxidative reactions mediated by hypervalent iodine(III) reagent to access to polyspirocyclohexa-2,5-dienone cores in very concise manner. Efforts in this field have allowed to identify cyclohexa-2,5-dienone group as a new potent class of pharmacophoric group for treating malaria disease. This article sums up recent contributions devoted to the synthesis of complex and diverse polycyclic structures using the concept of tandem oxidative activations, with p-phenol as co-reactant. More recently, we have explored a variant of the new tandem oxidative reactions that employs a catalytic amount of 4-iodotoluene in the presence of mCPBA as the stoichiometric oxidant (Kita’s procedure).     

A study on the species present in solutions of hypervalent iodine(III) reagents by electrospray ionization mass spectrometry

Solutions of iodobenzene diacetate in CH₃CN, AcOH, MeOH/H₂O and MeOH (with or without base) were analyzed by electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS/MS). The major species in CH₃CN, AcOH and MeOH/H₂O solutions are [PhI(OAc)₂Na]⁺, [PhI(OAc)₂K]⁺, [PhI]⁺, [PhIOAc]⁺, [PhIOH]⁺, [PhIO₂Ac]⁺, [PhIO₂H]⁺ and the dimer [Ph₂I₂O₂Ac]⁺. On the other hand, MeOH solutions showed [PhIOMe]⁺ as the most abundant species. A similar result was observed adding 2, 3 or 4 equiv of KOH to MeOH solutions. However, in the presence of 10 equiv of KOH, probably occurs the formation of a polymeric material. Similarly, ESI-MS analysis of the MeOH solution of iodobenzene bis(trifluoroacetate) showed a pattern analogous to that observed for the corresponding solutions of PhI(OAc)₂. However, ESI-MS spectral data of PhI(O₂CCF₃)₂ of CH₃CN suggests that the main species in solutions is iodosylbenzene, which contrasts with the results obtained for PhI(OAc)₂.     

Oxidative rearrangements of arylalkenes with [hydroxy(tosyloxy)iodo]benzene in 95% methanol: a general, regiospecific synthesis of α-aryl ketones

The treatment of arylalkenes with [hydroxy(tosyloxy)iodo]benzene in 95% methanol affords the corresponding α-aryl ketones. This oxidative rearrangement is general for acyclic and cyclic arylalkenes and permits regioselective syntheses of isomeric α-phenyl ketone pairs.     

m-Iodosylbenzoic acid, a tagged hypervalent iodine reagent for the iodo-functionalization of alkenes and alkynes

An efficient and facile method for the iodo-functionalization of alkenes 5 and alkynes 6 by using recyclable m-iodosylbenzoic acid (2) was developed. The final products can be easily isolated without any chromatographic purification by simple treatment of the crude mixture with an anionic exchange resin. Unreacted m-iodosylbenzoic acid and reduced m-iodobenzoic acid are effectively recovered from the resin by acidification with hydrochloric acid.     

Organic reactions in water: an efficient one-pot synthesis of acyloxiranes from Baylis-Hillman adducts using hypervalent iodine

Treatment of Baylis-Hillman adducts with iodosobenzene (PhIO) in the presence of a catalytic amount of KBr in water at room temperature afforded the corresponding acyloxiranes in good yields.     

Stereoselective nitrenium ion cyclizations: asymmetric synthesis of the (+)-Kishi lactam and an intermediate for the preparation of fasicularin

The asymmetric synthesis of the (+)-Kishi lactam and an intermediate for the preparation of the marine natural product fasicularin is reported. The keystone of this divergent synthesis is the diastereoselective azaspirocyclization of an N-methoxy γ-arylbutanoamide, which is believed to proceed through the intermediacy of an N-acylnitrenium ion.     

Facile and efficient synthesis of lactols by a domino reaction of 2,3-epoxy alcohols with a hypervalent iodine(III) reagent and its application to the synthesis of lactones and the asymmetric synthesis of (+)-tanikolide

The domino reaction of 2,3-epoxy-1-alcohol derivatives, namely tetrasubstituted 2,3-epoxy-1-alcohols and 2- or 3-alkyl trisubstituted 2,3-epoxy-1-alcohols, with PhI(OCOCF(3))(2) in the presence of H(2)O is described in detail. In this reaction, several types of lactol derivatives can be directly obtained from the 2,3-epoxy-1-alcohol derivatives in a single operation. The obtained lactols were successively converted into the corresponding lactones. This reaction is applicable to the construction of optically active lactone compounds. The asymmetric total synthesis of (+)-tanikolide, an antifungal marine natural product, has been effectively achieved by using this reaction.     

First example of the activation of polymethylhydrosiloxane with molecular iodine: a facile synthesis of 3,6-dihydropyran derivatives

Glycals react rapidly with polymethylhydrosiloxane (PMHS) in the presence of a catalytic amount of molecular iodine under mild conditions to afford the corresponding 3,6-dihydropyran derivatives in excellent yields. Et₃SiH/I₂ was also found to be effective for this conversion.     

Oxidative C-H functionalization: a novel strategy for the acetoxylation/alkoxylation of arenes tethered to 3,4-dihydroisoquinolines

1-Aryl-3,4-dihydroisoquinolines undergo smooth acetoxylation/alkoxylation in the presence of 5 mol % Pd(OAc)₂ and a stoichiometric amount of PhI(OAc)₂ by means of C-H activation to produce the corresponding acetoxy- and alkoxy-1-aryl-3,4-dihydroisoquinoline derivatives respectively in good yields with high regioselectivity. It is a first example on oxidative functionalization of arenes tethered to dihydroisoquinoline moiety via the C-H activation.     

A highly stereoselective route to medium-ring-sized trans-alkenolides via oxidative fragmentation of bicyclic oxycyclopropane precursors: application to the synthesis of (+)-recifeiolide

A new approach to the synthesis of medium-ring-sized trans-alkenolides, based on the oxidative fragmentation of a three-carbon ring in hydroxyalkyl substituted bicyclo[n.1.0]alkan-1-ols readily available from 2-alkylidenecycloalkanones, is described. This methodology was applied to the six-step transformation of cyclooctanone to the natural 12-membered trans-alkenolide antibiotic (+)-recifeiolide.     

An innovative strategy for the synthesis of a new series of potent aminopeptidase (APN or CD13) inhibitors derived from the oxepin-4-one family

Derivatives from the aminobenzosuberone family have been recently synthesized and recognized as highly selective inhibitors of aminopeptidase N (APN)/CD13 (EC 3.4.11.2), an important target for cell migration processes involved in particular in tumor invasion. We present here a much more straightforward synthesis of analogues belonging to a novel isosteric oxo series which also possesses excellent inhibitory potential against APN. Their synthesis, as reported here, relied on an interesting iodine(III)-mediated rearrangement originally described by Koser and Justik as the key step. This represents the second application of this rearrangement in medicinal chemistry.     

Reaction of α-halo ketone with 2-aminothiol: a new synthesis of thiazolidines with the oxo group migrated to the original position occupied by halogen atom

The reaction of 2-bromo-3-oxo steroids with 2-aminoethanethiol led to the stereoselective formation of spiro[steroid-3,2′-thiazolidin]-2-ones as the major product. With both cyclic and acyclic α-halo alkanones, the reaction gave the thiazolidines with the oxo group migrated to the original position occupied by the halogen atom. In addition, it was found that the use of microwaves affords improvement of yields and shortening the reaction time in comparison with usual conditions.