Nucleophilic Ring Closure Research Articles

A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid.

Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for the API, which will limit the potential uptake of this treatment in lower income regions. In this work, an alternative, lower-cost synthetic strategy to a known p-phenylenediamine intermediate to sutezolid has been demonstrated. The key step in this process is the construction of the thiomorpholine ring by a nucleophilic sulfide ring closure on an activated bis(2-hydroxyethyl)-functionalized aniline, which was in turn made by reaction of 3,4-difluoronitrobenzene and diethanolamine. This sulfide treatment has the added benefit of affecting a Zinin reduction of the nitro functional group, which alleviates the need for the transition metal reduction used in previous routes. After optimization, this key reaction was able to provide the desired aniline intermediate in yields between 65 and 80% and, after a standard charcoal treatment, purity of >94%. Initial demonstrations of the full 3-step strategy were successfully conducted on scales up to 100 g with overall yields of 53-68%. This preliminary work will serve as the foundation for a broader low-cost redesign of the sutezolid synthetic process.

Microwave-assisted safe and efficient synthesis of α-ketothioesters from acetylenic sulfones and DMSO

ABSTRACT α-Ketothioesters are safely and efficiently synthesized from arylacetylenic sulfones and dimethyl sulfoxide (DMSO) in the presence of equivalent of water and catalytic amount of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) under microwave irradiation. Arylacetylenic sulfones and dimethyl sulfoxide first form arenecarbonyl sulfonyl dimethylsulfonium methylides via nucleophilic addition, ring closure, and 4e ring opening. The methylides undergo a radical process to generate α-methylthio-α-sulfonylacetophenones, which further convert to α-ketothioesters through the Pummerer oxidation. Compared to the previous methods, the current method is safer and more efficient.

Microwave-enhanced, stereospecific ring-closure of medium-ring cyanamide ethers to yohimbine

A highly efficient acid-promoted, stereospecific, transannular ring-closure of medium-ring ether compounds to the indole alkaloid yohimbine is described. Microwave-enhanced acetic acid degradation of cyanamide compounds involves loss of (R)- or (S)-ethers, followed by a stereospecific, nucleophilic ring-closure from the cyanamide to afford yohimbine in up to 74% yield in as little as one minute. This nucleophilic reactivity of the amino moiety of the cyanamide highlights an alternative reactivity profile from its traditional electrophilic properties. Additionally, this reaction pathway highlights a rare case of an SN1 pathway that proceeds with complete stereospecificity.

Synthesis of 2-Pyrrolidinones by Palladium-Catalyzed [3+2] Cycloaddition of Isocyanates

Pd/DPEphos catalyzes the [3+2] cycloaddition of various alkyl isocyanates with 2-acetoxymethyl-3-allyltrimethylsilane as a synthetic equivalent of trimethylenemethane (TMM). Taking advantage of 2-acetoxymethyl-3-allyltrimethylsilane acting both as nucleophile as well as electrophile this reaction gives a convenient access to 5-ring lactams with an exocyclic alkene moiety. The formation of the β,γ-unsaturated 2-pyrrolidinones occurs without olefin isomerization and without epimerization of the stereogenic centers. Mechanistic investigations suggest an initial N-allylation of the isocyanate followed by nucleophilic ring closure furnishing the desired 2-pyrrolidinones.

Isolation of Ruthenium–Indoline and −Indole Zwitterion Complexes: Insight into the Metal-Induced Cyclization of Aniline-Tethered Alkynes and Strategy to Lower the Activation Barrier of Metal−Vinylidene Formation

Isolation of the first examples of Ru(II)–indoline and −indole zwitterion complexes derived from reactions between [Ru([14]aneS4)Cl2] ([14]aneS4 = 1,4,8,11-tetrathiacyclotetradecane) and aniline-tethered alkynes has been achieved. Mechanistic studies regarding the selectivity between a “vinylidene-involving pathway” and a “direct nucleophilic ring closure mechanism” for these reactions have been conducted experimentally and theoretically. Employment of 1,2-silyl shift as a strategy to lower the activation barrier for the formation of Ru–vinylidene species has also been proved to be successful.

ChemInform Abstract: Asymmetric Cyclopropanation Reactions

AbstractReview: [198 refs.

Asymmetric Cyclopropanation Reactions

Both physical and organic chemists are interested in the cyclopropane ring, the former owing to the strain inherent to the small ring structure, the latter prompted by the importance of this ring in naturally occurring compounds. In recent years, the increasing interest in enantioselective organic synthesis has led to a large number of papers on the preparation of cyclopropane compounds in enantioenriched form. The last review on asymmetric cyclopropanation reactions is dated 2008, thus an update is necessary with critical comparison of preparations using chiral auxiliaries, chiral metal complexes and organocatalysts. The aim of this review is an overview of these topics from 2008 to mid-2013. 1 Introduction 2 Simmons–Smith Cyclopropanation 2.1 Chiral Auxiliaries 2.2 Chiral Catalysts 3 Transition-Metal-Catalyzed Decomposition of Diazoalkanes 3.1 Cobalt 3.2 Copper 3.3 Rhodium 3.4 Ruthenium 3.5 Other Metals 4 Michael-Initiated Ring Closure (MIRC) 4.1 Chiral Auxiliaries 4.2 Organocatalysis 4.3 Metal Catalysis 5 Miscellaneous 5.1 C–H Insertion 5.2 Nucleophilic Ring Closure 5.3 Cycloisomerization of 1,<i>n</i>-Enynes 5.4 Other Methods 6 Conclusion 7 Abbreviations

Rack-mounted chemistry IV: the thermal rearrangement of 7-oxabenzonorbornadienes into benzo[b]oxepines on and off the polycyclic rack

Abstract The thermal rearrangement of [3]polynorbornane bis - imide rack-mounted 7-oxabenzonorbornadienes has been conducted using flash vacuum pyrolysis (FVP) at 520 °C and is compared with the FVP of similar 7-oxabenzonorbornadienes off the rack. The isomerisation is considered to involve (a) C–O bond cleavage to a vinylogous 1,5-dipole, (b) formation of a benzene epoxide by nucleophilic ring-closure and (c) valence-isomerisation of the benzene epoxide to the oxepine. Competing fragmentation to the isobenzofuran by ejection of acetylene and other rearrangements become prominent pathways off the rack, whereas isomerisation to the oxepine is highly favored on the rack.

ChemInform Abstract: Rapid Synthesis of Substituted Pyrrolines and Pyrrolidines by Nucleophilic Ring Closure at Activated Oximes.

AbstractSubstituted pyrrolidines are synthesized by ring closure initiated by direct nucleophilic attack of stabilized enolates at the nitrogen of oximes (I), (IV), (VII) and (IX) activated with an appropriate leaving group.

ChemInform Abstract: New Synthesis of Multi‐Substituted α‐Chlorocyclobutanones from 1‐Chloro‐3‐cyanoalkyl p‐Tolyl Sulfoxides by 4‐exo‐dig Nucleophilic Ring Closure of Magnesium Carbenoids to Nitrile Group as the Key Reaction.

1-Chloro-3-cyanoalkyl p-tolyl sulfoxides were easily prepared from 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from carbonyl compounds and chloromethyl p-tolyl sulfoxide, with lithium α-cyano carbanion of acetonitrile derivatives in good yields. Treatment of these sulfoxides with i-PrMgCl resulted in the formation of multi-substituted α-chlorocyclobutanones in good to high yields via the 4-Exo-Dig nucleophilic ring closure of the generated magnesium carbenoid intermediates to the nitrile group. This procedure provides a new and good way for the synthesis of multi-substituted α-chlorocyclobutanones from carbonyl compounds and substituted acetonitriles with formation of three carbon–carbon bonds in relatively short steps.

Approach to the Synthesis of Indoline Derivatives from Diaryliodonium Salts

An effective method of constructing the indoline moiety via intramolecular nucleophilic ring closure of a diaryliodonium salt is described. Diacetoxyiodoarene compounds (1a-1e) were converted into intermediate Koser's reagent and coupled with arylstannanes (7-10) to form diaryliodonium salts (11a-14e). Indoline compounds with different N-protecting groups, 15, 16, 17, and 18, were synthesized in higher yields by treating salts (11a-14e) with Cs(2)CO(3) and TEMPO. Regardless of the electronic environment of five para-substituted iodoarenes and the natures of four N-protected arylstannane groups, the conversion proceeded well to afford corresponding indolines in yields of 72-84 and 70-84%, respectively.

New synthesis of multi-substituted α-chlorocyclobutanones from 1-chloro-3-cyanoalkyl p-tolyl sulfoxides by 4-Exo-Dig nucleophilic ring closure of magnesium carbenoids to nitrile group as the key reaction

1-Chloro-3-cyanoalkyl p-tolyl sulfoxides were easily prepared from 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from carbonyl compounds and chloromethyl p-tolyl sulfoxide, with lithium α-cyano carbanion of acetonitrile derivatives in good yields. Treatment of these sulfoxides with i-PrMgCl resulted in the formation of multi-substituted α-chlorocyclobutanones in good to high yields via the 4-Exo-Dig nucleophilic ring closure of the generated magnesium carbenoid intermediates to the nitrile group. This procedure provides a new and good way for the synthesis of multi-substituted α-chlorocyclobutanones from carbonyl compounds and substituted acetonitriles with formation of three carbon–carbon bonds in relatively short steps.

Rapid synthesis of substituted pyrrolines and pyrrolidines by nucleophilic ring closure at activated oximes

Substituted pyrrolines are available by ring closure initiated by direct nucleophilic attack of stabilized enolates at the nitrogen of oximes activated with a leaving group, in a process which effectively out-competes the more usual Beckmann rearrangement. Subsequent reduction provides diastereoselective access to the corresponding pyrrolidines. This provides a rapid route to saturated heterocyclic systems from readily available precursors.

ChemInform Abstract: Synthesis of Substituted Acetylenic Epoxides Followed by Indium‐Catalyzed Rearrangement to 2,3,5‐Trisubstituted Furans.

Syntheses of various aromatic and aliphatic 2,3,5-trisubstituted furans from acetylenic epoxides are described. These epoxides are directly prepared by nucleophilic ring closure of propargylic alkoxides generated by lithium acetylide addition to α-haloketones.

Synthesis of Substituted Acetylenic Epoxides Followed by Indium-Catalyzed Rearrangement to 2,3,5-Trisubstituted Furans

Syntheses of various aromatic and aliphatic 2,3,5-trisubstituted furans from acetylenic epoxides are described. These epoxides are directly prepared by nucleophilic ring closure of propargylic alkoxides generated by lithium acetylide addition to α-haloketones.

ChemInform Abstract: Nucleophilic Ring Closure and Opening of Aminoiodohydrins.

Abstract Enantiopure aminoiodohydrins obtained from α-aminoaldehydes and Sm/CH 2 I 2 have been transformed into regioisomeric aminoiodohydrins, aminoepoxides, azetidines or 1,3-oxazolidines. The key step in these transformations is a nucleophilic opening–closing process.

Critical importance of leaving group ‘softness’ in nucleophilic ring closure reactions of ambident anions to 1,2-diazetidines

Highly strained, four-membered 1,2-diazetidine rings are produced in good yields (50–98%) in nucleophilic ring closure reactions provided ‘soft’ leaving groups such as iodide are used, a finding that can be rationalised in terms of the Hard Soft Acids and Bases principle.

Enantioselective Total Synthesis of (−)‐Candelalides A, B and C: Potential Kv1.3 Blocking Immunosuppressive Agents

Novel Kv1.3 blocking immunosuppressants, (-)-candelalides A, B and C, were efficiently synthesized for the first time in a convergent and unified manner starting from (+)-5-methyl-Wieland-Miescher ketone. The synthetic method involved the following key steps: i) a strategic [2,3]-Wittig rearrangement of a stannylmethyl ether to install the stereogenic center at C9 and the exo-methylene function at C8 present in the decalin portion; ii) a straightforward coupling of a trans-decalin portion (BC ring) and a gamma-pyrone moiety through the C16-C3' bond to assemble the requisite carbon framework; and iii) a construction of a characteristic di or tetrahydropyran ring (A ring) by internal nucleophilic ring closure of a hydroxy aldehyde or a hydroxy epoxide. The present total synthesis has fully established the absolute configuration of these natural products.

Atom efficient cyclotrimerization of dimethylcyanamide catalyzed by aluminium amide: a combined experimental and theoretical investigation

A novel method for the cyclotrimerization of dimethylcyanamide to form hexamethylmelamine has been developed using an aluminium amide catalyst; detailed DFT modelling of the catalytic cycle supports a triple insertion, nucleophilic ring closure, deinsertion mechanism.

Palladium-Catalyzed Synthesis of Spiro[2.4]heptanes: Ligand-Dependent Position Control in the Nucleophilic Attack to a π-Allylpalladium Intermediate

A palladium-catalyzed intermolecular cycloaddition of gamma-methylidene-delta-valerolactones with electron-deficient olefins has been developed for the synthesis of spiro[2.4]heptanes with high selectivity through a nucleophilic ring closure to the central carbon of a pi-allylpalladium intermediate. It was found that the course of the reaction is dependent on the ligand employed, and selective [4 + 2] cycloadditions can also be achieved by the use of a bulky monophosphine ligand.