Competitive Gold‐Promoted Meyer–Schuster and oxy‐Cope Rearrangements of 3‐Acyloxy‐1,5‐enynes: Selective Catalysis for the Synthesis of (+)‐(S)‐γ‐Ionone and (−)‐(2S,6 R)‐cis‐γ‐Irone

We report a simple, highly stereoselective synthesis of (+)‐(S)‐γ‐ionone and (‐)‐(2S,6R)‐cis‐γ‐irone, two characteristic and precious odorants; the latter compound is a constituent of the essential oil obtained from iris rhizomes. Of general interest in this approach are the photoisomerization of an endo trisubstituted cyclohexene double bond to an exo vinyl group and the installation of the enone side chain through a [(NHC)Au^I]‐catalyzed Meyer–Schuster‐like rearrangement. This required a careful investigation of the mechanism of the gold‐catalyzed reaction and a judicious selection of reaction conditions. In fact, it was found that the Meyer–Schuster reaction may compete with the oxy‐Cope rearrangement. Gold‐based catalytic systems can promote either reaction selectively. In the present system, the mononuclear gold complex [Au(IPr)Cl], in combination with the silver salt AgSbF₆ in 100:1 butan‐2‐one/H₂O, proved to efficiently promote the Meyer–Schuster rearrangement of propargylic benzoates, whereas the digold catalyst [{Au(IPr)}₂(μ‐OH)][BF₄] in anhydrous dichloromethane selectively promoted the oxy‐Cope rearrangement of propargylic alcohols.     

Synthesis of 3,4‐dihydro‐1(2H)‐isoquinolinonesxs

Approaches toward the preparative‐scale synthesis of target 3,4‐dihydro‐1(2H)‐isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large‐scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high‐temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)‐isoquinolinone ( 9 ). Catalytic hydrogenation of 9 provided the desired 3,4‐dihydro‐5‐methyl‐1(2H)‐isoquinolinone ( 2 ) in 65 % overall yield. Similar reduction of a commercially available 5‐hydroxy‐1(2H)‐isoquinolinone precursor 10 followed by an O ‐alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4‐dihydro‐1(2H)‐isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.     

Photochemical Reactions of Regioisomeric 2,2‐Dimethyl‐5,5‐diphenyl‐ and 5,5‐Dimethyl‐2,2‐diphenyl‐Substituted Diazo Ketones of a Tetrahydrofuran Series

The principal direction of conventional photolysis of the regioisomeric 2,2‐dimethyl‐5,5‐diphenyl‐ and 5,5‐dimethyl‐2,2‐diphenyl‐substituted 4‐diazodihydrofuran‐3(2H)‐ones 1a and 1b , respectively, is the Wolff rearrangement, while other photochemical processes, which are giving rise to the formation of C? H‐insertion, 1,2‐alkyl‐ or ‐aryl‐shifts, as well as H‐atom‐abstraction products occur to a much lower degree (Schemes 2 and 3). The ratio of similar reaction products from both regioisomers 1a and 1b is essentially independent of their structure, and a substantial effect of the relative position of the Ph and diazo group to each other on the yield of C? H‐insertion products does not occur. Based on stereochemical considerations, the Wolff rearrangement of diazodihydrofuran‐3(2H)‐ones apparently proceeds in a concerted manner, whereas the appearance in the reaction mixture of 1,2‐shift and H‐atom‐abstraction products points to the parallel generation during photolysis of singlet and triplet carbenes (Schemes 4 and 5).     

Alkylations of N4‐(4‐Pyridyl)‐3,5‐di(2‐pyridyl)‐1,2,4‐triazole: First Observation of Room‐Temperature Rearrangement of an N4‐Substituted Triazole to the N1 Analogue

Attempts to use alkylation to introduce a positive charge at the nitrogen atom of the 4‐pyridyl ring in the bis(bidentate) triazole ligand N⁴‐(4‐pyridyl)‐3,5‐di(2‐pyridyl)‐1,2,4‐triazole ( pydpt ) were made to ascertain what effect a strongly electron‐withdrawing group would have on the magnetic properties of any subsequent iron(II) complexes. Alkylation of pydpt under relatively mild conditions led in some cases to unexpected rearrangement products. Specifically, when benzyl bromide is used as the alkylating agent, and the reaction is carried out in refluxing acetonitrile, the N⁴ substituent moves to the N¹ position. However, when the same reaction is performed in dichloromethane at room temperature, the rearrangement does not occur and the desired product containing an alkylated N⁴ substituent is obtained. Heating a pure sample of N⁴‐Bzpydpt?Br to reflux in MeCN resulted in clean conversion to N1Bzpydpt.Br . This is consistent with N4‐Bzpydpt.Br being the kinetic product whereas N1Bzpydpt.Br is the thermodynamic product. When methyl iodide is used as the alkylating agent, the N⁴ to N¹ rearrangement occurs even at room temperature, and at reflux pydpt is doubly alkylated. The observation of the lowest reported temperatures for an N⁴ to N¹ rearrangement is due to this particular rearrangement involving nucleophilic aromatic substitution: a possible mechanism for this transformation is suggested.     

Formic Acid Catalyzed Rearrangement of Thevinols (=4,5‐Epoxy‐3,6‐dimethoxy‐α,17‐dimethyl‐6,14‐ethenomorphinan‐7‐methanols) and Their Vinylogous Analogues: Effects of 5β‐Methyl Substitution

In a limited number of cases, 14‐alkenylcodeinones (=14‐alkenyl‐7,8‐didehydro‐4,5‐epoxy‐3‐methoxy‐17‐methylmorphinan‐6‐ones) can be obtained by formic acid treatment of thevinols (=4,5‐epoxy‐3,6‐dimethoxy‐α,17‐dimethyl‐6,14‐ethenomorphinan‐7‐methanols), but under these conditions the equivalent 14‐alkenyl‐7,8‐dihydrocodeinones undergo further rearrangement (Scheme 1 and Table). Introduction of a 5β‐methyl group allows the 18,19‐dihydrothevinol precursors to be rearranged to 14‐alkenyl‐7,8‐dihydrocodeinones, but similar manipulation of the vinylogues of these thevinols is generally unable to prevent full rearrangement to 5,14‐bridged thebainone derivatives.     

A New Zincate‐Mediated Rearrangement Reaction of 2‐(1‐Hydroxyalkyl)‐1‐alkylcyclopropanol

A novel rearrangement of 2‐(1‐hydroxyalkyl)‐1‐alkylcyclopropanol has been found. It proceeds in the presence of a catalytic amount of organozinc ate complex to give vic‐diols. The rearrangement can be applied to various types of 2‐(1‐hydroxyalkyl)‐1‐alkylcyclopropanol, which can be easily prepared from the corresponding α,β‐epoxyketones and bis(iodozincio)methane. When bicyclo[13.1.0]pentadecane‐1,15‐diol was treated with the organozinc ate complex, the corresponding 14‐membered cyclic vic‐diol was obtained. Thus, this rearrangement is also useful for changing the ring size of cyclic substrates.     

Mass spectrometric studies of cis‐ and trans‐1a,3‐disubstituted‐1,1‐dichloro‐4‐formyl‐1a, 2,3,4‐tetrahydro‐lH‐azirino[1,2‐a]1,5]benzodiazepines

The mass spectrometric behaviour of four cis‐ and trans‐1a,3‐disubstituted‐1,1‐dichloro‐4‐formyl‐1a,2,3,4‐tetrahydro‐1H‐azirino [1, 2‐a][1,5]benzodiazepines has been studied with the aid of mass‐analysed ion kinetic energy spectrometry and exact mass measurements under electron impact ionization. All compounds show a tendency to eliminate a chlorine atom from the aziridine ring, and then eliminate a neutral propene or styrene from the diazepine ring to yield azirino [1,2‐b][1,3] benzimidazole ions. These azirino [1,2‐a][1,5]‐benzodiazepimes can also eliminate HCl, or Cl plus HCl simultaneously to undergo a ring enlargement rearrangement to yield 1,6‐benzodiazocine ions, which further lose small molecular fragments, propyne or phenylacetylene, with rearrangement to give quinoxaline ions.     

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ‐unsaturated α‐ketoesters has been realized by employing a chiral Ni^II/N,N′‐dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy‐Cope rearrangement sequence, providing a facile and rapid route to γ‐allyl‐α‐ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2‐allylboration products provided insight into the mechanism of the subsequent oxy‐Cope rearrangement reaction: substrate‐induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition‐state model is proposed as the origin of high chirality transfer during the oxy‐Cope rearrangement.     

Regioselective synthesis of pentacyclic polyheterocycles: Sequential [3,3] sigmatropic rearrangement of 4‐(4′‐aryloxybut‐2′‐ynyloxy)‐1‐phenyl‐1,8‐naphthyridin‐2(1H)‐ones

A number of 4‐aryloxymethyl‐6‐phenyl‐2H‐pyrano[3,2‐c][1,8]naphthyridin‐5(6H)‐ones ( 4a‐f ) are regioselectively synthesized in 72‐78% yield by the Claisen rearrangement of 4‐(4′‐aryloxybut‐2′‐ynyloxy)‐1‐phenyl‐1,8‐naphthyridin‐2(1H)‐ones ( 3a‐f ) in refluxing chlorobenzene for 4‐6 h. These products are then subjected to a second Claisen rearrangement catalyzed by anhydrous AlCl₃ at room temperature for 2 h to give hitherto unreported pentacyclic heterocycles ( 5a‐f ) in 78‐85% yield.     

Pinacol Rearrangement of 3,4‐Dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones: An Alternative Pathway to Viridicatin Alkaloids and Their Analogs

3‐Alkyl/aryl‐3‐hydroxyquinoline‐2,4‐diones were reduced with NaBH₄ to give cis‐3‐alkyl/aryl‐3,4‐dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones. These compounds were subjected to pinacol rearrangement by treatment with concentrated H₂SO₄, resulting in 4‐alkyl/aryl‐3‐hydroxyquinolin‐2(1H)‐ones. When a benzyl (Bn) group was present in position 3 of the starting compound, its elimination occurred during the rearrangement, and the corresponding 3‐hydroxyquinolin‐2(1H)‐one was formed. The reaction mechanisms are discussed for all transformations. All compounds were characterized by IR, ¹H‐ and ¹³C‐NMR spectroscopy, as well as mass spectrometry.     

Unexpected Thermal Transformation of Aryl 3‐Arylprop‐2‐ynoates: Formation of 3‐(Diarylmethylidene)‐2,3‐dihydrofuran‐2‐ones

A number of aryl 3‐arylprop‐2‐ynoates 3 has been prepared (cf. Table 1 and Schemes 3 – 5). In contrast to aryl prop‐2‐ynoates and but‐2‐ynoates, 3‐arylprop‐2‐ynoates 3 (with the exception of 3b ) do not undergo, by flash vacuum pyrolysis (FVP), rearrangement to corresponding cyclohepta[b]furan‐2(2H)‐ones 2 (cf. Schemes 1 and 2). On melting, however, or in solution at temperatures >150°, the compounds 3 are converted stereospecifically to the dimers 3‐[(Z)‐diarylmethylidene]‐2,3‐dihydrofuran‐2‐ones (Z)‐ 11 and the cyclic anhydrides 12 of 1,4‐diarylnaphthalene‐2,3‐dicarboxylic acids, which also represent dimers of 3 , formed by loss of one molecule of the corresponding phenol from the aryloxy part (cf. Scheme 6). Small amounts of diaryl naphthalene‐2,3‐dicarboxylates 13 accompanied the product types (Z)‐ 11 and 12 , when the thermal transformation of 3 was performed in the molten state or at high concentration of 3 in solution (cf. Tables 2 and 4). The structure of the dihydrofuranone (Z)‐ 11c was established by an X‐ray crystal‐structure analysis (Fig. 1). The structures of the dihydrofuranones 11 and the cyclic anhydrides 12 indicate that the 3‐arylprop‐2‐ynoates 3 , on heating, must undergo an aryl O→C(3) migration leading to a reactive intermediate, which attacks a second molecule of 3 , finally under formation of (Z)‐ 11 or 12 . Formation of the diaryl dicarboxylates 13 , on the other hand, are the result of the well‐known thermal Diels‐Alder‐type dimerization of 3 without rearrangement (cf. Scheme 7). At low concentration of 3 in decalin, the decrease of 3 follows up to ca. 20% conversion first‐order kinetics (cf. Table 5), which is in agreement with a monomolecular rearrangement of 3 . Moreover, heating the highly reactive 2,4,6‐trimethylphenyl 3‐(4‐nitrophenyl)prop‐2‐ynonate ( 3f ) in the presence of a twofold molar amount of the much less reactive phenyl 3‐(4‐nitrophenyl)prop‐2‐ynonate ( 3g ) led, beside (Z)‐ 11f , to the cross products (Z)‐ 11fg , and, due to subsequent thermal isomerization, (E)‐ 11fg (cf. Scheme 10), the structures of which indicated that they were composed, as expected, of rearranged 3f and structurally unaltered 3g . Finally, thermal transposition of [¹⁷O]‐ 3i with the ¹⁷O‐label at the aryloxy group gave (Z)‐ and (E)‐[¹⁷O₂]‐ 11i with the ¹⁷O‐label of rearranged [¹⁷O]‐ 3i specifically at the oxo group of the two isomeric dihydrofuranones (cf. Scheme 8), indicating a highly ordered cyclic transition state of the aryl O→C(3) migration (cf. Scheme 9).     

Catalyst‐ and solvent‐free synthesis of 2‐fluoro‐N‐(3‐methylsulfanyl‐1H‐1,2,4‐triazol‐5‐yl)benzamide through a microwave‐assisted Fries rearrangement: X‐ray structural and theoretical studies

An efficient approach for the regioselective synthesis of (5‐amino‐3‐methylsulfanyl‐1H‐1,2,4‐triazol‐1‐yl)(2‐fluorophenyl)methanone, C₁₀H₉FN₄OS, (3), from the N‐acylation of 3‐amino‐5‐methylsulfanyl‐1H‐1,2,4‐triazole, (1), with 2‐fluorobenzoyl chloride has been developed. Heterocyclic amide (3) was used successfully as a strategic intermediate for the preparation of 2‐fluoro‐N‐(3‐methylsulfanyl‐1H‐1,2,4‐triazol‐5‐yl)benzamide, C₁₀H₉FN₄OS, (4), through a microwave‐assisted Fries rearrangement under catalyst‐ and solvent‐free conditions. Theoretical studies of the prototropy process of (1) and the Fries rearrangement of (3) to provide (4), involving the formation of an intimate ion pair as the key step, were carried out by density functional theory (DFT) calculations. The crystallographic analysis of the intermolecular interactions and the energy frameworks based on the effects of the different molecular conformations of (3) and (4) are described.     

Mass spectrometric properties of N‐(2‐methoxybenzyl)‐2‐(2,4,6‐trimethoxyphenyl)ethanamine (2,4,6‐TMPEA‐NBOMe), a new representative of designer drugs of NBOMe series and derivatives thereof

Emergence of new psychoactive substances, hallucinogenic phenethylamines in particular, in illicit market is a serious threat to human health in global scale. We have detected and identified N‐(2‐methoxybenzyl)‐2‐(2,4,6‐trimethoxyphenyl)ethanamine (2,4,6‐TMPEA‐NBOMe), a new compound in NBOMe series. Identification was achieved by means of gas chromatography/mass spectrometry (GC/MS), including high‐resolution mass spectrometry with tandem experiments (GC/HRMS and GC/HRMS²), ultra‐high performance liquid chromatography/high‐resolution mass spectrometry with tandem experiments (UHPLC/HRMS and UHPLC/HRMS²), and ¹H and ¹³C nuclear magnetic resonance spectroscopy. The peculiarities of fragmentation of the compound under electron ionization (EI) and collision‐induced dissociation were studied. Despite of the empirical rule denying migration of the hydrogen atom in McLafferty rearrangement to the benzene ring with substituents in the both ortho‐positions, it easily occurs for 2,4,6‐TMPEA‐NBOMe in EI conditions. We have noticed that electron‐donating substituents, e.g. methoxy groups in the both ortho‐positions and para‐positions favor the rearrangement. For specially synthesized N‐methyl and N‐acyl derivatives McLafferty rearrangement is not observed. N‐Acyl derivatives demonstrate McLafferty rearrangement, but the charge retains at the alternative fragment involving N‐acyl carbonyl group. We have also showed that the hydrogen atoms in 2,4,6‐trimethoxybenzene ring may be easily substituted for deuterium or for strong electrophiles like trifluoroacetyl. Analytical characteristics of 2,4,6‐TMPEA‐NBOMe and of some derivatives thereof which enable their determination in various criminal seizures are given. Copyright © 2016 John Wiley & Sons, Ltd.     

Unexpected Ring Enlargement of 2‐Hydrazono‐2,3‐dihydro‐1,3‐thiazoles to 1,3,4‐Thiadiazines

The cyclization of thiosemicarbazide with α‐bromoacetophenone can result in the formation of isomeric 1,3,4‐thiadiazines and two different thiazoles. We studied the use of 4‐methyl‐ and 4‐ethylthiosemicarbazide as dinucleophilic building blocks. In this context, we observed an unprecedented rearrangement of a 2‐hydrazono‐2,3‐dihydrothiazole to a 1,3,4‐thiadiazine. While ring contractions of 1,3,4‐thiadiazines to thiazoles are quite common, ring enlargements are new. The course of the reaction depends on the substitution pattern of the substrate.     

A Stereospecific `2‐Aza‐divinylcyclopropane' Rearrangement

The stereochemical course of the thermal 2‐aza‐Cope rearrangement of the optically pure acyl azide (−)‐(1S)‐ 5 was investigated by determination of the absolute configuration of the rearrangement product (1R,8S)‐ 9 . The reaction proceeds by a sequence of stereospecific steps from 5 to an equilibrating mixture of exo‐ and endo‐isocyanates 6 and 7 . The endo‐isomer 7 undergoes Cope rearrangement to the putative intermediate 8 , which is trapped and characterized as the adduct 9b of butan‐1‐ol. The absolute configuration of 9b was determined by its reduction to the amide 20 , and determination of the X‐ray structure of the N‐camphanoylamide 21 derived from camphanic acid of known absolute configuration.     

Synthesis of (3,5‐Aryl/methyl‐1H‐Pyrazol‐1‐yl)‐(5‐Arylamino‐2H‐1,2,3‐Triazol‐4‐yl)Methanone

Some new (3,5‐aryl/methyl‐1H‐pyrazol‐1‐yl)‐(5‐arylamino‐2H‐1,2,3‐triazol‐4‐yl)methanones were synthesized and characterized by ¹HNMR, ¹³C NMR, MS, IR spectra data and elemental analyses or high resolution mass spectra (HRMS). During the procedure, Dimroth rearrangement was used in this synthesis.     

Tandem Insertion–[1,3]‐Rearrangement: Highly Enantioselective Construction of α‐Aminoketones

An enantioselective synthesis of α‐aminoketone derivatives were readily available through a tandem insertion–[1,3] O‐to‐C rearrangement reaction. The rhodium salt and chiral N,N′‐dioxide‐indium(III) complex make up relay catalysis, which enables the O?H insertion of benzylic alcohols to N‐sulfonyl‐1,2,3‐triazoles, and asymmetric [1,3]‐rearrangement of amino enol ether intermediates, subsequently. Preliminary mechanistic studies suggested that the [1,3] O‐to‐C rearrangement step proceeded through an ion pair pathway.     

Synthesis of Racemic Δ3‐2‐Hydroxybakuchiol and Its Analogues

The first synthetic approach to (±)‐Δ³‐2‐hydroxybakuchiol (=4‐[(1E,5E)‐3‐ethenyl‐7‐hydroxy‐3,7‐dimethylocta‐1,5‐dien‐1‐yl]phenol; 14 ) and its analogues 13a – 13f was developed by 12 steps (Schemes 2 and 3). The key features of the approach are the construction of the quaternary C‐center bearing the ethenyl group by a Johnson–Claisen rearrangement (→ 6 ); and of an (E)‐alkenyl iodide via a Takai–Utimoto reaction (→ 11 ); and an arylation via a Negishi cross‐coupling reaction (→ 12e – 12f ).     

Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans‐dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester–enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six‐ring vinylogous ester intermediate, which is generated from the γ,δ‐unsaturated ester functional group of the Claisen rearrangement product in an efficient three‐step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel–Crafts‐type cyclization to form the B ring via an isocyanate intermediate derived from an N‐Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N‐Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.     

Total Synthesis of (+)‐β‐Himachalene

An enantioselective synthesis of (+)‐β‐himachalene ( 2 ) was accomplished starting from (1S,2R)‐1,2‐epoxy‐p‐menth‐8‐ene ( 3 ) in 15 or 16 steps with an overall yield of ca. 6% (Schemes 3, 5, and 6). Key transformations include an Ireland–Claisen rearrangement, a Corey oxidative cyclization, and a ring expansion.