Computational study of conformations and of sulfinyl oxygen-induced pentacoordination at silicon in 4-chloro-4-silathiacyclohexane 1-oxide and 4,4-dichloro-4-silathiacyclohexane 1-oxide

Second-order Møller-Plesset theory (MP2) and density functional theory (B3LYP) with the 6-311G(d,p) and 6-311+G(d,p) basis sets have been used to calculate the equilibrium geometries and relative energies of the chair, twist, and boat conformations of 4-chloro-4-silathiacyclohexane 1-oxide and 4,4-dichloro-4-silathiacyclohexane 1-oxide. The chair conformers of the axial sulfoxides are lower in energy than the chair conformers of the corresponding equatorial sulfoxides. MP2/6-311+G(d,p) predicted the chair conformer of axial trans-4-chloro-4-silathiacyclohexane 1-oxide (4a) to be 6.12, 0.44, and 0.45 kcal/mol, respectively, more stable than the corresponding 1,4-twist (4b), 2,5-twist (4c) and 1,4-boat (4d) conformers and 6.93 kcal/mol more stable than the 2,5-boat transition state ([4e]^‡). Structures 4c and 4d are stabilized by intramolecular coordination of the sulfinyl oxygen with silicon that results in trigonal bipyramidal geometry at silicon. The 1,4-boat conformer (7d) of axial 4,4-dichloro-4-silathiacyclohexane 1-oxide is also stabilized by transannular coordination of the sulfinyl oxygen with silicon. The energy difference (E_rel = 4.23 kcal/mol) between the chair conformer (7a) and 7d is larger than that between 4a and 4d. The relatively lower stability of the 1,4-boat conformer (7d) of axial 4,4-dichloro-4-silathiacyclohexane 1-oxide (7a) may be due to repulsive interactions of the axial halogen and sulfinyl oxygen atoms. The relative energies and structures of the conformers and transition states of cis- and trans-4-chloro-4-silathiacyclohexane 1-oxide and 4,4-dichloro-4-silathiacyclohexane 1-oxide are discussed in terms of hyperconjugative interactions, orbital interactions, nonbonded interactions, and intramolecular sulfinyl oxygen-silicon coordination.     

Synthesis of the alkaloid tyroscherin by an aldol/Curtius strategy

The alkaloid tyroscherin (2), which contains a vicinal anti-amino alcohol subunit was prepared from 4-hydroxyphenylpropionic acid (5) and meso-diol 9. After desymmetrization of diol 9 and suitable protecting group manipulations, one terminus was extended via a Claisen rearrangement giving rise to enoate ent-15. The missing carbon on the other end could be incorporated using MeMgCl/CuBr·SMe₂ leading eventually to aldehyde ent-22. The acylated oxazolidinone 32 derived from acid 5 and aldehyde ent-22 were combined in an aldol reaction. A subsequent Curtius rearrangement on the carboxylic group furnished the amino function of tyroscherin (2). In a proof of concept study the same strategy was used to prepare tyroscherin analog 28.     

A new approach for the asymmetric syntheses of 2-epi-deoxoprosopinine and azasugar derivatives

A new approach to 2-epi-deoxoprosopinine 11, 1-deoxygulonojirimycin 7, and l-gulono-1,5-lactam 9 was described. The C-2 hydroxymethyl group was introduced regioselectively using SmI₂ mediated coupling of (S)-3-silyloxyglutarimide 13b with either chloromethyl benzyl ether 16a or the Beau-Skrydstrup reagent 16b, followed by debenzylation and highly cis-diastereoselective reductive deoxygenation. Adoption of the Savoi's chemoselective ring-opening alkylation method allowed a highly diastereoselective introduction of the lipid side chain of 2-epi-deoxoprosopinine 11 in a straightforward manner. Dehydration followed by highly trans-diastereoselective dihydroxylation led to polyoxygenated lactam derivative 27 as a key intermediate for the syntheses of 7 and 9.     

Synthesis of the novel conjugated ω,ω′-diaryl/heteroaryl hexatriene system with the central double bond in a heteroaromatic ring: photochemical transformations of 2,3-divinylfuran derivatives

New β,β′-aryl/heteroaryl 2,3-divinylfuran derivatives (9a-d) in which a hexatriene system is a part of heteroaromatic ring have been synthesized and their photochemical properties were investigated. The primary process observed was the isomerization to trans,trans-isomers 9a-d followed by photochemical rearrangement of the furan ring giving the phototransposition products (I-IV). Stilbenes (20, 21) and phenanthrenes (22, 25, and 26), formed as secondary products from the competitive intermolecular cycloadditions, were also observed.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.     

Synthesis of new bicyclic lactam peptidomimetics by ring-closing metathesis reactions

An efficient and versatile synthetic method for the preparation of new fused bicyclic lactams 3a and 3b is described. The spirane cyclopentane nucleus was easily installed by diallylation of the pyroglutamate derivative 18 followed by ring-closing metathesis (RCM). A more practical and stereoselective method for the allylation of the α-methoxy carbamate 21, involving the use of InCl₃ as a Lewis acid, was developed. In the crucial coupling reaction of the diastereomeric mixture of cis- and trans-pirrolidine derivatives 5a and 5b with N-Cbz vinyl phenylalanine only the cis isomer was found to react. An RCM reaction on the dipeptides 25a and 25b followed by catalytic hydrogenation, gave the final epimeric bicyclic lactams 3a and 3b. The same synthetic sequence on the model compound 7, lacking the spiro cyclopentane nucleus, is also reported.     

Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels-Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo-exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13. It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16, whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18. These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.     

Click reactions of 2H-azaphosphirene chromium and molybdenum complexes and a surprisingly facile access to a 2H-1,4,2-diazaphosphole derivative

Ring expansion reactions of 2H-azaphosphirene chromium and molybdenum complexes 1a,b with dimethyl cyanamide, triflic acid, and, subsequently at ambient temperature, with triethylamine gave a mixture of the respective 2H-1,4,2-diazaphosphole complex 2a,b and the non-ligated heterocycle 3. If the deprotonation with NEt₃ was carried out at low temperature, the selective formation of complexes 2a,b was observed, which were isolated in excellent yields and fully characterized (including single-crystal X-ray crystallography). Experimental and computational results revealed that the P, Cr and P, Mo bonds of 2H-1,4,2-diazaphosphole complexes are significantly weakened upon N-protonation of the heterocyclic ligand. When mixtures of 1a,b, TfOH, and Me₂NCN were warmed to ambient temperature, the primarily formed N-protonated of 2H-1,4,2-diazaphosphole complexes 4a,b could be observed by ³¹P NMR spectroscopy. The latter underwent decomplexation to give the N-protonated free ligand 5, which could be isolated and characterized by multinuclear NMR experiments. The neutral non-ligated heterocycle 3 was isolated from a one-pot reaction of 1b with TfOH and Me₂NCN by adding NEt₃ to a solution of intermediately formed 5.     

Synthesis of ‘thianthrene dimer’ by the coupling reaction of stannylthianthrenes in the presence of copper catalysts

The coupling reaction of 1-tributylstannylthianthrene (5) and 2-tributylstannylthianthrene (7) in the presence of copper catalysts at rt afforded the thianthrene dimer 1,1′-bithianthrene (3), 2,2′-bithianthrene (8), and 1,2′-dithianthrene (9) in high yields. Also we obtained thianthrene oxide dimer (R,R) (S,S)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (12) and (R,S) (S,R)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (13) from 1-tributylstannyl-10-S-monoxythianthrene (10) under the same reaction condition. The final structural conformation of 3, 8, 9, and 12 was performed by X-ray crystallographic analysis. Further, the solvent effects in the coupling reactions were also examined.     

Design and synthesis of (E)-4-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid

(E)-4-((3-Ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid, 6, was synthesized in 87% starting from β-cyclocitral. The target compound 6 was synthesized starting from 1 via a Grignard reaction to form alcohol 2. Compound 2 was converted to Wittig salt 3 by treatment with aldehyde 4 in butyllithium and hexane at −78 °C to form ester 5. Ester 5 was saponified and, following acidification, acid 6 was isolated as white solid yield 87%.     

A Pd[0]-catalyzed Ullmann cross-coupling/reductive cyclization approach to C-3 mono-alkylated oxindoles and related compounds

The Pd[0]-catalyzed Ullmann cross-coupling of o-nitrohaloarenes 1a-e with the brominated heterocycles 2a-f delivers the expected products 3a-j in good to excellent yields. The reductive cyclization of such products, as well as N-acyl derivatives 3k, l, and m, has been investigated and provided the C-3 mono-substituted oxindoles 5a-d, f, g, k, and m, the direct reduction products 4i and j or indole 5l.     

Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal

A series of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d]pyrimidines 9a-q were obtained by the three-component reaction between 6-aminopyrimidines 6, 7, 8, dimedone 2, and arylglyoxal 5a,b. The unexpected cyclization process was established by NMR and X-ray diffraction measurements.     

A substrate controlled, very highly diastereoselective Morita-Baylis-Hillman reaction: a remote activation of the diastereofacial selectivity in the synthesis of C-3-branched deoxysugars

The Morita-Baylis-Hillman (MBH) reaction of p-nitrobenzaldehyde with C (6) acyl protected enuloside 1 in the presence of TiCl₄/TBAI yielded highly diastereoenriched C-3-branched deoxysugar derivative or MBH adduct 1′a in high yield, while reactions of unprotected enuloside 2a and C (6) alkyl protected enulosides 2d-e with p-nitrobenzaldehyde under the same conditions afforded the adducts 2′a and 2′d-e, respectively, in low yield with moderate selectivity. Several representative aromatic and aliphatic aldehydes were selected to undergo MBH reaction with 1 to give their respective adducts in very good yield with a very high diastereoselectivity. A plausible mechanism based on the assumption of a Zimmerman-Traxler-type transition state was proposed to explain the excellent selectivity observed with adducts derived from 1. The synthetic application of these adducts were shown by their stereoselective reduction to corresponding threo isomers in very good yield.     

Synthesis and reactions of sulfur-substituted indolizidinones

An aza-Diels-Alder reaction product 2 was readily converted to a tetrahydropyridine derivative 6, but its N-benzyl group was unexpectedly difficult to cleave under various conditions. On the other hand, the N-tosyl α,β-unsaturated ester 14 was transformed in one step by Mg/MeOH/Et₃N to a thio-substituted indolizidinone 3. This method was also extended to a methyl-substituted diene 16, which stereoselectively provided the cis-2,6-disubstitutedproduct 17. Further synthetic transformations yielded indolizidinones 20-24, including a formal synthesis of the natural product monomorine I.     

Regioselective cyclization of unsymmetrical dicyanoanilines to novel 2,3-bifunctionalised indole regioisomers and their use in the synthesis of 4,5-dihydro[1,3]oxazino[5,4-b]indole-6-carbonitriles

Synthesis of novel-2,3-bifunctionalised indole regioisomers (2/3 and 6/7) from unsymmetrical dicyanoanilines 1 by regioselective cyclization in two independent ways. Regioisomers 6 are further utilized in synthesis of novel 4,5-dihydro[1,3]oxazino[5,4-b] indole-6-carbonitriles 9.     

Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2-C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels-Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels-Alder cycloaddition. An alternative domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a-c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.     

Selenoether ligand assisted Heck catalysis

Selenoether ligands, 2,2′-methylenebis(selanediyl)bis(2,1-phenylene)dimethanol (5), (2,2′-(ethane-1,2-diylbis(selanediyl))bis(2,1-phenylene))dimethanol (6) and (2-(benzylselanyl)phenyl)methanol (7) have been synthesized by reducing di-o-formylphenyl diselenide and reacting the in situ generated selenolate with dibromomethane, 1,2-dibromoethane and benzyl chloride, respectively. The ligands, bis(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenylselanyl)methane (8) and 1,2-bis(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenylselanyl)ethane (9) have been synthesized similarly from bis[2-(4,4-dimethyl-2-oxazolinyl)phenyl] diselenide using electrophiles dibromomethane and 1,2-dibromoethane, respectively. Activity of ligands 5-9 along with 2-(2-(benzylselanyl)phenyl)-4,4-dimethyl-4,5-dihydrooxazole (10) and 1-(2-(benzylselanyl)phenyl)-N,N-dimethylmethanamine (11) were examined for the Heck reaction of aryl halides with olefins. Bidentate Se,N ligand 11 was found to be the best one in the series and constitutes an efficient phosphine-free catalytic system with PdCl₂. The catalytic system showed moderate activity for the coupling of activated aryl chlorides in the presence of tetra-n-butyl ammonium bromide (TBAB). Complexes [10-PdCl₂] (12) and [11-PdCl₂] (13) have shown marginally better activity in comparison to the in situ generated catalysts from PdCl₂ and 10 and 11, respectively in the coupling of 4-bromoacetophenone with n-butylacrylate. Ligand 9 and complex 13 have been characterized by single crystal X-ray diffraction analysis.     

Environmentally benign syntheses of flavanones

Mild and environmentally benign methods for the syntheses of flavanones are described. The reaction of o-hydroxyacetophenones (1) and benzaldehydes (2) in water in the presence of DABCO at room temperature gave 3-hydroxy-1-(2-hydroxylphenyl)-3-arylpropan-1-ones (3a-i) as intermediates. Followed by an intramolecular dehydration of the 3a-i with the modified Mitsunobu’s reaction, the target flavanones (4a-i) were obtained. Moreover, the reaction of 1 and 2 at the same conditions but at reflux gave flavanones in one pot with good yields.     

An unexpected formation of pyrazolopyrimidines during the attempted to obtain 5-substituted tetrazoles from carbonitriles

In this Letter, we described the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a–c from 5-amino-1-aryl-1H-pyrazole-4-carbonitriles 1a–c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidine derivatives 6a–c from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a–c, instead of 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a–c as desired. In an attempt to obtain these tetrazole derivatives containing the methyl group at C3-position in the pyrazole ring, the amino group in 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile 4c was protected by the reaction with sodium hydride and di-tert-butyl-dicarbonate (Boc). The tetrazole derivative 5c was synthesized from the protected compound 7c using analogue methodology to obtain 2a–c and 6a–c.     

Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.