Inversion of Configuration at the Phosphorus Nucleophile in the Diastereoselective and Enantioselective Synthesis of P‐Stereogenic syn‐Phosphiranes from Chiral Epoxides

Nucleophilic substitution results in inversion of configuration at the electrophilic carbon center (S_N2) or racemization (S_N1). The stereochemistry of the nucleophile is rarely considered, but phosphines, which have a high barrier to pyramidal inversion, attack electrophiles with retention of configuration at P. Surprisingly, cyclization of bifunctional secondary phosphine alkyl tosylates proceeded under mild conditions with inversion of configuration at the nucleophile to yield P‐stereogenic syn‐phosphiranes. DFT studies suggested that the novel stereochemistry results from acid‐promoted tosylate dissociation to yield an intermediate phosphenium‐bridged cation, which undergoes syn‐selective cyclization.     

Pnictogen-Bonding Catalysis: An Interactive Tool to Uncover Unorthodox Mechanisms in Polyether Cascade Cyclizations

Pnictogen-bonding catalysis and supramolecular σ-hole catalysis in general is currently being introduced as the non-covalent counterpart of covalent Lewis acid catalysis. With access to anti-Baldwin cyclizations identified as unique characteristic, pnictogen-bonding catalysis appeared promising to elucidate one of the hidden enigmas of brevetoxin-type epoxide opening polyether cascade cyclizations, that is the cyclization of certain trans epoxides into cis-fused rings. In principle, a shift from S_N2- to S_N1-type mechanisms could suffice to rationalize this inversion of configuration. However, the same inversion could be explained by a completely different mechanism: Ring opening with C−C bond cleavage into a branched hydroxy-5-enal and the corresponding cyclic hemiacetal, followed by cascade cyclization under conformational control, including stereoselective C−C bond formation. In this report, a pnictogen-bonding supramolecular Sb^V catalyst is used to demonstrate that this unorthodox polyether cascade cyclization mechanism occurs.     

Stereoselective synthesis of anti-2-oxazolidinones by Ph3P-CCl4-Et3N mediated SN2 cyclization of N-Boc-β-amino alcohols

Ethyl anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates were synthesized stereoselectively in excellent yields using the Ph₃P-CCl₄-Et₃N system by S_N2 cyclization of N-Boc-β-amino alcohols. syn to anti conversion of ethyl 4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates using DBU as base is also described.     

New synthesis of isoxazolidines

A new synthesis of 5-substituted isoxazolidines was developed by direct isoxazolidine ring formation of allylic hydroxylamines under acidic conditions. The cyclization process is an electrophilic S_N1 type reaction. The formed carbocation intermediate is stabilized by electron rich groups (i.e., phenyl). A moiety that mediates oxonium ion formation (i.e., para-methoxy) accelerates the rate of product formation.     

α-Methylidene- and α-Alkylidene-β-lactams from Nonproteinogenic Amino Acids

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2 , which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (S_N2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4 (S_N2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the S_N2 reaction occurring in MeCN and the S_N2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8 , containing an exocyciic alkylidene and methylidene group at C(3), respectively.     

N-alkylation of 2,3-dihydroimidazo[2,1-b]quinazolin-1(10)H-5-one. On the cryptoanionic mechanism of N-substitution

Quantum chemical methods involving studies of transition states of the reaction showed that the main products of N-alkylation of prototropic 2,3-dihydroimidazo[2,1-b]quinazolin-1(10)H-5-one (1) in the gas phase and under neutral conditions in solution occurring via the S_N2 mechanism should be N(10)-alkyl-substituted derivatives formed from the 1H-tautomer. Minor N(1)-substituted derivatives in solution can be produced from both tautomers. For the alkylation of the free N-anion of compound 1, position 1 is attacked first. Validity of conclusions concerning the overall regioselectivity of the reaction was confirmed experimentally. In the absence of solvent, the alkylation proceeds abnormally with a sharp increase in the content of the 1-substituted isomers up to inversion of the regioselectivity of the reaction, which is explained by the participation in the process of the H-bonded dimer of the substrate (1a)₂, which undergoes alkylation via the cryptoanionic mechanism. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 876–887, May, 2006.     

Synthesis of (−)-Hobartine and Related Indole Alkaloids

An improved method for obtaining optically pure (S)-(l-p-menthen-8-yl)amine ( 12 ) has led to expedient syntheses of two hypothetical biogenetic intermediates on the way to aistoteline ( 7 ), namely (S)-(N)-(l-p-menthen-8-yl)-2-(3-indolyl)ethylamine ( 3 ) and (S)-(N)-(l-p-menthen-8-yl)-2-(3-indolyl)ethylideneamine ( 4 ). The latter has been transformed into (?)-hobartine ( 6 ) in 64% yield via a stereoselective biomimetic cyclization by treatment with HCOOH. This unambiguous synthesis establishes the hitherto unknown absolute configuration of (?)-hobartin ( 6 ). Several model cyclization reactions of N-substituted α-(terpen-8-yl)imine derivatives yielding unsaturated 3azabicyclo [3.3.1]nonane compounds are described.     

Intramolecular SN2 reaction α- to a trifluoromethyl group: preparation of 1-cyano-2-trifluoromethylcyclopropane

The first intramolecular S_N2 reaction of α-trifluoromethylated secondary alcohols by a carbanion is described. A stereoselective intramolecular cyclization of 3-substituted-3-cyano-1-trifluoromethylpropyl sulfonate via the cyano stabilized carbanion provides 1-substituted-1-cyano-2-trifluoromethylcyclopropanes in good yields. The product has the opposite configuration to the starting alcohol at the carbon attached to trifluoromethyl group, revealing the reaction takes place in S_N2 manner with Walden inversion at the reaction center.     

Synthesis of poly-substituted pyrazolo[1,5-a]quinolines through one-pot two component cascade reaction

A diversity-oriented method for the synthesis of novel poly-substituted pyrazolo[1,5-a]quinolines has been developed on the basis of an S_NAr/Knoevenagel cyclization cascade reaction or an S_NAr/Dieckmann–Thorpe cyclization cascade reaction. The methods provide a variety of poly-substituted pyrazolo[1,5-a]quinolines bearing an amino, alkyl or aryl substituent at the 5-position. In addition, a diversity-oriented method for the synthesis of 2-substituted pyrazolo[1,5-a]quinolines from a readily available 2-[[(trifluoromethyl)sulfonyl]oxy]pyrazolo[1,5-a]quinoline has also been disclosed.     

Nitropyrazoles. 11. Isomeric 1-methyl-3(5)-nitropyrazole-4-carbonitriles in nucleophilic substitution reactions. Comparative reactivity of the nitro group in positions 3 and 5 of the pyrazole ring

With reactions of isomeric 1-methyl-3-nitro- and 1-methyl-5-nitropyrazole-4-carbonitriles with anionic S-, O-, and N-nucleophiles (RSH, PhOH, and 3,5-dimethyl-4-nitropyrazole in the presence of K₂CO₃ or MeONa), it was shown that for N-substituted 3(5)-nitropyrazoles, the nitro group in position 5 is much more reactive than in position 3.     

Synthesis of chiral 2-oxazolidinones, 2-oxazolines, and their analogs

Chiral five-membered ring 2-oxazolidinones and six-membered ring 1,3-oxazinan-2-ones are synthesized from the corresponding amino alcohols with complete inversion or retention of stereochemistry. Chiral 5-substituted 2-oxazolines and 6-substituted 2-oxazines are also synthesized from the same starting materials with inversion of stereochemistry through an intramolecular S_N2 reaction. These compounds are useful intermediates in organic synthesis and crucial building blocks for many pharmaceutical compounds.     

RCM-mediated stereoselective synthesis of three novel tetrahydroisoquinoline tetracyclic core frameworks

Three novel tetrahydroisoquinoline tetracyclic core frameworks were stereoselectively synthesized. The key steps included a ring-closing metathesis (RCM)-mediated cyclization and a subsequent intramolecular S_N2 N(O)-substituted reaction. This simple method for tetracyclic core synthesis facilitates the further exploration of the chemical space of tetrahydroisoquinoline alkaloids.     

New Optically Active Bis‐Heterocycles Derived from (S)‐Proline

Enantiomerically pure bis‐heterocycles containing a (S)‐proline moiety have been prepared starting from (S)‐N‐benzylprolinehydrazide ( 2b ). The reactions with isothiocyanates or butyl isocyanate in refluxing MeOH led to the corresponding thiosemicarbazide 5 and semicarbazide 9 with a N‐benzylprolinoyl residue. The structure of the tert‐butyl derivative 5d was established by X‐ray crystallography. Base‐catalyzed cyclization of 5 and 9 led to (S)‐3‐(pyrrolidin‐2‐yl)‐1H‐1,2,4‐triazole‐5(4H)‐thiones 6 and the corresponding 5(4H)‐one 8 , respectively, whereas, in concentrated H₂SO₄, compounds 5 undergo cyclization to give (S)‐5‐amino‐2‐(pyrrolidin‐2‐yl)‐1,3,4‐thiadiazoles 7 . Furthermore, 2b reacted with hexane‐2,5‐dione in boiling ⁱPrOH to yield the (S)‐N‐(2,5‐dimethylpyrrol‐1‐yl)prolinamide 10 . In the case of the bis‐heterocycle 8 , treatment with HCOONH₄ and Pd/C in MeOH gave the debenzylated product 12 .     

Analogies between silicon and phosphorus stereochemistry—II : Influence of the attacking anion upon the stereochemistry of nucleophilic displacement at tetrahedral phosphorus

The stereochemistry of reactions of cyclic halogenophosphates with a representative series of p-substituted aryloxides emphasizes the relative influence of the attacking anion. For a given leaving group, the stereochemistry depends essentially upon the electronic character of the p-substituent and the ion-pair dissociation of the nucleophile. Both stereochemical and kinetic data rule out a cation-assisted mechanism to explain retention at phosphorus. Meanwhile, a comparison between S_N2(P) and S_N2(Si) suggests similar mechanisms in the two series. Retention and/or inversion are the consequence of two competing reactions of similar energies. The stereochemistry is determined by the factors which affect the approach of the nucleophile to give two initial intermediates of different geometries.     

Regioselectivity of heterocyclization of 2-substituted 3,3-bis(methylsulfanyl)acrylo-nitriles with 2-benzimidazoleacetonitrile

Functionalized pyrido[1,2-a]benzimidazoles have been synthesized by the interaction of 2-substituted 2-cyano-3,3-bis(methylsulfanyl)acrylonitriles with 2-benzimidazoleacetonitrile under S _N Vin reaction conditions.     

Reaktionen mit phosphororganischen Verbindungen. XLI[1]. Neuartige synthetische Aspekte des Systems Triphenylphosphin-Azodicarbonsäureester-Hydroxyverbindung

New preparative methods using triphenylphosphine-diethyl-azodicarboxylate-hydroxycompound. The present paper deals with new preparative methods by which the system of triphenylphosphine-diethylazodicarboxylate-hydroxycompound is treated with many nucleophiles. On one side, the transformation of 5α-cholestane-3β-ol to the 3α-substituted derivatives 2a-2e (Scheme 1) by hitherto unregarded nucleophiles like azide, cyanide, thiocyanate, trifluoroacetate and thiophenoxide is shown. Further examples demonstrate the great applicability of the reaction in the case of sensitive substrates. Cholesterol ( 5 ) is transformed to the 3α-derivative 6a without any neighbouring group participation by the Δ⁵-double bond. The analogous transformation of the hydroxysteroides 7 and 9 to the corresponding 3α-substituted compounds 8a and 10a represent further examples to be noted. Noteworthy is also the formation of the epi-vitamine D₃-p-nitrobenzoate from the vitamin-D₃ itself. On the other side the sources for nucleophils require special consideration. Scheme 1 demonstarates that the anions of phosphonium salts can be used as the nucleophils as is shown by the preparation of the derivatives 2a, 2c, 2f, 2h and 2i from 5α-cholestane-3β-ol ( 1 ). From scheme 2 one can see the very useful preparative fact ( 1 → 2f, 2g, 2h, 21 and 2m ) that alkylhalides, alkylsulfates and alkylsulfonates can be used for supplying of the corresponding nucleophile. The possibility of a direct tosylation of a chiral hydroxycompound with inversion of configuration-as it is shown by transformation of (S)-2-butanol to the tosylate, obtained also from (R)-2-butanol and tosylchloride is a further is a further remarkable point. The absence of neighbouring group effects allows also to prepare cis-1, 2- disubstituted cyclohexane compounds type C₆H₁₀ (X) (Y) (X = N₃, Cl, Y = N₃, J) from the corresponding trans-1,2-disubstituted cyclohexanoles C₆H₁₀ (X) (OH) (X = N₃, Cl). The synthesis of the compounds 14a - 15d can be regarded as representative of this new useful methodic principle.     

Inherent Reactivity of Spiro-Activated Electrophilic Cyclopropanes

The kinetics of the ring-opening reactions of thiophenolates with geminal bis(acceptor)-substituted cyclopropanes in DMSO at 20 °C was monitored by photometric methods. The determined second-order rate constants of the S_N2 reactions followed linear relationships with Mayr nucleophilicity parameters (N/s_N) and Brønsted basicities (pK_aH) of the thiophenolates as well as with Hammett substituent parameters (σ) for groups attached to the thiophenolates. Phenyl-substituted cyclopropanes reacted by up to a factor of 15 faster than their unsubstituted analogues, in accord with the known activating effect of adjacent π-systems in S_N2 reactions. Variation of the electronic properties of substituents at the phenyl groups of the cyclopropanes gave rise to parabolic Hammett relationships. Thus, the inherent S_N2 reactivity of electrophilic cyclopropanes is activated by electron-rich π-systems because of the more advanced C1−C2 bond polarization in the transition state. On the other hand, electron-poor π-systems also lower the energetic barriers for the attack of anionic nucleophiles owing to attractive electrostatic interactions.     

N-Trifluoroacetyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline ozonides

A three-component condensation of aromatic amine, aldehyde, and cyclopentadiene with subsequent N-trifluoroacetylation leads to 4- and 4,8-substituted N-trifluoroacetyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolines. Ozonation of the double bond in the latter produced the corresponding isomeric stable ozonides having (1R*,4S*,5aR*,6S*,11bR*)-configuration and differing in inversion at the carboxamide nitrogen atom.     

Novel Diastereoselective Synthesis of trans-Fused Pyrrolo[3,4-b]quinolines Through Intramolecular Imino Diels–Alder Reaction

Synthesis of a series of 1aR,2S,4aS-hexahydropyrrolo[3,4-b]quinolines has been achieved by the intramolecular cyclization reaction of aldimines derived from aromatic amines and (S)-2-(N-(3-methylbut-2-enyl)-N-tosyamino)-3-methylpropanal/(S)-2-(N-(3-methylbut-2-enyl)-N-tosyamino)-3-phenylpropanal in acetonitrile with InCl₃ as a catalyst, in excellent yields and in short duration of time, under mild conditions.     

N-Heteroaralkyl substituted α-amidinium thiolsulfates

The syntheses of a number of N-substituted α-amidinium thiolsulfates, CH₂(S₂O₃^?)-C(=NH₂⁺)NH(CH₂)nR are described, where n was varied from 1 to 3 and R represents such heteroaryl groups as 2-furyl, 2-thienyl, 3-indolyl and 2-, 3- and 4-pyridyl. The preparation of S-(2-imidazolinemethyl)thiolsulfuric acid, as an example of an N, N'-disubstituted α-amidinium thiolsulfate, is also reported.