Acyl iodides in organic synthesis: VII. Reactions with trialkyl(alkynyl)silanes,-germanes, and-stannanes

Reactions of acyl iodides R¹COI (R¹=Me, Ph) with trialkyl(alkynyl)silanes,-germanes, and stannanes (R²C≡CMR ₃ ³ ; M=Si, Ge, Sn) were studied. Acyl iodides reacted with the germanium and tin derivatives with cleavage of the M-C_sp bond and formation of the corresponding trialkyl(iodo)germanes and-stannanes R ₃ ³ MI (M=Ge, Sn) and alkynyl ketones R¹C(O)C≡CR² and R¹C(O)C≡CC(O)R¹. By contrast, the reaction of acetyl iodide with ethynyl(trimethyl)silane gave only a small amount of 1,2-diiodovinyl(trimethyl) silance as a result of iodine addition at the triple bond. Bis(trimethylsilyl)ethyne failed to react with acetyl iodide.     

An Arylation Strategy to Propargylamines: Catalytic Asymmetric Friedel–Crafts‐type Arylation Reactions of C‐Alkynyl Imines

The first arylation strategy for the synthesis of enantioenriched propargylamines is disclosed. This approach, which is complementary to previous alkynylation and alkylation strategies, involves a C(sp²)?C(sp³) bond formation, and is based on the first asymmetric Friedel–Crafts‐type arylation reaction of C‐alkynyl imines. Asymmetric Friedel–Crafts reactions with electron‐deficient phenols, a longstanding unsolved challenge, have thus been realized for the first time, enabled by the combination of our recently introduced C‐alkynyl N‐Boc‐protected N,O‐acetals as electrophiles and chiral phosphoric acids as catalysts. The synthetic utility of the resulting structurally diverse and polyfunctional chiral propargylamines was demonstrated by a series of selective transformations, including controlled reduction of the alkynyl group and iterative cross‐couplings.     

Silyl modification of biologically active compounds. 11. Synthesis,physico‐chemical and biological evaluation of N‐(trialkoxysilylalkyl)tetrahydro(iso,silaiso) quinoline derivatives

N‐(trialkoxysilylalkyl) derivatives of 1,2,3,4‐tetrahydroquinoline, 1,2,3,4‐tetrahydroisoquinoline and 4,4‐dimethyl‐4‐sila‐1,2,3,4‐tetrahydroisoquinoline were prepared and characterized by elemental analysis, ¹H, ¹³C and ²⁹Si NMR spectroscopy. In vivo psychotropic properties and in vitro cytotoxic effects of 3‐[N‐(1,2,3,4‐tetrahydroisoquinolyl)]propyltriethoxysilane methiodide and 3‐[N‐(1,2,3,4‐tetrahydroisoquinolyl)]propylsilatrane are reported. Comparative study of ²⁹Si shifts in newly synthesized compounds suggested donor–acceptor interaction between nitrogen and silicon atom, which increased electron density at Si nuclei, revealing a stronger increment of N → Si transannular bond in comparison with N → Si α‐effect. The molecular structure of 3‐[N‐(1,2,3,4‐tetrahydroisoquinolyl)]propylsilatrane features a penta‐coordinate silicon atom having CSiO₃ pattern and Si…N intramolecular interaction. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of tetrahydroisoquinoline-diamine ligands and their application in asymmetric transfer hydrogenation

The use of the tetrahydroisoquinoline scaffold is well documented in biologically active compounds. However, reports of the utilisation of tetrahydroisoquinoline compounds in asymmetric catalysis are limited. The synthesis of novel diamine ligands possessing the tetrahydroisoquinoline (tetrahydroisoquinoline) backbone and evaluation of their activity in the asymmetric transfer hydrogenation of acetophenone are presented. The diamine ligands in conjunction with i-PrOH as the hydrogen source and [RhCl₂(Cp1)]₂ as the metal precursor proved to be the most effective of the tetrahydroisoquinoline derivatives for this catalytic system. Water was found to have a profound influence on the enantioselectivity of the reaction. Optimisation of the amount water, i-PrOH and catalytic loading content rendered the best result of 70% enantioselectivity for the (S)-1-phenylethanol isomer product.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Enantioconvergent Reductive C(sp)−C(sp3) Cross-Coupling to Access Chiral α-Alkynyl Phosphonates Under Dual Nickel/Photoredox Catalysis

Transition-metal-catalyzed asymmetric carbon−carbon bond formation to forge phosphonates with an α-chiral carbon center through C(sp³)−C(sp³) and C(sp²)−C(sp³) couplings has been successful. However, the enantioselective C(sp)−C(sp³) coupling has not yet been disclosed. Reported herein is an unprecedented enantioconvergent cross-coupling of alkynyl bromides and α-bromo phosphonates to deliver chiral α-alkynyl phosphonates.     

Synthesis, NMR characterization and reactivity of 1-silacyclohex-2-ene derivatives

The chloro functionality of allyldichlorosilane (HSiCl₂(C₃H₅)) and allyldichloromethylsilane (MeSiCl₂(C₃H₅)) were replaced by alkynyl groups and new compounds, allyldialkynylsilane 1 and allyldialkynylmethylsilane 2, were obtained. These silanes, which served as starting materials for the onward reactions, were purified by fractional distillation. They were further subjected to hydroboration with 9-BBN (9-borabicyclo[3.3.1]nonane) and were converted into 1-silacyclohex-2-ene derivatives 5 and 6. The competition between C≡C and C=C in the reaction was studied. The hydroborating reagent 9-BBN was expected to prefer terminal C=C bonds and to leave C≡C bond untouched. This hypothesis of preferable hydroboration was experimentally proved, and hence, 1-silacyclohex-2-ene derivatives were obtained in reasonably pure form. The reaction of allyldialkynylsilane 2 with one equivalent of 9-BBN affords 1-silacyclohex-2-ene bearing Si-C≡C-function, ready to be hydroborated further with one equivalent of 9-BBN. The obtained compound bears two C-B bonds, which are attractive synthones for further transformations. This study aims to highlight the chemistry of C-B and Si-H functional groups. All new compounds obtained were colorless air and moisture sensitive oils, and they were studied by multinuclear magnetic resonance spectroscopy (¹H, ¹³C, ¹¹B, ²⁹Si NMR) in solution.      

Synthesis of 4‐silaspiro[3.4]octa‐1,5‐diene derivatives: hybrid spiro compounds

Trialkynyl(vinyl)silanes CH₂?CH? Si(C?C? R)₃ (R = Bu, Ph, p‐tolyl) were prepared and treated with 9‐borabicyclo[3.3.1]nonane (9‐BBN). Consecutive 1,2‐hydroboration and intramolecular 1,1‐carboboration reactions (each requires different reaction conditions) were studied. 1,2‐Hydroboration of the Si? vinyl group takes place at ambient temperature (23°C in tetrahydrofuran), followed by intramolecular 1,1‐vinylboration to give 1‐silacyclopent‐2‐ene derivatives, bearing still two alkynyl functions at the silicon atom. Further treatment with a second equivalent of 9‐BBN affords 1‐alkenyl‐1‐(alkynyl)‐1‐silacyclopent‐2‐ene derivatives. These undergo intramolecular 1,1‐vinylboration to give 4‐silaspiro[3.4]octa‐1,5‐dienes bearing the boryl groups at 2 and 6 positions. Protodeborylation of all new compounds (intermediates and final products) using acetic acid in slight excess afforded corresponding silanes including spirosilanes. All compounds were characterized using multinuclear NMR spectroscopy (¹H, ¹¹B, ¹³C, ²⁹Si) in solution state. Solid‐state structures for one of the trialkynyl(vinyl)silanes (R = p‐tolyl) and one of the 1‐silacyclopent‐2‐ene derivatives (R = Ph) were confirmed using X‐ray diffraction. Copyright © 2015 John Wiley & Sons, Ltd.     

An Efficient Approach to Regio- and Stereodefined Fully-Substituted Alkenylsilanes by Pd-Catalyzed Allenic C(sp3)−H Oxidation

A highly efficient palladium-catalyzed functionalization of allenylsilanes to give regio- and stereodefined fully-substituted alkenylsilanes has been developed. This oxidative coupling reaction showed good functional group compatibility with exclusive regio- and stereoselectivity. The pending olefin on the silyl group was shown to be an indispensable element for the initial allenic C(sp³)−H bond cleavage, and performs as the directing group to control the overall selectivity. The addition of substoichiometric amounts of Et₃N was found to increase the reaction rate leading to a higher reaction yield. The reaction can be easily scaled up and applied for the late-stage functionalization of natural products and pharmaceutical compounds, including amino acids and steroid derivatives. The newly introduced functional groups include aryl, alkynyl, and boryl groups. The highly strained four-membered ring, silacyclobutene was obtained when B₂pin₂ was employed as the coupling partner. Mechanistic studies, including kinetic isotope effects, showed that the allenic C(sp³)−H bond cleavage is the rate-limiting step.     

Formal Gold‐to‐Gold Transmetalation of an Alkynyl Group Mediated by Palladium: A Bisalkynyl Gold Complex as a Ligand to Palladium

The reaction of [Au(C?C?n‐Bu)]_n with [Pd(η³‐allyl)Cl(PPh₃)] results in a ligand and alkynyl rearrangement, and leads to the heterometallic complex [Pd(η³‐allyl){Au(C?C?n‐Bu)₂}]₂ ( 3 ) with an unprecedented bridging bisalkynyl–gold ligand coordinated to palladium. This is a formal gold‐to‐gold transmetalation that occurs through reversible alkynyl transmetalations between gold and palladium.     

Optically active diaryl tetrahydroisoquinoline derivatives

In (1R,3S)‐6,7‐dimethoxy‐3‐(methoxydiphenylmethyl)‐1‐phenyl‐1,2,3,4‐tetrahydroisoquinoline, C₃₁H₃₁NO₃, (I), and (1R,3S)‐2‐benzyl‐3‐[diphenyl(trimethylsiloxy)methyl]‐6,7‐dimethoxy‐1‐phenyl‐1,2,3,4‐tetrahydroisoquinoline, C₄₀H₄₃NO₃Si, (II), the absolute configurations have been confirmed to be R and S at the isoquinoline 1‐ and 3‐positions, respectively, by NMR spectroscopy experiments. Both structures have monoclinic (P2₁) symmetry and the N‐containing six‐membered ring assumes a half‐chair conformation. The asymmetric unit of (I) contains one molecule, while (II) has two molecules within the asymmetric unit. These structures are of interest with respect to the conformation around the exocyclic C—C bond: (I) displays an ap (antiperiplanar) conformation, while (II) displays an sc‐exo (synclinal) conformation around this bond. These conformations are significant for stereocontrol when these compounds are used as catalysts. Various C—H...π and C—H...O bonds link the molecules together in the crystal structure of (I). In the crystal structure of (II), three intermolecular C—H...π hydrogen bonds help to establish the packing.     

Enantioselective Direct Alkynylation of Ketones Catalyzed by Chiral CCN Pincer RhIII Complexes

A direct asymmetric alkynylation of ketones with new chiral CCN Rh catalysts containing N‐heterocyclic carbene and oxazoline hybrid ligands is described. The catalytic reaction of fluoroalkyl‐substituted ketones, ArCOCF₂X (X=F, Cl, H), with aromatic and aliphatic alkynes yielded the corresponding chiral propargyl alcohols with high enantioselectivity. Control and kinetic experiments suggested a bis(alkynyl) Rh intermediate as the active species for the C?C bond‐forming step.     

π-π Chelation controlled chemoselective conjugate addition of lithium dimethylcuprate

The conjugate addition of Me₂CuLi to ethyl cinnamate derivatives bearing an alkynyl group at the ortho-position, took place preferentially in the presence of the corresponding α,β-unsaturated esters bearing an alkynyl group at the distal position or having no alkynyl groups. The observed chemoselectivity is most probably a reflection of the π-π chelation between π-electrons of the olefinic moiety of the enoates and those of the C-C triple bond located at the proximal position.     

Oligonucleotides Containing 7‐Deaza‐2′‐deoxyinosine as Universal Nucleoside: Synthesis of 7‐Halogenated and 7‐Alkynylated Derivatives,Ambiguous Base Pairing,and Dye Functionalization by the Alkyne–Azide ‘Click’ Reaction

Oligonucleotides containing 7‐deaza‐2′‐deoxyinosine derivatives bearing 7‐halogen substituents or 7‐alkynyl groups were prepared. For this, the phosphoramidites 2b – 2g containing 7‐substituted 7‐deaza‐2′‐deoxyinosine analogues 1b – 1g were synthesized (Scheme 2). Hybridization experiments with modified oligonucleotides demonstrate that all 2′‐deoxyinosine derivatives show ambiguous base pairing, as 2′‐deoxyinosine does. The duplex stability decreases in the order C_d>A_d>T_d>G_d when 2b – 2g pair with these canonical nucleosides (Table 6). The self‐complementary duplexes 5′‐d(F⁷c⁷I‐C)₆, d(Br⁷c⁷I‐C)₆, and d(I⁷c⁷I‐C)₆ are more stable than the parent duplex d(c⁷I‐C)₆ (Table 7). An oligonucleotide containing the octa‐1,7‐diyn‐1‐yl derivative 1g , i.e., 27 , was functionalized with the nonfluorescent 3‐azido‐7‐hydroxycoumarin ( 28 ) by the Huisgen–Sharpless–Meldal cycloaddition ‘click’ reaction to afford the highly fluorescent oligonucleotide conjugate 29 (Scheme 3). Consequently, oligonucleotides incorporating the derivative 1g bearing a terminal C?C bond show a number of favorable properties: i) it is possible to activate them by labeling with reporter molecules employing the ‘click’ chemistry. ii) Space demanding residues introduced in the 7‐position of the 7‐deazapurine base does not interfere with duplex structure and stability (Table 8). iii) The ambiguous pairing character of the nucleobase makes them universal probes for numerous applications in oligonucleotide chemistry, molecular biology, and nanobiotechnology.     

Phosphorus NMR Characterisation of P–N Bond Rotamers of a α‐P4S3 Amide with a Conformationally Constrained Chiral Substituent

Reactions of bicyclic α‐P₄S₃I₂ with Hpthiq gave solutions containing α‐P₄S₃(pthiq)I and α‐P₄S₃(pthiq)₂, where Hpthiq is the conformationally constrained chiral secondary amine 1‐phenyl‐1,2,3,4‐tetrahydroisoquinoline. The expected diastereomers have been characterised by complete analysis of their ³¹P{¹H} NMR spectra. Hindered P–N bond rotation in the amide iodide α‐P₄S₃(pthiq)I caused greater broadening of peaks in the room‐temperature spectrum of one diastereomer than in that of the other. At 183 K, spectra of two P–N bond rotamers for each diastereomer were observed and analysed. The minor rotamers showed strong evidence for steric crowding, having large diastereomeric differences in ¹J(P–P) and ²J(P–S–P) couplings (49 Hz, 16 % of value, and 4.4 Hz, 19 % of value, respectively).     

Copper-Catalyzed Regioselective [3+3] Annulations of Alkynyl Ketimines with α-Cyano Ketones: the Synthesis of Polysubstituted 4H-Pyran Derivatives with a CF3-Containing Quaternary Center

Regioselective [3+3] annulation of alkynyl ketimines with α-cyano ketones for the synthesis of polysubstituted 4H-pyran derivatives with a quaternary CF₃-containing center has been realized by using Cu(OAc)₂ as the catalyst. The novel strategy tolerates a wide range of α-CF₃ alkynyl ketimines and α-cyano ketones with both aryl and alkyl substitutents. A preliminary asymmetric synthesis of chiral product 3 has been attempted by using copper and chiral thiourea as the cocatalyst with excellent yields (86-99 %) and good enantioselectivities (71–78 % ee). Furthermore, product 3 aa could be obtained on a gram-scale reaction with 75 % yield and 99 % ee after recrystallization. Several products were also transformed readily. Control experiments indicate that the reaction involves a process with a base-catalyzed or chiral thiourea-catalyzed Mannich-type reaction followed by a highly regioselective copper-catalyzed ring-closing reaction on the alkynyl moiety in a 6-endo-dig fashion.     

Formal Total Synthesis of Fostriecin by 1,4‐Asymmetric Induction with an Alkyne–Cobalt Complex

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis‐cis‐trans‐triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary. Although remote stereoinduction in a 1,4‐relationship is considered difficult, we have developed a notable 1,4‐asymmetric induction that utilizes an alkyne–cobalt complex for the control of C5 stereochemistry by the C8 stereogenic center. The stereochemistry at C11 was established by 1,3‐asymmetric induction with a higher‐order alkynyl‐zinc reagent. Thus, only one asymmetric reaction requiring an external chiral auxiliary was employed in this route. The labile cis‐cis‐trans‐triene unit was constructed at a late stage of the synthesis by diastereoselective coupling of a dienyne and an aldehyde unit, followed by reduction.     

Oxidative CH Bond Functionalization and Ring Expansion with TMSCHN2: A Copper(I)‐Catalyzed Approach to Dibenzoxepines and Dibenzoazepines

Tricyclic dibenzoxepines and dibenzazepines are important therapeutic agents for the pharmaceutical industry and academic research. However, their syntheses are generally rather tedious, requiring several steps that involve a Wagner–Meerwein‐type rearrangement under harsh conditions. Herein, we present the first copper(I)‐catalyzed oxidative C? H bond functionalization and ring expansion with TMSCHN₂ to yield these important derivatives in a facile and straightforward way.     

SYNTHESIS AND NMR SPECTROSCOPIC INVESTIGATION OF PHENYLPHOSPHORYL DERIVATIVES

Abstract

The syntheses of 16 phenyl- (1 and 3) and phenylthiophosphoryl (2) derivatives are described. The ¹³C and ¹⁷O NMR data sensitively reflect electron density changes in the phosphoryl substituents caused by p^π–d^π back-donation from X/Y to P. Taft constants σ₁ and σ_R ⁰ were derived for 16 phosphoryl substituents.     

Terminal Alkyne Coupling Reactions Through a Ring: Effect of Ring Size on Rate and Regioselectivity

Terminal alkyne coupling reactions promoted by rhodium(I) complexes of macrocyclic NHC-based pincer ligands—which feature dodecamethylene, tetradecamethylene or hexadecamethylene wingtip linkers viz. [Rh(CNC-n)(C₂H₄)][BAr^F₄] (n=12, 14, 16; Ar^F=3,5-(CF₃)₂C₆H₃)—have been investigated, using the bulky alkynes HC≡CtBu and HC≡CAr’ (Ar’=3,5-tBu₂C₆H₃) as substrates. These stoichiometric reactions proceed with formation of rhodium(III) alkynyl alkenyl derivatives and produce rhodium(I) complexes of conjugated 1,3-enynes by C−C bond reductive elimination through the annulus of the ancillary ligand. The intermediates are formed with orthogonal regioselectivity, with E-alkenyl complexes derived from HC≡CtBu and gem-alkenyl complexes derived from HC≡CAr’, and the reductive elimination step is appreciably affected by the ring size of the macrocycle. For the homocoupling of HC≡CtBu, E-tBuC≡CCH=CHtBu is produced via direct reductive elimination from the corresponding rhodium(III) alkynyl E-alkenyl derivatives with increasing efficacy as the ring is expanded. In contrast, direct reductive elimination of Ar'C≡CC(=CH₂)Ar’ is encumbered relative to head-to-head coupling of HC≡CAr’ and it is only with the largest macrocyclic ligand studied that the two processes are competitive. These results showcase how macrocyclic ligands can be used to interrogate the mechanism and tune the outcome of terminal alkyne coupling reactions, and are discussed with reference to catalytic reactions mediated by the acyclic homologue [Rh(CNC-Me)(C₂H₄)][BAr^F₄] and solvent effects.