- Difluorocyclobutylacetylenes as positive allosteric modulators of mGluR5 with reduced bioactivation potential
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Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.
- Degnan, Andrew P.,Maxwell, Darrell,Balakrishnan, Anand,Brown, Jeffrey M.,Easton, Amy,Gulianello, Michael,Hanumegowda, Umesh,Hill-Drzewi, Melissa,Miller, Regina,Santone, Kenneth S.,Senapati, Arun,Shields, Eric E.,Sivarao, Digavalli V.,Westphal, Ryan,Whiterock, Valerie J.,Zhuo, Xiaoliang,Bronson, Joanne J.,Macor, John E.
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p. 5871 - 5876
(2016/12/06)
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- Lanthanide-Catalyzed Reversible Alkynyl Exchange by Carbon–Carbon Single-Bond Cleavage Assisted by a Secondary Amino Group
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Lanthanide-catalyzed alkynyl exchange through C?C single-bond cleavage assisted by a secondary amino group is reported. A lanthanide amido complex is proposed as a key intermediate, which undergoes unprecedented reversible β-alkynyl elimination followed by alkynyl exchange and imine reinsertion. The in situ homo- and cross-dimerization of the liberated alkyne can serve as an additional driving force to shift the metathesis equilibrium to completion. This reaction is formally complementary to conventional alkyne metathesis and allows the selective transformation of internal propargylamines into those bearing different substituents on the alkyne terminus in moderate to excellent yields under operationally simple reaction conditions.
- Shao, Yinlin,Zhang, Fangjun,Zhang, Jie,Zhou, Xigeng
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supporting information
p. 11485 - 11489
(2016/10/24)
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- "quick and click" assembly of functionalised indole rings via metal-promoted cyclative tandem reactions
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An efficient and convenient synthesis of a variety of decorated indoles using a three-component tandem metal-catalysed process is described. We propose here a new "synthetic kit" that allows for the "quick and click" assembly of indole rings using readily available, and inexpensive starting materials under environmentally friendly reaction conditions. This journal is
- Capitta, Francesca,De Luca, Lidia,Porcheddu, Andrea
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p. 59297 - 59301
(2015/02/19)
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- Thieme Chemistry Journal Awardees - Where are they now? A general one-step synthesis of alkynes from enolisable carbonyl compounds
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Terminal and internal acetylenes were obtained in good to excellent isolated yields from carbonyl compounds by converting the carbonyl functionality into the enol nonaflate intermediate followed by elimination to give the C-C triple bond. The one-pot transformations were uniformly induced by phosphazene bases combined with mildly electrophilic nonafluorobutane-1-sulfonyl fluoride. The method is the most general among those reported to date as it applies to both acyclic ketones and aldehydes. Only moderate kinetic regioselectivity in favour of alk-1-yne achieved from methyl n-alkyl ketone represents a limitation of the method. In all the other instances, individual acetylenic products were obtained. Georg Thieme Verlag Stuttgart.
- Lyapkalo, Ilya M.,Vogel, Michael A. K.,Boltukhina, Ekaterina V.,Vav?ík, Ji?í
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scheme or table
p. 558 - 561
(2009/07/09)
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- Terminal alkynes from aldehydes via dehydrohalogenation of (Z)-1-iodo-1-alkenes with TBAF
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Terminal alkynes were prepared in near quantitative yields via dehydrohalogenation of (Z)-1-iodo-1-alkenes with tetrabutylammonium fluoride (TBAF) under mild conditions. The methodology was expanded to include a one-pot, direct synthesis of terminal alkynes from aldehydes without the necessity of isolating and purifying the intermediate iodoalkene.
- Beshai, Mira,Dhudshia, Bhartesh,Mills, Ryan,Thadani, Avinash N.
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supporting information; experimental part
p. 6794 - 6796
(2009/04/07)
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- Design, synthesis and biological evaluation of novel, simplified analogues of laulimalide: Modification of the side chain
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Novel, simplified analogues of the microtubule-stabilizing anticancer agent laulimalide, including the first derivatives with unnatural side chains, were designed by molecular modelling, synthesized by a late-stage diversification strategy, and evaluated in vitro for growth inhibition of human ovarian carcinoma cell lines (A2780, A2780/AD10).
- Paterson, Ian,Menche, Dirk,Hakansson, Anders E.,Longstaff, Adrian,Wong, David,Barasoain, Isabel,Buey, Ruben M.,Diaz, J. Fernando
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p. 2243 - 2247
(2007/10/03)
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- Process for the preparation of cyclopropylacetylene
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The present invention relates generally to novel methods for the preparation of cyclopropylacetylene which is an essential reagent in the asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; a useful human immunodeficiency virus (HIV) reverse transcriptase inhibitor with superior anti-retroviral activity. In the process, for example, cyclopropane carboxaldehyde is alkylated to form 1,1,1-trichloro-2-cyclopropyl-ethanol; which in turn undergoes elimination to form 1,1-dichloro-2-cyclopropyl-ethene; which in turn undergoes elimination to form cyclopropyl acetylene.
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Page column 14, 15-16
(2008/06/13)
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- Reaction of Grignard compounds with 4-chloro-2-methyl-3-butyn-2-ol in Diethyl Ether equivalents
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Reactions of RMgX · THF complexes with 4-chloro-2-methyl-3-butyn-2-ol in aromatic hydrocarbons were studied. The complexes formed by arylmagnesium halides require the presence of anisole for the reaction to occur. 4-Chloro-2-methyl-3-butyn-2-ol can be synthesized by reaction of 2-methyl-3-butyn-2-ol with sodium hypochloride in the two-phase system water-benzene.
- Shchelkunov,Sivolobova,Mataeva,Minbaev,Muldakhmetov
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- A new and practical synthesis of vinyl dichlorides via a non-Wittig-type approach
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A practical approach for the conversion of aldehydes to vinyl dichlorides has been developed. These are three-step, one-pot reactions involving the formation of trichlorocarbinol by treatment of aldehydes with trichloroacetic acid and sodium trichloroacetate followed by in situ protection and elimination reactions to form the desired vinyl dichlorides in 85 to 95% yields. (C) 2000 Dupont Pharmaceuticals Company.
- Wang, Zhe,Campagna, Silvio,Xu, Guoyou,Pierce, Michael E.,Fortunak, Joseph M.,Confalone, Pat N.
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p. 4007 - 4009
(2007/10/03)
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- Total synthesis of parvaquone and the serendipitous discovery of a novel chromium-mediated method for β-lactone formation
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During attempts to synthesise the 2-hydroxy-1,4-naphthoquinone, parvaquone, 1, a novel chromium-mediated method for the synthesis of functionalised β-lactones from propargyl alcohols has been discovered. Additionally, using both dry state and ultrasound conditions, the total synthesis of parvaquone (1) has been achieved; the most efficient techniques deliver this target compound in up to 46% overall yield over, as low as, two synthetic processes.
- Harrity, Joseph P. A.,Kerr, William J.,Middlemiss, David,Scott, James S.
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p. 219 - 227
(2007/10/03)
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- Heterocyclic pesticidal compounds
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Compounds of the formula (I) STR1 which contain between 10 and 27 carbon atoms, and wherein m and n are independently selected from 0, 1 and 2; R2a is hydrogen, methyl, or ethyl; R2b is acetylene or contains between 3 and 18 carbon atoms and is a group R7, wherein R7 is a C1-13 non-aromatic hydrocarbyl group, optionally substituted by a cyano or C1-4 carbalkoxy group and/or by one or two hydroxy groups and/or by one to five halo atoms which are the same or different and/or by one to three groups R8 which are the same or different and each contain one to four hetero atoms, which are the same or different and are chosen from oxygen, sulphur, nitrogen and silicon, 1 to 10 carbon atoms and optionally 1 to 6 fluoro or chloro atoms or R2b is a 6-membered aromatic ring substituted by cyano and/or by one to three groups R8 and/or by a group --C CH, --C C-R7 or C C-halo and/or by one to five halo atoms and/or by one to three C1-4 haloalkyl groups wherein R7 and R8 are as hereinbefore defined; R4 and R6 are the same or different and are chosen from hydrogen, methyl, trifluoromethyl or cyano; and R5 is hydrogen or methyl provided that R2b is not propyl or butyl are described which have pesticidal activity, particularly against arthropod pests. Pesticidal formulations containing the compounds of the formula (I), their use in the control of pests and method for their preparation are also disclosed.
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- Flash Vacuum Pyrolysis of Stabilised Phosphorus Ylides. Part 2. Two-step Conversion of Acid Chlorides into Acetylenic Esters and Terminal Alkynes
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The known thermal extrusion of Ph3PO from α-acyl-α-ethoxycarbonyl ylides 1 to give acetylenic esters 2 can be accomplished in excellent yield by using flash vacuum (FVP) at 500 deg C.Upon rasing the furnace temperature to 750 deg C, this reaction is accompanied by unexpected loss of the ethoxycarbonyl group to give the terminal alkynes 7 in moderate yield.A mechanism is proposed for this reaction based on isotopic labelling studies.Ten new examples of ylides 1 have been prepared for the first time.
- Aitken, R. Alan,Horsburg, Caroline E. R.,McCreadie, J. Graeme,Seth, Shirley
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p. 1727 - 1732
(2007/10/02)
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- Flash Vacuum Pyrolysis of Stabilised Phosphorus Ylides. Part 1. Preparation of Aliphatic and Therminal Alkynes
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Thermal extrusion of Ph3PO from β-oxoalkylidenetriphenylphosphoranes 4 to give the alkynes 5, which under conventional pyrolysis conditions is restricted to cases in which R1 is an electron withdrawing group, has been successfully achieved for R1=H or alkyl by using FVP.The method allows convenient construction of multigram quantities of the alkynes 5 from alkyl halides 1 and allows convenient construction of multigram quantities of the alkynes 5 from alkyl halides 1 and acid chlorides 3 in three steps with good overall yields.Under the conditions used the ylides with R2 = cyclobutyl also undergo less of ethene to provide convenient access to the vinylalkynes 6.
- Aitken, R. Alan,Atherton, J. Ian
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p. 1281 - 1284
(2007/10/02)
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- Selective debromination of 1,1-dibromoalkenes; a new access to di- or trisubstituted alkenes
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1,1-Dibromoalkenes were selectivity debrominated by halogen-metal exchange. Depending on reagents and conditions, E-bromoalkenes can be obtained with very high stereoselectivity.
- Grandjean,Pale
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p. 1155 - 1158
(2007/10/02)
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- Generation of Alkylidenecarbenes from 1,1-Dibromoalk-1-enes by the Reaction with Samarium Diiodide in Hexamethylphosphoric Triamide-Benzene
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Reaction of 1,1-dibromoalk-1-enes with samarium diiodide in benzene containing 10percent of hexamethylphosphoric triamide (HMPA) affords rearranged alkynes; generation of alkylidenecarbenes is probably involved.
- Kunishima, Munetaka,Hioki, Kazuhito,Ohara, Takashi,Tani, Shohei
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p. 219 - 220
(2007/10/02)
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- Chiral Synthesis via Organoboranes. 29. A General Synthesis of α-Chiral Monosubstituted Acetylenes and Their Trimethylsilyl Derivatives from Enantiomerically Pure Boronic Esters
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The procedure for the synthesis of by the iodination of is impractical for the synthesis of the corresponding chiral derivatives, , due to the unavailability of the required R*3B compounds.RThxBOMe and R*ThxBOCH3, now readily available by established procedures, serve handily for the syntheses of and respectively from , but fail for the syntheses of either or , in reasonable yield, from .Fortunately, this difficulty can be circumvented by utilizing .Indeed, treatment of enantiomerically pure monoalkylthexylborinates, R*ThxBOCH3, readily prepared from enantiomerically pure boronic esters, with forms an ate complex which readily undergoes the desired iodine-induced rearrangement, forming α-chiral (trimethylsilyl)acetylenes, .The (trimethylsilyl)acetylenes are easily desilylated to afford the corresponding α-chiral terminal acetylenes, , in yields of ca. 70percent and essentially 100percent enantiomeric excess (99percent).These intermediates, and , can be readily converted by simple procedures into a wide variety of pure enantiomers: R*CH=CH2, R*CH2CHO, R*COOH, R*CH2COOH, R*COCOOR, etc.Since both (+)- and (-)-alkylboronic esters are now readily available in essentially 100percent enantiomeric purity, it is now possible to synthesize (+)- and (-)-α-chiral monosubstituted acetylenes and their trimethylsilyl derivatives in very high enantiomeric purities.This provides the first general, efficient synthesis of these valuable synthons in such high enantiomeric purities.
- Brown, Herbert C.,Mahindroo, Verinder K.,Bhat, N. G.,Singaram, Bakhtan
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p. 1500 - 1505
(2007/10/02)
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- Preparation of Allenic Sulfones and Allenes from the Selenosulfonation of Acetylenes
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β-(Phenylseleno)vinyl sulfones 2 are readily obtained from the free-radical selenosulfonation of acetylenes.Compounds 2 isomerize to allyl sulfones 4 under base-catalyzed conditions in nearly quantitative yield, with high stereoselectivity favoring the Z configuration.Allyl sulfones 4 afford generally high yields of allenic sulfones 1 when subjected to oxidation with m-chloroperbenzoic acid or tert-butyl hydroperoxide, followed by selenoxide syn-elimination.The sulfone-stabilized anion intermediates in the isomerizations of 2 to 4 can be alkylated, deuterated,or silylated in the α-position prior to oxidation, providing allenic sulfones with an additional α-substituent.In some cases, spontaneous elimination of the phenylseleno group occurred, producing the allenic sulfone without the need for an oxidation step.Desulfonylation of allyl sulfones 4f, 4c, and 25 with sodium amalgam afforded vinyl selenides that were converted to allenes in moderate to good yields by oxidation-elimination.The copper catalyzed coupling of allyl sulfones 4 with Grignard reagents comprises an alternative route to vinyl selenide precursors of allenes.These procedures permit the synthesis of various α- and γ-substituted allenic sulfones and allenes from acetylenes.
- Back, Thomas G.,Krishna, M. Vijaya,Muralidharan, K. Raman
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p. 4146 - 4153
(2007/10/02)
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- Vinylic Organoboranes. 1. A Convenient Synthesis of Acetylenes via the Reaction of Lithium (1-Alkynyl)organoborates with Iodine
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Lithium (1-alkynyl)organoborates, readily prepared from organoboranes and lithium acetylides, undergo a facile reaction at low temperature with iodine to for internal acetylenes in high yield.Unlike conventional methods for the preparation of acetylenes via nucleophilic displacement, the reaction is applicable to both primary and secondary as well as aromatic and functionally substituted groups.The use of lithium acetylide-ethylenediamine form the formation of the organoborate extends the reaction to terminal acetylenes.This reaction occurs with complete retention of the configuration about the boron-carbon bond.The procedure, with its exceptionally broad applicability, provides a simple, general route to internal and terminal acetylenes.
- Suzuki, Akira,Miyaura, Norio,Abiko, Shigeo,Itoh, Mitsuomi,Midland, M., Mark,et al.
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p. 4507 - 4511
(2007/10/02)
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- A New General Synthesis of Aliphatic and Terminal Alkynes: Flash Vacuum Pyrolysis of β-Oxoalkylidenetriphenylphosphoranes
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By using flash vacuum conditions the thermal elimination of Ph3PO from β-oxoalkylidenetriphenylphosphoranes, previously confined to cases with an α-electron withdrawing group, has been extended to provide a general, high yielding synthesis of aliphatic and terminal alkynes.
- Aitken, R. Alan,Atherton, J. Ian
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p. 1140 - 1141
(2007/10/02)
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- Poly(ethylene glycols) Are Extraordinary Catalysts in Liquid-Liquid Two-Phase Dehydrohalogenation
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Poly(ethylene glycols) 3> are highly active and selective in catalyzing dehydrohalogenation in organic-aqueous hydroxide two-phase systems.
- Kimura, Yoshikazu,Regen, Steven L.
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p. 2493 - 2494
(2007/10/02)
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- Relative Migratory Aptitudes of Alkyl Groups in the Iodination of Lithium Ethynyltrialkylborates
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Relative migratory aptitudes of various alkyl groups have been determined in the iodine-induced rearrangement of lithium ethynyltrialkylborates.Trialkylboranes of types R3-nBR'n and thexyl-BRR' were complexed with lithium acetylide-ethylenediamine.Iodination, followed by deiodoboration of the rearranged intermediates, produced 1-alkynes in amounts which depend, after statistical correction, on the relative rates of alkyl group migration in an intramolecular competition.In some cases, the migratory aptitude was found to depend on the alkyl substitution pattern in the organoborate.The overall migratory aptitude order is bicyclooctyl > n-butyl > cyclohexyl, isobutyl, sec-butyl > thexyl.When the secondary and primary migrating carbon series are considered separately, the order is consistently bicyclooctyl > cyclohexyl > sec-butyl, and n-butyl > isobutyl.
- Slayden, Suzanne W.
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p. 2311 - 2314
(2007/10/02)
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