- Catalytic Aldehyde and Alcohol Arylation Reactions Facilitated by a 1,5-Diaza-3,7-diphosphacyclooctane Ligand
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We report a catalytic method to access secondary alcohols by the coupling of aryl iodides. Either aldehydes or alcohols can be used as reaction partners, making the transformation reductive or redox-neutral, respectively. The reaction is mediated by a Ni catalyst and a 1,5-diaza-3,7-diphosphacyclooctane. This P2N2ligand, which has previously been unrecognized in cross-coupling and related reactions, was found to avoid deleterious aryl halide reduction pathways that dominate with more traditional phosphines and NHCs. An interrupted carbonyl-Heck type mechanism is proposed to be operative, with a key 1,2-insertion step forging the new C-C bond and forming a nickel alkoxide that may be turned over by an alcohol reductant. The same catalyst was also found to enable synthesis of ketone products from either aldehydes or alcohols, demonstrating control over the oxidation state of both the starting materials and products.
- Isbrandt, Eric S.,Nasim, Amrah,Newman, Stephen G.,Zhao, Karen
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supporting information
p. 14646 - 14656
(2021/09/18)
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- Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase
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Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2.
- Winters, Maria,DuHadaway, James B.,Pham, Khoa N.,Lewis-Ballester, Ariel,Badir, Shorouk,Wai, Jenny,Sheikh, Eesha,Yeh, Syun-Ru,Prendergast, George C.,Muller, Alexander J.,Malachowski, William P.
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supporting information
p. 455 - 464
(2018/11/25)
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- Grignard Reagents on a Tab: Direct Magnesium Insertion under Flow Conditions
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An on-demand preparation of organomagnesium reagents is presented using a new flow protocol. The risks associated with the activation of magnesium are circumvented by a new on-column initiation procedure. Required amounts of solutions with a precise titration were obtained. Telescoped flow or batch reactions allow access to a diverse set of functional groups.
- Huck, Lena,De La Hoz, Antonio,Díaz-Ortiz, Angel,Alcázar, Jesus
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supporting information
p. 3747 - 3750
(2017/07/26)
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- Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
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A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC50 values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.
- Pajouhesh, Hassan,Feng, Zhong-Ping,Ding, Yanbing,Zhang, Lingyun,Pajouhesh, Hossein,Morrison, Jerrie-Lynn,Belardetti, Francesco,Tringham, Elizabeth,Simonson, Eric,Vanderah, Todd W.,Porreca, Frank,Zamponi, Gerald W.,Mitscher, Lester A.,Snutch, Terrance P.
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scheme or table
p. 1378 - 1383
(2010/07/06)
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- Glycine transporter-1 inhibitors
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The present invention provides compounds that are glycine transporter 1 (hereinafter referred to as GlyT-1) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of GlyT1 such as cognitive disorders associated with Schizophrenia, ADHD (attention deficit hyperactivity disorder), MCI (mild cognitive impairment), and the like. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 27
(2008/06/13)
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- Nonracemic diarylmethanols from CuH-catalyzed hydrosilylation of diaryl ketones
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(Chemical Equation Presented) An efficient method for the synthesis of nonracemic diarylmethanols has been developed. The use of (R)-(-)-(DTBM-SEGPHOS) CuH effects highly enantioselective 1,2-hydrosilylation of prochiral diaryl ketones.
- Lee, Ching-Tien,Lipshutz, Bruce H.
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supporting information; experimental part
p. 4187 - 4190
(2009/05/30)
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- An electrochemical coupling of organic halide with aldehydes, catalytic in chromium and nickel salts. the Nozaki-Hiyama-Kishi reaction.
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[reaction: see text] Electrochemical arylation of arenecarboxaldehydes using an iron sacrificial anode in the presence of chromium and nickel catalysts afforded the corresponding arylated secondary alcohols in moderate to good yields. The chromium and nickel salts as catalysts are obtained by oxidation of a stainless steel rod during a preelectrolysis in 7% and 3%, respectively. The process was also applied to the addition of vinyl halide, allyl acetate, or alpha-chloroester to aromatic aldehydes.
- Durandetti,Nedelec,Perichon
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p. 2073 - 2076
(2007/10/03)
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- Nickel- and chromium-catalysed electrochemical coupling of aryl halides with arenecarboxaldehydes
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Electrochemical arylation of arenecarboxaldehydes using a stainless steel sacrificial anode in the presence of Ni catalysts afforded the corresponding arylated secondary alcohols in good yields.
- Durandetti, Muriel,Perichon, Jacques,Nedelec, Jean-Yves
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p. 9009 - 9013
(2007/10/03)
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- Solvolysis of benzylic chlorides with extended charge delocalization. α-tert-Butyl(2-naphthyl)methyl, 9-fluorenyl and monosubstituted benzhydryl chlorides
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Rate constants of solvolysis of α-tert-butyl(2-naphthyl)methyl chloride (1), 9-fluorenyl chloride (2) and a series of monosubstituted benzhydryl chlorides (3) in a wide range of solvents were measured. Grunwald-Winstein-type correlation analysis of log k for 2 and 3 against YBnCl, with or without nucleophilicity N, yielded less satisfactory linear correlations than that against log k(l). A new scale of solvent ionizing power, YxBnCl for the correlation of solvolytic reactivities of benzylic chlorides with extended charge delocalization based on log k(1) was developed. Application to the mechanistic study suggested the solvolysis of 2 and 4-nitrobenzhydryl chloride were non-limiting. Hammett plots against α+ constants exhibited more negative ρ values in less nucleophilic solvents. In a benzhydryl chloride containing a strong deactivating substituent, such as 4-nitro, the positive charge delocalizes mainly over the unsubstituted ring in the cationic transition state. The uneven charge distribution was also confirmed by Mulliken population analysis at the level of the RHF/6-31G*//RHF/3-21G(*) basis set for cations. Comparison of the results of correlation analysis using the equation log(k/k0) = mY vs the equation log(k/k0) = mY + hI, and using the equation log(k/k0) = mY +IN vs the equation log(k/ko) = mY + IN + hI indicated the use of YBnCl or YxBncl could give a better understanding of solvolytic mechanisms than the combinatorial use of YCl and I.
- Liu, Kwang-Ting,Lin, Yen-Shyi,Tsao, Meng-Lin
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p. 223 - 229
(2007/10/03)
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- 3'-Chloro-3α-(diphenylmethoxy)tropane but not 4'-chloro-3α- (diphenylmethoxy)tropane produces a cocaine-like behavioral profile
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A series of 2'- and 3'-substituted and 3',3''-disubstituted 3α- (diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (K(i)). Generally, meta- substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported parasubstituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same metasubstituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K(i) = 0.41-2.52 nM). Interestingly, 3'-chloro-3α- (diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.
- Kline, Richard H.,Izenwasser, Sari,Katz, Jonathan L.,Joseph, David B.,Bowen, Wayne D.,Newman, Amy Hauck
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p. 851 - 857
(2007/10/03)
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- Benzylphosphonic acid inhibitors of human prostatic acid phosphatase
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A series of α-substituted benzylphosphonic acids is described as inhibitors of human prostatic acid phosphatase, an enzyme has been used as a model to study aryl phosphatases. The most potent inhibitors in this series are 2-trifluoromethylbenzhydrylphosphonic acid (9 μM), and α-(2-phenylethyl)benzylphosphonic acid (14 μM). The structure-activity studies suggest that bulk tolerance beyond the phosphate binding area limits the steric or hydrophobic contribution to inhibitor potency achieved through α-carbon substitution.
- Schwender,Beers,Malloy,Cinicola,Wustrow,Demarest,Jordan
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p. 311 - 314
(2007/10/03)
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- SOLVOLYSES OF MONOSUBSTITUTED BENZHYDRYL BROMIDES. NUCLEOPHILIC SOLVENT INTERVENTION AND DEPENDENCE OF SOLVATATION ON THE EXTENT OF CHARGE DELOCALIZATION IN CATIONIC TRANSITION STATES
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Solvolyses of monosubstituted benzhydryl bromides gave excellent linear correlations of logk with ?(1+) constants, and not with Y(BnBr) or Y(Br).Correlation analyses against corresponding logk of α-tert-butyl-(2-naphthyl)methyl bromide provided evidence for the importance of different extent of solvation in delocalized transition state and for nucleophilic solvent intervention in the solvolysis of benzhydryl systems.
- Liu, Kwang-Ting,Chin, Chien-Pu,Lin, Yen-Shyi,Tsao, Meng-Lin
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p. 6919 - 6922
(2007/10/02)
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- Comparative Mechanistic Study of the Reaction of Benzophenone with n-BuMgBr and n-BuLi
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Substituent effects on reactivity and product distribution (addition vs reduction) were determined for the reactions of benzophenones with n-BuMgBr and n-BuLi at 0 deg C.In case of the reaction with n-BuMgBr, meta and para-substituted benzophenones gave a reasonably linear Hammet plot, from which the ρ value of 1.45 was calculated, while ortho-substituted derivatives deviated downward from the correlation line.In contrast, the reaction with n-BuLi exhibit very small substituent effects on reactivity.The product distrubution is highly dependent on substituents in the n-BuMgBr reaction, whereas it is essentially independent of substituents in the n-BuLi reaction.Mechanistic differences between the reactions of these two reagents are discussed on the basis of these experimental results.
- Yamataka, Hiroshi,Miyano, Nobutaka,Hanafusa, Terukiyo
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p. 2573 - 2575
(2007/10/02)
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- Extent of Charge Transfer in the Photoreduction of Phenyl Ketones by Alkylbenzenes
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Rate constants for triplet-state reaction of various ring-substituted benzophenones (BPs), acetophenones (APs), and α,α,α-trifluoroacetophenones (TFAs) with toluene and p-xylene have been determined by a combination of flash kinetics, steady-state quenching, and quantum yield measurements.The relative amounts of primary and tertiary radicals formed by reaction of the same ketons with p-cymene have also been measured.For all three types of ketones, rate constants correlate well with triplet ketone reduction potentials.The magnitude of the kinetic isotope effects observed with toluene-d8 and p-xylene-d10 diminishes as the ketones become easier to reduce.All of the ketone triplets react with alkylbenzenes primarily by a charge-transfer mechanism, with the rate-determining step changing from complexation to hydrogen transfer as the ketones become harder to reduce.The least reactive AP triplets probably react significantly via simple hydrogen atom abstraction as well.Those ketones with n,?* lowest triplets (all BPs and some APs) react with p-cymene to give primary/tertiary radical ratios that vary no more than a factor of 2 from the 0.40 value displayed by tert-butoxy radicals; those with ?,?* lowest triplets (TFAs and some APs) give ratios that favor primary radicals and that vary by an order of magnitude with the triplet ketone reduction potential.The variation in cymene product ratios reflect different orientations for attack on cymene by n,?* and ?,?* triplets and differing degrees of partial electron transfer within the exciplexes, which are not tight radical ion pairs.The variation seen for ?,?* triplets represents a stereoelectronic effect within face-to-face exciples, as evidenced by the excerptional behavior of p-diacylbenzenes, which give the highest ratio of tertiary radicals from cymene.There is no set intrinsic ratio of reactivity for ?,?* triplets vs. n,?* triplets in these CT reactions.The two types of triplets show similar reactivity for the more easily reduced triplets, with the harder to reduce ?,?* triplets being only one-tenth as reactive as n,?* triplets of comparable triplet reduction potential.When the extent of electron transfer in the exciplex is small, hydogen transfer is rate determining and ?,?* reactivity drops.A study of two radical reactions which generate benzyl and α-hydroxy-α-methylbenzyl radicals indicates that radical disproportionation cannot explain the low quantum yields (0.10) of most ketone-toluene photoreductions, which apparently involve substantial radiation less decay by the exciplex intermediates.
- Wagner, Peter J.,Truman, Royal J.,Puchalski, Alan E.,Wake, Ronald
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p. 7727 - 7738
(2007/10/02)
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