- Photoassisted Cross-Coupling Reaction of α-Chlorocarbonyl Compounds with Arylboronic Acids
-
A Suzuki-Miyaura cross-coupling reaction of α-chloroacetates or α-chloroacetamides with arylboronic acids is made possible by visible-light irradiation. This reaction provides a useful method for the synthesis of α-arylacetates and α-arylacetamides from chlorides under mild reaction conditions. An indole-3-acetic acid derivative that is the key intermediate of the plant hormone auxin can be synthesized from 1-Boc-indole in two steps by combining an iridium-catalyzed C-H borylation and a palladium-catalyzed cross-coupling reaction.
- Miura, Tomoya,Murakami, Masahiro,Oku, Naoki
-
supporting information
p. 1616 - 1619
(2022/03/14)
-
- Copper-Catalyzed Ullmann-Type Coupling and Decarboxylation Cascade of Arylhalides with Malonates to Access α-Aryl Esters
-
We have developed a high-efficiency and practical Cu-catalyzed cross-coupling to directly construct versatile α-aryl-esters by utilizing readily available aryl bromides (or chlorides) and malonates. These gram-scale approaches occur with turnovers of up to 1560 and are smoothly conducted by the usage of a low catalyst loading, a new available ligand, and a green solvent. A variety of functional groups are tolerated, and the application occurs with α-aryl-esters to access nonsteroidal anti-inflammatory drugs (NSAIDs) on the gram scale.
- Cheng, Fei,Chen, Tao,Huang, Yin-Qiu,Li, Jia-Wei,Zhou, Chen,Xiao, Xiao,Chen, Fen-Er
-
supporting information
p. 115 - 120
(2022/01/04)
-
- Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide-Functionalized Phosphine Ligands
-
The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α-aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide-functionalized phosphines to fit the requirements of Negishi couplings. Record-setting activities were achieved in palladium-catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl-YPhos ligand bearing an ortho-tolyl-substituent in the backbone. This highly electron-rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.
- Hu, Zhiyong,Wei, Xiao-Jing,Handelmann, Jens,Seitz, Ann-Katrin,Rodstein, Ilja,Gessner, Viktoria H.,Goo?en, Lukas J.
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supporting information
p. 6778 - 6783
(2021/02/01)
-
- Enantioselective Desymmetrization of 2-Aryl-1,3-propanediols by Direct O-Alkylation with a Rationally Designed Chiral Hemiboronic Acid Catalyst That Mitigates Substrate Conformational Poisoning
-
Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is described and applied in the highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined chairlike six-membered anionic complex with the hemiboronic heterocycle. The optimal binaphthyl-based catalyst 1g features a large aryloxytrityl group to effectively shield one of the two prochiral hydroxy groups on the diol complex, whereas a strategically placed "methyl blocker"on the boroxarophenanthrene unit mitigates the deleterious effect of a competing conformation of the complexed diol that compromised the overall efficiency of the desymmetrization process. This methodology affords monoalkylated products in enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols with various 2-aryl/heteroaryl groups.
- Estrada, Carl D.,Ang, Hwee Ting,Vetter, Kim-Marie,Ponich, Ashley A.,Hall, Dennis G.
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supporting information
(2021/04/07)
-
- Preparation of Organic Nitrates from Aryldiazoacetates and Fe(NO3)3·9H2O
-
A thermal protocol is reported for the formal insertion of nitric acid into aryldiazoacetates using Fe(NO3)3·9H2O. This strategy is mild and high yielding and allows the preparation of a large variety of members of an unprecedented family of organic nitrates. The nitrate group can be also readily transformed into other functional groups and heterocyclic moieties and can possibly allow new biological explorations of untapped potential associated with their NO-releasing ability.
- Thurow, Samuel,Fernandes, Alessandra A. G.,Quevedo-Acosta, Yovanny,De Oliveira, Matheus F.,De Oliveira, Marcelo G.,Jurberg, Igor D.
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p. 6909 - 6913
(2019/09/12)
-
- Catalytic Asymmetric γ-Lactam Synthesis from Enolisable Anhydrides and Imines
-
An anion-binding approach to the problem of preparing enantioenriched γ-lactams from enolisable anhydrides and imines is reported. A simple bisurea catalyst promotes the cycloaddition between α-aryl succinic anhydrides and either PMP- or benzhydryl-protec
- Collar, Aarón Gutiérrez,Trujillo, Cristina,Lockett-Walters, Bruce,Twamley, Brendan,Connon, Stephen J.
-
supporting information
p. 7275 - 7279
(2019/05/15)
-
- Discovery of Orally Bioavailable and Liver-Targeted Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors for the Treatment of Anemia
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We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we
- Liu, Ping,Wang, Liping,Dubois, Byron G.,Colandrea, Vincent J.,Liu, Rongqiang,Cai, Jiaqiang,Du, Xiaoxing,Quan, Weiguo,Morris, William,Bai, Jianwu,Bishwokarma, Bimjhana,Cheng, Mangeng,Piesvaux, Jennifer,Ray, Kallol,Alpert, Carla,Chiu, Chi-Sung,Zielstorff, Mark,Metzger, Joseph M.,Yang, Liming,Leung, Dennis,Alleyne, Candice,Vincent, Stella H.,Pucci, Vincenzo,Li, Xiaofang,Crespo, Alejandro,Stickens, Dominique,Hale, Jeffrey J.,Ujjainwalla, Feroze,Sinz, Christopher J.
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p. 1193 - 1198
(2018/12/11)
-
- Dynamic kinetic resolution of bis-aryl succinic anhydrides: Enantioselective synthesis of densely functionalised γ-butyrolactones
-
The efficient Dynamic Kinetic Resolution (DKR) of disubstituted anhydrides has been shown to be possible for the first time. Using an ad hoc designed organocatalyst and an enantio- and diastereoselective cycloaddition process with aldehydes, stereochemically complex γ-butyrolactone derivatives can be obtained-with control over three contiguous stereocentres, one of which is all carbon quaternary.
- Claveau, Romain,Twamley, Brendan,Connon, Stephen J.
-
supporting information
p. 3231 - 3234
(2018/04/05)
-
- Synthesis of α-alkylated γ-butyrolactones with concomitant anhydride kinetic resolution using a sulfamide-based catalyst
-
The Kinetic Resolution (KR) of α-alkylated enolisable disubstituted anhydrides has been shown to be possible for the first time. In the presence of an ad hoc designed novel class of bifunctional sulfamide organocatalyst, a regio-, diastereo- and enantioselective cycloaddition reaction between the enolisable anhydride and benzaldehydes provides densely functionalised γ-butyrolactones in one pot (up to 19:1 dr, 94% ee) with control over three contiguous stereocentres. The concomitant resolution of the starting material anhydride, provides access to a range of chiral succinate derivatives with selectivity factors up to S? = 10.5.
- Claveau, Romain,Twamley, Brendan,Connon, Stephen J.
-
supporting information
p. 7574 - 7578
(2018/11/02)
-
- Mechanistic studies on gold-catalyzed direct arene c-h bond functionalization by carbene insertion: The coinage-metal effect
-
The catalytic functionalization of the Csp2-H bond of benzene by means of the insertion of the CHCO2Et group from ethyl diazoacetate (N2= CHCO2Et) has been studied with the series of coinage-metal complexes IPrMCl (IPr = 1,3-bis- (diisopropylphenyl)imidazol-2-ylidene) and NaBArF 4 (BArF 4 = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate). For Cu and Ag, these examples constitute the first use of such metals toward this transformation, which also provides ethyl cyclohepta-2,4,6-trienecarboxylate as a byproduct from the so-called Buchner reaction. In the case of methyl-substituted benzenes, the reaction exclusively proceeds onto the aromatic ring, the Csp3-H bond remaining unreacted. A significant coinage-metal effect has been observed, since the gold catalyst favors the formation of the insertion product into the Csp2-H bond whereas copper and silver preferentially induce the formation of the cycloheptatriene derivative. Experimental studies and theoretical calculations have explained the observed selectivity in terms of the formation of a common Wheland intermediate, resembling an electrophilic aromatic substitution, from which the reaction pathway evolves into two separate routes to each product.
- Fructos, Manuel R.,Besora, Maria,Braga, Ataualpa A. C,Díaz-Requejo, M. Mar,Maseras, Feliu,Perez, Pedro J.
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p. 172 - 179
(2017/04/04)
-
- Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane
-
Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.
- Bailey, William F.,Lambert, Kyle M.,Stempel, Zachary D.,Wiberg, Kenneth B.,Mercado, Brandon Q.
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p. 12116 - 12127
(2016/12/23)
-
- INHIBITORS OF HIF PROLYL HYDROXYLASE
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The present invention concerns compounds of formula I or pharmaceutically acceptable salts thereof, which inhibit HIF prolyl hydroxylase, their use for enhancing endogenous production of erythropoietin, and for treating conditions associated with reduced endogenous production of erythropoietin such as anemia and like conditions, as well as pharmaceutical compositions comprising such a compound and a pharmaceutical carrier.
- -
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Page/Page column 122
(2016/04/20)
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- Chemoenzymatic synthesis and antileukemic activity of novel C9- and C14-functionalized parthenolide analogs
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Parthenolide is a naturally occurring terpene with promising anticancer properties, particularly in the context of acute myeloid leukemia (AML). Optimization of this natural product has been challenged by limited opportunities for the late-stage functionalization of this molecule without affecting the pharmacologically important α-methylene-γ-lactone moiety. Here, we report the further development and application of a chemoenzymatic strategy to afford a series of new analogs of parthenolide functionalized at the aliphatic positions C9 and C14. Several of these compounds were determined to be able to kill leukemia cells and patient-derived primary AML specimens with improved activity compared to parthenolide, exhibiting LC50values in the low micromolar range. These studies demonstrate that different O–H functionalization chemistries can be applied to elaborate the parthenolide scaffold and that modifications at the C9 or C14 position can effectively enhance the antileukemic properties of this natural product. The C9-functionalized analogs 22a and 25b were identified as the most interesting compounds in terms of antileukemic potency and selectivity toward AML versus healthy blood cells.
- Tyagi, Vikas,Alwaseem, Hanan,O'Dwyer, Kristen M.,Ponder, Jessica,Li, Qi Ying,Jordan, Craig T.,Fasan, Rudi
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p. 3876 - 3886
(2016/08/04)
-
- Method for producing hematopoietic stem cells using pyrazole compounds
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An expanding agent for hematopoietic stem cells and/or hematopoietic progenitor cells useful as a therapy for various hematopoietic diseases and useful for improvement in the efficiency of gene transfer into hematopoietic stem cells for gene therapy is provided. A method of producing hematopoietic stem cells and/or hematopoietic progenitor cells, which comprises expanding hematopoietic stem cells by culturing hematopoietic stem cells ex vivo in the presence of a compound represented by the formula following (I), a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof (wherein R1 to R8 are as defined in the description).
- -
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Page/Page column 181; 182
(2016/01/10)
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- Synthesis of diversely functionalised 2,2-disubstituted oxetanes: Fragment motifs in new chemical space
-
Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O-H insertion and C-C bond forming cyclisation.
- Davis, Owen A.,Croft, Rosemary A.,Bull, James A.
-
supporting information
p. 15446 - 15449
(2015/10/20)
-
- Synthesis of α-aryl esters and nitriles: Deaminative coupling of α-aminoesters and α-aminoacetonitriles with arylboronic acids
-
Transition-metal-free synthesis of α-aryl esters and nitriles using arylboronic acids with α-aminoesters and α-aminoacetonitriles, respectively, as the starting materials has been developed. The reaction represents a rare case of converting C(sp3)-N bonds into C(sp3)-C(sp2) bonds. The reaction conditions are mild, demonstrate good functional-group tolerance, and can be scaled up. Touch base: A transition-metal-free protocol for the synthesis of α-aryl esters and nitriles by deaminative coupling is presented. Strong bases and transition-metal catalysts are not needed. The new synthetic method uses readily available starting materials and demonstrates wide substrate scope.
- Wu, Guojiao,Deng, Yifan,Wu, Chaoqiang,Zhang, Yan,Wang, Jianbo
-
supporting information
p. 10510 - 10514
(2016/02/18)
-
- PROCESS FOR PREPARING ARYL- AND HETEROARYLACETIC ACID DERIVATIVES
-
The invention relates to a process for preparing aryl- and heteroarylacetic acids and derivatives thereof by reaction of aryl or heteroaryl halides with malonic diesters in the presence of a palladium catalyst, of one or more bases and optionally of a phase transfer catalyst. This process enables the preparation of a multitude of functionalized aryl- and heteroarylacetic acids and derivatives thereof, especially also the preparation of arylacetic acids with sterically demanding substituents.
- -
-
Paragraph 0091; 0092; 0101
(2014/06/23)
-
- Iron(II) bromide-catalyzed intramolecular c-h bond amination [1,2]-shift tandem reactions of aryl azides
-
Iron(II) bromide catalyzes the transformation of ortho-substituted aryl azides into 2,3-disubstituted indoles through a tandem ethereal C-H bond amination [1,2]-shift reaction. The preference for the 1,2-shift component of the tandem reaction was established to be Me 1 2 Ph.
- Nguyen, Quyen,Nguyen, Tuyen,Driver, Tom G.
-
supporting information
p. 620 - 623
(2013/03/13)
-
- PYRAZOLE COMPOUNDS HAVING THERAPEUTIC EFFECT ON MULTIPLE MYELOMA
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Novel therapeutic agents for myeloma are provided. A therapeutic agent for multiple myeloma containing a pyrazole compound represented by the formula (1): wherein R1 is C1-C6 alkyl, C1-C6 alkyl substituted with R17, C1-C6 haloalkyl, phenyl, phenyl substituted with a R11's or the like, R2 is a hydrogen atom, C1-C6 alkyl, phenyl or phenyl optionally substituted with e R21's or the like, R3 is a hydrogen atom or the like, X is a single bond or —(CR6, R7)n—, each of R4 and R5 is independently C1-C6 alkyl or the like, R6 and R7 are hydrogen atoms or C1-C6 alkyl, R8 is phenyl, phenyl optionally substituted with k R81's or the like, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient.
- -
-
Paragraph 0255; 0256; 0257
(2013/10/07)
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- Pd-catalyzed decarboxylative cross-couplings of potassium malonate monoesters with aryl halides
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An efficient catalytic protocol for Pd-catalyzed decarboxylative cross-coupling of potassium malonate monoesters and derivatives with aryl bromides and chlorides are described. Because of its broad applicability, this new catalytic system provides an alternative method for the preparation of diverse aryl acetic acids and derivatives.
- Feng, Yi-Si,Wu, Wei,Xu, Zhong-Qiu,Li, Yan,Li, Ming,Xu, Hua-Jian
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experimental part
p. 2113 - 2120
(2012/03/26)
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- Practical synthesis of 2-arylacetic acid esters via palladium-catalyzed dealkoxycarbonylative coupling of malonates with aryl halides
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A new palladium-based system was developed that catalyzes the coupling of aryl halides with diethyl malonates in the presence of mild bases. In the course of the reaction, the intermediately formed diethyl arylmalonate is directly converted into the arylacetic acid ester via liberation of carbon dioxide and an alkanol. This cross-coupling/dealkoxycarbonylation process provides an efficient and high-yielding synthetic entry to diversely functionalized arylacetic acid esters. Two complementary protocols were developed, one of which is optimal for electron-rich, the other for electron-poor aryl halides. Both make use of low loadings of palladium(0) bis(dibenzylideneacetone) (0.5 mol%)/tri-tert-butylphosphonium tetrafluoroborate (1.1 mol%) as the catalyst and diethyl malonate as the reaction solvent. The new procedures are particularly effective for sterically hindered substrates. Copyright
- Song, Bingrui,Rudolphi, Felix,Himmler, Thomas,Goossen, Lukas J.
-
supporting information; experimental part
p. 1565 - 1574
(2011/08/03)
-
- Synthesis of α-Aryl nitriles through palladium-catalyzed decarboxylative coupling of cyanoacetate salts with aryl halides and triflates
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Worth its salt: The palladium-catalyzed decarboxylative coupling of the cyanoacetate salt as well as its mono- and disubstituted derivatives with aryl chlorides, bromides, and triflates is described (see scheme). This reaction is potentially useful for the preparation of a diverse array of α-aryl nitriles and has good functional group tolerance. S-Phos=2-(2,6- dimethoxybiphenyl)dicyclohexylphosphine), Xant-Phos=4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene. Copyright
- Shang, Rui,Ji, Dong-Sheng,Chu, Ling,Fu, Yao,Liu, Lei
-
supporting information; experimental part
p. 4470 - 4474
(2011/06/24)
-
- Water works: An efficient palladium-catalyzed cross-coupling reaction between boronic acids and bromoacetate with aminophosphine ligand
-
Water greatly restrained the formation of self-coupling of boronic acids in a palladium-catalyzed cross-coupling reaction between boronic acids and ethyl bromoacetate with an aminophosphine ligand; good to excellent yields of cross-coupling product were obtained.
- Peng, Zhi-Yong,Wang, Jian-Ping,Cheng, Jiang,Xie, Xiao-Min,Zhang, Zhaoguo
-
experimental part
p. 8238 - 8241
(2010/10/21)
-
- Enzymatic desymmetrization of prochiral 2-substituted-1,3-diamines: Preparation of valuable nitrogenated compounds
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A wide range of prochiral 1, 3-diamines were first efficiently synthesized and subsequently desymmetrized by using lipase from Pseudomonas cepacia as catalyst and diallyl carbonate as alkoxycarbonylating agent. In all cases, the amino carbamates of R-configuration were recovered. Final selective cleavage of the N-allyloxycarbonyl moiety was carried out under mild reaction conditions, which demonstrates the high versatility and potential of this chemoenzymatic route as a source of intermediates in the synthesis of related optically active nitrogenated derivatives.
- Rios-Lombardia, Nicolas,Busto, Eduardo,Garcia-Urdiales, Eduardo,Gotor-Fernandez, Vicente,Gotor, Vicente
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supporting information; experimental part
p. 2571 - 2574
(2009/07/25)
-
- NAPHTHALENONE COMPOUNDS EXHIBITING PROLYL HYDROXYLASE INHIBITORY ACTIVITY, COMPOSITIONS, AND USES THEREOF
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Compounds of Formula (I) and Formula (II) are useful as inhibitors of HIF prolyl hydroxylases. Compounds of Formula(I) and Formula (II) have the following structures, where the definitions of the variables are provided herein.
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Page/Page column 66
(2008/12/06)
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- Growth hormone secretagogues
-
What is disclosed are growth hormone secretagogues, and their uses, of the formula wherein R1 is C6H5CH2OCH2—, C6H5(CH2)3— or indol-3-ylmethyl; Y is pyrrolidin-1-yl, 4-C1-C6alkylpiperidin-1-yl or NR2R2; R2 are each independently a C1to C6alkyl; R3 is 2-napthyl or phenyl para-substituted by W; W is H, F, CF3, C1-C6alkoxy or phenyl; and R4 is H or CH3, or a pharmaceutically acceptable salt or solvate thereof.
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Page column 34
(2010/02/09)
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- Remarkable co-catalysis by copper(I) oxide in the palladium catalyzed cross-coupling of arylboronic acids with ethyl bromoacetate
-
Copper(I) oxide can effectively co-catalyze the Suzuki type cross-coupling reactions of arylboronic acids with ethyl bromoacetate. As an alternative protocol for introducing the methylenecarboxy group into functionalized molecules, this reaction occurs in
- Liu, Xing-Xin,Deng, Min-Zhi
-
p. 622 - 623
(2007/10/03)
-
- 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
-
6-Substituted pyrazolo[3,4 -d]pyrimidin-4-one derivatives, pharmaceutical compositions containing them and methods for effecting c-GMP-phosphodiesterase inhibition and for treating heart failure and/or hypertension.
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-
-
- Electrochemistry of Ethyl α-Bromo-α-fluoro(phenyl)acetate and some Ethyl α-Bromo(trifluoromethylphenyl)acetates and Electrochemical Synthesis of the Corresponding Diastereoisomeric Diethyl Succinates.
-
Ethyl α-bromoesters (1)-(5) (ABr) were prepared through NBS bromination of (6)-(10) (AH) respectively.Controlled potential electrolysis of (1)-(5), dissolved in dry dimethylformamide (DMF) containing Et4NClO4 (0.1 M) allows the corresponding succinates (1
- Mattiello, Leonardo,Rampazzo, Liliana,Sotgiu, Giovanni
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p. 2732 - 2754
(2007/10/02)
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- SYNTHESIS OF FLUORINATED DERIVATIVES OF GLUTETHIMIDE AND AMINOGLUTETHIMIDE
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Aminoglutethimide (1), used in the treatment of hormone dependent breast cancer, interacts with enzyme complexes desmolase and aromatase.Its action is not specific and its metabolism gives rise to toxic and non-inhibitory metabolites.The work described here explores the impact of fluorine substitution within the glutethimide (2) framework, on the enzyme inhibitory properties of aminoglutethimide.Four new fluorinated derivatives (5), (6), (8) and (9) have been prepared, in which fluorine substituents have been introduced into the phenyl ring and the ethyl side chain. 4-Fluoroglutethimide (5) and 3-trifluoroglutethimide (6) were synthesised from the corresponding fluorophenylacetonitriles (10) and (14) via sequential monoethylation, Michael addition to methyl propenoate and cyclisation.An alternative strategy, devised for the synthesis of (8), involved the monoarylation of ethyl cyanoacetate, and gave rise to the intermediate (29).Incorporation of fluorine was carried out by SF4 fluorination of the cyanoketoester (33), which was subsequently converted to the difluoroaminoglutethimide (8).For the synthesis of trifluoromethyl glutethimide (9), the trifluoromethyl group was introduced by alkylation of phenylcyanoacetate (16) with 2-iodo-1,1,1-trifluoroethane.Preliminary in vitro enzyme inhibition results have been obtained for compounds (5), (6) and (8).
- Hammond, Gerald B.,Plevey, Raymond G.,Sampson, Paul,Tatlow, John Colin
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