Pyridine elaboration through organometallic intermediates: regiochemical control and completeness.

Pyridines carrying heterosubstituents (such as carboxy, amido, amino, alkoxy or trifluoromethyl groups or solely individual halogen atoms) can be readily and site selectively metalated. Subsequent reaction with a suitable electrophile opens rational access to a wealth of new building blocks for the synthesis of biologically active compounds. This approach relies on organometallic methods, which are both efficacious and extremely flexible as far as the substitution site and the product structure are concerned (86 references).

[1]  Ann Thayer,et al.  Enzymes at Work , 2006, Science.

[2]  M. Schlosser CF3-substituierte aromatische und heterocyclische Bausteine , 2006 .

[3]  F. Wagner,et al.  Regioselective 5-, 4-, and 2-Substitution of (S)-6-Chloronicotine and 4-Substitution of (S)-5-Chloronicotine , 2006 .

[4]  P. Gros,et al.  TMSCH2Li–LiDMAE: a new nonnucleophilic reagent for C-2 lithiation of halopyridines , 2006 .

[5]  A. Thayer CONSTRUCTING LIFE SCIENCES COMPOUNDS , 2006 .

[6]  D. Comins,et al.  Regioselective C-2 and C-6 substitution of (S)-nicotine and nicotine derivatives. , 2005, Organic letters.

[7]  M. Schlosser,et al.  Converting core compounds into building blocks : The concept of regiochemically exhaustive functionalization , 2005 .

[8]  M. Schlosser,et al.  Selective functionalization of 2-fluoropyridine, 2,3-difluoropyridine, and 2,5-difluoropyridine at each vacant position. , 2005, The Journal of organic chemistry.

[9]  M. Schlosser,et al.  Removal of fluorine from and introduction of fluorine into polyhalopyridines: an exercise in nucleophilic hetarenic substitution. , 2005, Chemistry.

[10]  M. Schlosser,et al.  Regiochemically flexible substitutions of di-, tri-, and tetrahalopyridines: the trialkylsilyl trick. , 2005, The Journal of organic chemistry.

[11]  M. Schlosser Der 2×3‐Werkzeugkasten der metallorganischen Methoden zur regiochemisch erschöpfenden Funktionalisierung , 2005 .

[12]  M. Schlosser,et al.  Rerouting nucleophilic substitution from the 4-position to the 2- or 6-position of 2,4-dihalopyridines and 2,4,6-trihalopyridines: the solution to a long-standing problem. , 2005, Organic letters.

[13]  M. Schlosser,et al.  Logistic flexibility in the preparation of isomeric halopyridinecarboxylic acids , 2004 .

[14]  M. Schlosser,et al.  Three Chloro(trifluoromethyl)pyridines as Model Substrates for Regioexhaustive Functionalization , 2004 .

[15]  M. Schlosser,et al.  Regioflexibility in the Functionalization of Multiply Halogenated Quinolines , 2004 .

[16]  M. Schlosser,et al.  The Structural Proliferation of 2,6‐Difluoropyridine through Organometallic Intermediates , 2004 .

[17]  M. Schlosser,et al.  Exploring Structural Opportunities: The Regioflexible Substitution of 1,3‐Difluorobenzene , 2003 .

[18]  P. Gros,et al.  Side-Chain Retention During Lithiation of 4-Picoline and 3,4-Lutidine: Easy Access to Molecular Diversity in Pyridine Series , 2003 .

[19]  M. Schlosser,et al.  Recommendable Routes to Trifluoromethyl‐Substituted Pyridine‐ and Quinolinecarboxylic Acids , 2003 .

[20]  M. Schlosser,et al.  The Direct Metalation and Subsequent Functionalization of Trifluoromethyl‐Substituted Pyridines and Quinolines , 2003 .

[21]  P. Gros,et al.  nBuLi/Lithium Aminoalkoxide Aggregates: New and Promising Lithiating Agents for Pyridine Derivatives , 2002 .

[22]  F. Mongin,et al.  Directed lithiation of unprotected pyridinecarboxylic acids: syntheses of halo derivatives , 2002 .

[23]  T. Hiyama How I came across the silicon-based cross-coupling reaction , 2002 .

[24]  P. Gros,et al.  Ring Selective Lithiation of 3,5-Lutidine. A New Route to Heterocyclic Building Blocks. , 2002 .

[25]  M. Schlosser,et al.  Trifluoromethyl-substituted pyridines through displacement of iodine by in situ generated (trifluoromethyl)copper , 2002 .

[26]  M. Schlosser,et al.  Regiochemical Flexibility: The Optional Functionalization of 2,3,5‐Trihalopyridines at the 4‐ or 6‐Position , 2001 .

[27]  M. Schlosser,et al.  Strategies for the Selective Functionalization of Dichloropyridines at Various Sites , 2001 .

[28]  M. Schlosser,et al.  Multiple hydrogen/lithium interconversions at the same benzene nucleus: two at the most. , 2001, Journal of the American Chemical Society.

[29]  P. Gros,et al.  First Regioselective C‐2 Lithiation of 3‐ and 4‐Chloropyridines , 2001 .

[30]  L. Yagupolskii,et al.  N-Trihalomethyl derivatives of benzimidazole, benzotriazole and indazole , 2000 .

[31]  Choppin,et al.  Unusual C-6 Lithiation of 2-Chloropyridine-Mediated by BuLi-Me(2)N(CH(2))(2)OLi. New Access to 6-Functional-2-chloropyridines and Chloro-bis-heterocycles. , 2000, Organic letters.

[32]  A. Rees,et al.  Preparation and reactions of 2,3,4,6-tetrafluoropyridine and its derivatives , 2000 .

[33]  P. Knochel,et al.  BROMINE-MAGNESIUM-EXCHANGE AS A GENERAL TOOL FOR THE PREPARATION OF POLYFUNCTIONAL ARYL AND HETEROARYL MAGNESIUM-REAGENTS , 1999 .

[34]  F. Mongin,et al.  Directed lithiation of unprotected pyridinecarboxylic acids , 1999 .

[35]  V. Bonnet,et al.  Pyridylmagnesium chlorides from bromo and dibromopyridines by brominemagnesium exchange: A convenient access to functionalized pyridines , 1999 .

[36]  Y. Kondo,et al.  TMP−Zincate as Highly Chemoselective Base for Directed Ortho Metalation , 1999 .

[37]  C. Holzapfel,et al.  CROSS COUPLING STRATEGIES TOWARDS THE SYNTHESIS OF THE STREPTONIGRIN CD MOIETY , 1999 .

[38]  J. Paris,et al.  Reactivity of 1-(des-3-hydroxy-picolinoyl) pristinamycin IA , 1998 .

[39]  D. J. Moody,et al.  ELECTROPHILIC IPSO SUBSTITUTION OF TRIMETHYLSILYL GROUPS IN FLUOROBENZENES , 1998 .

[40]  P. Gros,et al.  Aggregative activation in heterocyclic chemistry. Part 6.† A surprising NH3 effect during metallation of 2-methoxypyridine with a multimetal complex base: C-3 versus C-6 metallation , 1998 .

[41]  R. Chambers,et al.  Polyhalogenated heterocyclic compounds. Part 42.1 Fluorinated nitrogen heterocycles with unusual substitution patterns , 1998 .

[42]  A. Chan,et al.  New Rhodium Pyridylphosphine Complexes and Their Application in Hydrogenation Reactions , 1997 .

[43]  Paramjit Singh,et al.  Lewis Acid Complexation of Tertiary Amines and Related Compounds: A Strategy for alpha-Deprotonation and Stereocontrol. , 1997, Chemical reviews.

[44]  C. Avendaño,et al.  A NEW MODIFICATION OF THE FRIEDLANDER SYNTHESIS VIA ORTHO-DILITHIATED N-PIVALOYLANILINES , 1997 .

[45]  P. Gros,et al.  Aggregative activation in heterocyclic chemistry. Part 4. Metallation of 2-methoxypyridine: unusual behaviour of the new unimetal superbase BuLi–Me2N(CH2)2OLi (BuLi–LiDMAE) , 1997 .

[46]  P. Gros,et al.  Aggregative activation in heterocyclic chemistry. Part 5.† Lithiation of pyridine and quinoline with the complex base BuLi·Me2N(CH2)2OLi (BuLi·LiDMAE) , 1997 .

[47]  M. Schlosser,et al.  About bases and superbases , 1997 .

[48]  J. Zoltewicz,et al.  Inter-ring directed ortho lithiation by the 2-pyridyl group in bipyridines , 1996 .

[49]  F. Marsais,et al.  Synthesis of new pyridine intermediates as precursors for the elaboration of streptonigrin analogues by the metalation-cross-coupling strategy , 1996 .

[50]  M. Schlosser,et al.  Optional Site Selectivity in the Metalation of o- and p-Anisidine through Matching of Reagents with Neighboring Groups , 1996 .

[51]  D. Hands,et al.  A Convenient Method for the Preparation of 5-, 6- and 7-Azaindoles and Their Derivatives , 1996 .

[52]  E. Bayburt,et al.  Synthesis of 4-alkyl-3,5-dibromo-, 3-bromo-4,5-dialkyl- and 3,4,5-trialkylpyridines via sequential metalation and metal-halogen exchange of 3,5-dibromopyridine , 1996 .

[53]  E. Vedejs,et al.  Kinetic Resolution of Secondary Alcohols. Enantioselective Acylation Mediated by a Chiral (Dimethylamino)pyridine Derivative , 1996 .

[54]  P. Gros,et al.  Aggregative activation and heterocyclic chemistry III. Unusual regioselective lithiation of 2-alkoxy-pyridines , 1995 .

[55]  M. Schlosser,et al.  Metalated fluoropyridines and fluoroquinolines as reactive intermediates: new ways for their regioselective generation , 1994 .

[56]  M. Schlosser,et al.  Site selective hydrogen/metal exchange: Competition and cooperation between superbases and neighboring groups , 1994 .

[57]  W. Dmowski,et al.  Reactions of trifluoromethylpyridines with alkyllithium reagents. Directing effects of the trifluoromethyl groups , 1994 .

[58]  P. Caubére Unimetal super bases , 1993 .

[59]  G. Gribble,et al.  Regioselective ortho-Lithiation of Halopyridines. Syntheses of ortho-Disubstituted Pyridines and a Convenient Generations of 3,4-Pyridyne , 1993 .

[60]  M. Schlosser,et al.  A shortcut to α-Santalol , 1993 .

[61]  O. Mongin,et al.  New synthesis of Orelline by metalation of methoxypyridines , 1993 .

[62]  D. Comins The Synthetic Utility of α-Amino Alkoxides , 1993 .

[63]  J. Bourguignon,et al.  Metalation of pi-deficient heterocycles a facile synthesis of cerpegin , 1992 .

[64]  D. Comins,et al.  N-acyldihydropyridones as synthetic intermediates. synthesis of (±)-septicine and (±)-tylophorine. , 1991 .

[65]  F. Effenberger,et al.  Darstellung von Didehydropyridinen aus (Trimethylsilyl)pyridinen , 1991 .

[66]  M. Schlosser,et al.  A one-pot synthesis of ibuprofene involving three consecutive steps of superbase metalation , 1991 .

[67]  M. Khaimova,et al.  Lithiation of polychloropyrimidines and dichloropyridines , 1991 .

[68]  Paramjit Singh,et al.  Lewis acid complexed heteroatom carbanions; synthesis of some α-pyridyl alcohols , 1991 .

[69]  M. Schlosser,et al.  The metalation of fluoroanisoles: optional regioselectivity due to metal mediated control , 1991 .

[70]  D. Comins,et al.  Lithiation of methoxypyridines directed by .alpha.-amino alkoxides , 1990 .

[71]  C. A. Leonard,et al.  Benzo- and pyrido-1,4-oxazepin-5-ones and -thiones: synthesis and structure-activity relationships of a new series of H1 antihistamines. , 1989, Journal of medicinal chemistry.

[72]  A. Bieniek,et al.  Application of organolithium and related reagents in synthesis. Part 7. Synthesis and metallion of 4-methoxypicolin- and 2-methoxyisonicotin-anilides. A useful method for preparation of 2, 3, 4-trisubstituted pyridines , 1989 .

[73]  M. Venuti,et al.  Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline. , 1988, Journal of medicinal chemistry.

[74]  S. Kafafi,et al.  Carbon acidities of aromatic compounds. 1. Effects of in-ring aza and external electron-withdrawing groups , 1988 .

[75]  F. Marsais,et al.  Metalation/SRN1 coupling in heterocyclic synthesis. A convenient methodology for ring functionalization , 1988 .

[76]  J. Falck,et al.  A Convenient Synthesis of Pyrido[3,4-g]isoquinoline via ortho-Directed Metallation/Dimerization , 1988 .

[77]  F. Marsais,et al.  Catalyzed metalation applied to 2-methoxypyridine , 1988 .

[78]  M. Schlosser Superbases for organic synthesis , 1988 .

[79]  D. W. Strickland,et al.  Synthesis of 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro- 1,6-naphthyridines by a directed lithiation reaction , 1988 .

[80]  F. Marsais,et al.  Directed lithiation of 4-halopyridines: Chemoselectivity, regioselectivity and application to synthesis , 1988 .

[81]  E. Knaus,et al.  An improved synthesis of 1,3-dihydro-1-methyl-5-phenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-one via ortho-directed lithiation of 3-tert-butyl and 3-tert-butoxycarbonylaminopyridine , 1987 .

[82]  G. Olah,et al.  Desilylative nitration of alkyl- and allylsilanes with nitronium salts , 1987 .

[83]  A. Bell,et al.  A Direct Synthesis of 6-Pyridinyl-2(1H)-quinolinones via Palladium-Catalysed Cross-Coupling Reaction , 1987 .

[84]  E. Bisagni,et al.  A new route to [g]-fused 5-methyl-1-functionalized isoquinolines , 1987 .

[85]  M. Iwao,et al.  Synthesis of bostrycoidin via directed lithiation of tertiary nicotinamide , 1987 .

[86]  H. Fujihara,et al.  Preparation of pyridyl grignard reagents and cross coupling reactions with sulfoxides bearing azaheterocycles , 1987 .

[87]  L. W. Sieck,et al.  Relative acidities of water and methanol and the stabilities of the dimer anions , 1986 .

[88]  E. Thomas Synthesis of indolizinones and a pyridoazepinone: a new method for the annulation of pyridinones , 1986 .

[89]  M. Haimova,et al.  Synthesis of 4-Amino-3-pyridinyl and 4-Amino-5-pyrimidinyl Aryl Ketones and Related Compounds via an ortho-Lithiation Reaction , 1986 .

[90]  M. Mallet,et al.  Action du n-butyllithium sur les bromo-3 halogeno-2 pyridines fluoree, chloree et bromee : Principe et etude d'une possibilite reactionnelle nouvelle : l'homotransmetallation , 1985 .

[91]  L. Brandsma,et al.  Kinetic and thermodynamic control in the metalation of pyridine. A direct synthesis of 2-and 4-substituted pyridines , 1984 .

[92]  M. Ishikura,et al.  Total synthesis of SEN-215 by use of palladium catalyzed carbonylation , 1984 .

[93]  K. Akiba,et al.  A Convenient Method for the Regioselective Synthesis of 4-Alkyl(aryl)pyridines Using Pyridinium Salts , 1984 .

[94]  L. Brandsma,et al.  Functionalization of pyridine via direct metallation , 1984 .

[95]  M. Schlosser,et al.  The “super-basic” butyllithium/potassium tert-butoxide mixture and other lickor-reagents , 1984 .

[96]  T. Mano,et al.  AN ALTERNATIVE SYNTHESIS OF DIALKYLPYRIDYLBORANES , 1984 .

[97]  J. C. Martin,et al.  Direct, regiospecific 2-lithiation of pyridines and pyridine 1-oxides with in situ electrophilic trapping , 1983 .

[98]  J. A. Turner Regiospecific electrophilic substitution of aminopyridines: ortho lithiation of 2-, 3-, and 4-(pivaloylamino)pyridines , 1983 .

[99]  J. C. Martin,et al.  In situ trapping of ortho lithiated benzenes containing electrophilic directing groups , 1983 .

[100]  M. Iwao,et al.  Synthesis of (±)-sesbanine via directed metalation of tertiary nicotinamides , 1983 .

[101]  R. Ronald,et al.  Regioselective metallations of (methoxymethoxy)arenes , 1983 .

[102]  F. Marsais,et al.  Review on the metallation of π -deficient heteroaromatic compounds , 1983 .

[103]  K. Akiba,et al.  Facile synthesis of 4-substituted pyridines using grignard reagents , 1983 .

[104]  T. Güngör,et al.  ortho-Functionalization of Aminopyridines; Regioselective Lithiation of 3-Pivaloylaminopyridines , 1982 .

[105]  F. Marsais,et al.  Regioselective o-Lithiation of 3-Alkoxypyridines; A Convenient Route to New o-Disubstituted Pyridines , 1982 .

[106]  R. Gabel,et al.  Substitutions of pyridines activated by oxazolines via nucleophilic additions for metalation-alkylation , 1982 .

[107]  R. Ronald,et al.  Regioselective metalation reactions of some substituted (methoxymethoxy)arenes , 1982 .

[108]  M. Mallet,et al.  Reaction de la bromo-3 pyridine avec le diisopropylamidure de lithium. Mecanismes de metallation et de migration d'halogene. Regioselectivite de l'addition polaire sur la pyridyne-3,4 , 1982 .

[109]  G. Quéguiner,et al.  Etude des ortho-metallations regioselectives de la chloro-3 pyridine par des organolithiens et des amidures de lithium; effet d'orientation par le solvant, applications a la synthese , 1981 .

[110]  Y. Kita,et al.  Regioselective metalation of the 4-position of pyridine. New and convenient alkylation and acylation of 3-amino-5-methoxypyridine , 1981 .

[111]  A. Katritzky,et al.  3-Lithiated Pyridines and their Reactions with Electrophiles , 1981 .

[112]  G. Gribble,et al.  Regioselective ortho lithiation of halopyridines , 1981 .

[113]  M. Venuti,et al.  Ortho functionalization of N-(tert-butoxycarbonyl)aniline , 1980 .

[114]  J. Brzezinski,et al.  Reactions of the N,N-dialkylpyridylcarboxylic amides with lithium amides. Regioselective lithiation of N,N-diisopropylpyridylcarboxylic amides, a useful method for synthesis of 2,3- and 3,4-disubstituted pyridines☆ , 1980 .

[115]  J. Olah,et al.  Synthetic methods and reactions. 63. Pyridinium poly(hydrogen fluoride) (30% pyridine-70% hydrogen fluoride): a convenient reagent for organic fluorination reactions , 1979 .

[116]  R. Gabel,et al.  Oxazolines as activating groups in aromatic substitution. Regioselective metallation of the 3-position in pyridine. , 1978 .

[117]  I. Vlattas,et al.  LITHIATION OF 4,4-DIMETHYL-2-(2-THIENYL)-2-OXAZOLINE , 1977 .

[118]  P. Beak,et al.  THE ORTHO LITHIATION OF TERTIARY BENZAMIDES , 1977 .

[119]  H. Gschwend,et al.  Ortho-lithiation. A regiospecific route to ortho-substituted aryl ketones , 1976 .

[120]  C. D. Weis,et al.  Halogenierte Pyridine II. Reaktionen der 3‐Halogenmethyl‐pyridine , 1976 .

[121]  C. Eaborn Cleavages of aryl-silicon and related bonds by electrophiles , 1975 .

[122]  W. Paudler,et al.  CATALYTIC REDUCTION OF 4-NITROPYRIDINE 1-OXIDE , 1975 .

[123]  R. Abramovitch,et al.  The direct thionation and aminoalkylation of pyridine 1-oxides and related reactions† , 1975 .

[124]  A. Hamdan,et al.  Ortho-lithiation of aryloxazolines , 1975 .

[125]  B. Wakefield,et al.  Polyhalogenoaromatic compounds : XXIX. Hexachloro-5,5′-dilithio-4,4′-bipyridine as an intermediate for organometallic and organic syntheses , 1974 .

[126]  O. Meth–Cohn,et al.  Novel aspects of the metalation of heterocycles. Side-chain metalation of thiophen and ring metalation of six-membered nitrogen heterocycles , 1974 .

[127]  M. Schlosser,et al.  Ummetallierung und doppelter Metall-Austausch: ein bequemer Zugang zu Organolithium-Verbindungen vom Benzyl- und Allyl-Typ , 1973 .

[128]  R. Abramovitch,et al.  Direct acylamination of pyridine 1-oxides , 1972 .

[129]  A. Katritzky,et al.  The kinetics and mechanism of electrophilic substitution of heteroaromatic compounds. Part XX. Nitration of 3-hydroxypyridine, 6-hydroxy-2(1H)-pyridone, and some corresponding methyl derivatives , 1970 .

[130]  S. Taguchi,et al.  Studies on Organic Fluorine Compounds. VI. Preparations and Reactions of (Trifluoromethyl) quinoline N-Oxides , 1969 .

[131]  C. A. Heaton,et al.  Polyfluoroheterocyclic compounds. Part XVI. Tetrafluoropyridine-3- and -4-carbaldehydes and some derivatives of the latter , 1969 .

[132]  M. Schlosser Zur aktivierung lithiumorganischer reagenzien , 1967 .

[133]  E. Smith,et al.  A New and Convenient Alkylation and Acylation of Pyridine N-Oxides , 1967 .

[134]  A. Katritzky,et al.  The mechanism of the electrophilic substitution of heteroaromatic compounds. Part VIII. The α-, β-, and γ-nitration of pyridine 1-oxides , 1967 .

[135]  R. Chambers,et al.  926. Polyfluoroheterocyclic compounds. Part V. Catalytic reduction of perfluoro- and chlorofluoro-pyridines and the preparation of polyfluoropyridinecarboxylic acids , 1965 .

[136]  C. Hauser,et al.  Metalation of N-Methylbenzamide with Excess n-Butyllithium. Condensations with Electrophilic Compounds to Form ortho Derivatives. Cyclizations1 , 1964 .

[137]  A. F. Crowther Heterocyclic Chemistry , 1964, Nature.

[138]  M. S. Raasch The Chemistry of Sulfur Tetrafluoride. IX. Reaction with Amino Acids in Hydrogen Fluoride1 , 1962 .

[139]  W. Hasek,et al.  The Chemistry of Sulfur Tetrafluoride. II. The Fluorination of Organic Carbonyl Compounds1 , 1960 .

[140]  A. Katritzky,et al.  248. N-oxides and related compounds. Part X. The hydrogenation of some pyridine 1-oxides , 1958 .

[141]  F. Leonard,et al.  Synthesis of Some Sulfur-Containing Derivatives of Pyridine 1-Oxide and Quinoline 1-Oxide , 1956 .

[142]  J. A. Berson,et al.  SYNTHETIC APPROACHES TO IPECAC ALKALOIDS. II. A SYNTHESIS OF 4-CARBOMETHOXY-5-ETHYL-2-METHYLPYRIDINE1, 2 , 1955 .

[143]  E. Ochiai RECENT JAPANESE WORK ON THE CHEMISTRY OF PYRIDINE 1-OXIDE AND RELATED COMPOUNDS , 1953 .

[144]  H. French,et al.  Some Reactions of 3-Pyridyllithium1 , 1951 .

[145]  Scherer Über organische Fluorverbindungen , 1939 .

[146]  J. Simons,et al.  The Preparation of Benzotrifluoride , 1938 .

[147]  A. Kirpal,et al.  Über eine neuartige Isomerie in der Pyridin‐Reihe (I. Mitteil.) , 1932 .

[148]  A. Kirpal,et al.  Über 2‐Nitro‐pyridin. (Vorläufige Mitteilung) , 1931 .

[149]  K. Ziegler,et al.  Untersuchungen über alkaliorganische Verbindungen, VII. Mitteil.: Alkalimetallalkyle und Pyridin (Vorläufige Mitteilung) , 1930 .