Pyridine Synthesis: Cliff Notes Group Meeting O'Malley 6/9/2004 This procedure served as a key step in an elegant synthesis of the Rubrolone chromophore Note: Due to time constraints, this is not an exhaustive exploration of the myriad ways to create Kelly et. al., Tet. Lett. 1986, 27, 6049-6050. O O substituted pyridines. This summary focuses on ring-construction reactions, rather than functionalization NNMe BuLi; Me Me of existing pyridine rings. Quinolines and Isoquinolines can be considered substituted pyridines; however 2 PhSCu; they possess their own rich chemistry and deserve their own summary. This review summarizes their OTBS O N N chemistry only insofar as it pertains to pyridine chemistry in general. O O O nPr nPr NC C3H7 ; General approaches to pyridine rings: AcOH reflux 31% O O MEMO OTBS Most synthses of pyridine rings rely upon one of two approaches: the condensation of carbonyl OTBS OTBS Me H Me H Me H 1. TBAF, compounds or cycloaddition reactions. There are exceptions, such as ring expansion from 5-membered MEMCl 88% rings, but these approaches are generally low-yielding, narrow in applicability, or both. + N N N 2. HCl, air, O O MEMO H 100% H H H H H Condensation approaches to pyridines: O O nPr O O nPr O O nPr 1. Condensation of 1,5-dicarbonyls 67% 38% (recycled) 46% Me H HO O O Condensation of 2,3-ene-1,5-diones with ammonia is the simplest approach, but offers relatively O O little simplification: HO N HO N HO HO H NH3 nPr HO O nPr O O O N Rubralone chromophore Rubralone A somewhat simpler approach relies on condensation of 1,5 diones followed by oxidation H 2. Hantzsch Synthesis H H NH3 air, O2, HNO3 Condensation of an aldehyde, two equivalents of a 1,3-dicarbonyl, and ammonia yields symmetrical pyridines. N HNO2, CAN, N H O O O O Cu(NO3)2, MnO2 O H O O Me O Me NH3, NaNO2, The oxidation step can be avoided by using hydroxylamine instead of ammonia O rt, 4 days AcOH H 51% 83% O O N N H H NH2OH -H2O H N OH N O O Modifications have been made to allow for synthesis of asymmetric pyridines, by performing one or Several variations on these themes have been developed, such as the use of dimethyl hydrazones more of the condensation steps prior to the reaction. Kelly and Liu, JACS, 1985, 107, 4998-4999. Robinson et. al. J. Het. Chem. 1998, 35, 65. Ph Ph moderate to good yields for X = NO2, Yields were generally acceptable NNMe2 X R X R NHAc, or CN, R = H, Me, or CN, R = Ph, BuLi; N for enone procedure, low for acyl 1 NH4OAc 1 1 2 PhSCu; + Me, or 2-furyl cyanide procedure. Reaction AcOH O requires extended time. Ph O O R Ph N R 2 O2 2 ; Ph R AcOH (reflux) 82% X 2 alternate pathway improved yields for NH4OAc O X R1 some reactions, particularly X=CN NNMe2 BuLi; + O R AcOH PhSCu; N Ph O 1 O2 Ph N R2 O ; procedures have also been developed using enamine esters and enones AcCN; ; AcOH (reflux) 45% Pyridine Syntheses: Cliff Notes Group Meeting O'Malley 6/9/2004 4. Synthesis from 1,3 dicarbonyls and 3-aminoenones 3. Bohlmann-Rahtz Synthesis O O R2O2C R O C EtOH 2 2 R2O2C O + + 50 °C 120-160 °C R O O H N R1 NH2 E 1 R1 N 2 N NH2 E= RCO or CN CF Gives 70-80% yield for R1= Me or aryl, R2 = R1 3 R CO2Et or CN High temperatures in the dehydration step can be avoided by performing the condensation under O 2 EtOH or MeCN R2 acidic conditions. Bagley et. al. Synlett, 2001, 1149-1151. + reflux O H2N CH3 R1 N CH3 CF3 R4 AcOH or R4 yields 65-95% for R1= Me or 2-furyl, Shibata, Synthesis, 1997, 13211-1324 R2 amberlyst 15 R = EtO C or tBuO C R = Me or CO Et, + R2 2 2 2 3 2 When applied to quinolines, this is referred to as the Friedlander condensation. This procedure was used R = Alkyl, Ph, H, or TMS by Danishefsky and Stork in their syntheses of Camptothecin. Danishefsky et. al. JACS, 1971, 93, 4074 50 °C 4 CO Me R1 NH2 2 CO2H O R R1 N R3 3 NH2 NaOH N CO2H + O N use of amberlyst 15 improved yields for R2= tBuO2C and R4 = Ph N CO2H CHO O O Stork has developed a method of using isoxazoles as masked 3-amino-2-enones The Bohlmann-Rahtz procedure served as a key step in the synthesis of the thiopeptide promothiocin A Stork et. al. JOC. 1971, 36 Moody et. al. JACS, 2000, 122, 3301-3313 O O O Me O O Me O K2CO3 N 1. Pd-C. H2, 74% N + Me O Me Me 61% 2. [O] Me Me Me O OBn O ClH2C Me Me N Me EtO2C NH EtO2C 2 N Me BnO NH4OAc EtO2C O Me N N Me PhH, AcOH, EtOH, 50 °C; Me 5. Kröhnke annulation O N 85% O 140 °C, in vacuo, Condensation of a-pyridinium methyl ketone salts and eneones that proceeds through a 2,3-ene-1,5- Me Me 83% O dione O NHBoc NHBoc Me R2 Gives good yields for R= alkyl, aryl, or NHBoc alkenyl. R = COOH gives somewhat lower O R R 3 2 2 yields (40-80%). N R1 NH OAc, AcOH R 4 R1 N 3 Br I N NH OAc + 4 O 90 °C, 3 h N O 47% F F (Malkov et. al. Tet. Lett. 2001, 42, 3045-3048) 1-cyanomethylpyridinium salts can also be used to give 2-aminopyridines Kröhnke, Synthesis, 1976, 1-24. R3 R1 NH4OAc N + R2 CN AcOH ca. 60% H2N N R2 X O Pyridine Syntheses: Cliff Notes Group Meeting O'Malley 6/9/2004 The Kondrat'eva synthesis was used by Weinreb in his synthesis of Eupolauramine. Cycloaddition approaches to pyridines Weinreb et. al., JOC, 1984, 49, 4325-4339. 1. Diels-Alder reactions with 1-azadienes O CO Me The most straightforeward cycloaddition approach to pyridines involves a Diels-Alder reaction of an CO2Me 2 1-azadiene with an alkene or alkyne, followed by subsequent oxidation. However, this route is rarely N O N NMe used, as the Diels-Alder reaction is disfavored on electronic, conformational, and thermodynamic DBN N grounds. A modification of this approach uses an electron donating group on the nitrogen, which is subsequently eliminated. 76% OMe O O Me 1. ultrasound, Me 0.5 h 88% Eupolauramine + 2. air, 1 day, 92% N N Pyrimidines are also capable of serving as pyrrole precursors in a DA/Retro-DA sequence. The O NMe2 O regiochemistry of the resulting pyridine is dependent upon the dienophile and the substitution pattern of the parent pyrimidine. CO Et CO2Et 2 CO Et N 2 Me MeO C CO Me Me CO Me Me NEt Et2N 2 2 2 2 NEt2 N neat, 50 °C, ultrasound, 50h; N N 90% N N N Me Me CDCl3, reflux, 2h; air, 60% CO2Me NMe2 CO2Et Villacampa et. al. Tetrahedron, 1994, 50, 10047-10054 EtO2C Me NEt2 Me CO2Et N NEt This technique was used by Boger in his approach to the Rubrolone aglycon N N 2 Boger et. al. JACS, 2000, 122, 12169-12173. 81% N N Et2N CO2Et EtO2C Me O CO2Et 175 °C, 36 h NO2 O NO2 MeO Me Me 70% MeO MeO OMe nPr N Me nPr N Me N N N N NO2 OMe N Me 2. Inverse electron demand Diels-Alder approaches OMe Because of the intransigence of 1-azadienes in [4+2] cycloadditions, the use of a variety of heterocyclic Pyrimidines with two or three complementary electron donating groups are capable of undergoing azadienes in an inverse demand Diels-Alder reaction, followed by either extrusion of part of the resulting normal Diels-Alder reactions with activated dienophiles, although yields are moderate at best. bicycle in a retro-[4+2] reaction or scission of the resulting bridge has become the favored method for constructing pyridine rings. (Boger, Chem. Rev., 1986, 86, 781-793. Me N Me2N OMe 2 CO2Me MeO2C CO2Me Isozaxoles have been used for this reaction, but fragmentation of the oxo bridge can proceed by several N N N different pathways, complicating the reaction. Also, only isoxazoles with particular substitution patterns 70% CO2Me undergo cycloaddition in productive yields. This reaction is called the Kondrat'eva synthesis. NMe2 NMe2 Pyrazines can also undergo inverse electron demand DA/retro DA cascades to give pyridines, although R 1 R1 R1 this is less common. R1 R 2 HO R Me O R2 R2 2 HO R2 O N Me NEt2 NEt2 N Me N Me N Me N Me N Me -HCN (-HR ) CO Me N CO CH (-H2O) 1 (-H2) N 2 70% 2 3 not normally observed Pyridine Syntheses: Cliff Notes Group Meeting O'Malley 6/9/2004 3. Co-catalyzed [2 + 2 + 2] cycloadditions 1,2,4-triazenes readily undergo inverse demand Diels-Alder reaction with electron-rich dienophiles with well-defined regioselectivity. This makes them attractive precursors to pyridines, as addition across Reaction of excess acetylene with one equivalent of a nitrile and ca. 1 mol % of a cobalt catalyst, such C-3/C-5 is favored for all dieneophiles, with the exception of some ynamines. The most popular version as CpCo(COD), leads to 2-substituted pyridines in good yield under conditions where an initial excess of this reaction uses a pyrrolidine enamine or a ketone and pyrrolidine as the dienophile; this is called of nitrile is present.