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 . This summary focuses on ring-construction reactions, rather than functionalization NNMe BuLi; Me Me of existing pyridine rings. and can be considered substituted pyridines; however 2 PhSCu; they possess their own rich 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 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- 67% 38% (recycled) 46% Me H HO O O Condensation of 2,3-ene-1,5-diones with 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 , two equivalents of a 1,3-, 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 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 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 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 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 , 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 = , 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 O N 85% O 140 °C, in vacuo, Condensation of a- methyl 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 or , 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 donating group on the , which is subsequently eliminated. 76% OMe O O Me 1. ultrasound, Me 0.5 h 88% Eupolauramine + 2. air, 1 day, 92% N N are also capable of serving as 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 . 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] , 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 . This makes them attractive precursors to pyridines, as addition across Reaction of excess with one equivalent of a and ca. 1 mol % of a 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 enamine or a ketone and pyrrolidine as the dienophile; this is called of nitrile is present. However, when unsymmetrical are used mixtures of regioisomeric the Boger pyridine synthesis. products are often obtained. Electron-poor do not work in this reaction. Bönneman, ACIEE, 1978, 17, 505-515

N 74% Yields are > 90% for R= alkyl, Ph, or Bn. R= RCN CpCo(COD), ethenyl N N N R N 120-130 °C gives 78%. 100-600 turnovers per hour are possible. R 2 Yields of 50-85%, A:B of N R2 R 2 60:40 to 80:20 for R , R = R CN + 1 2 O 1 CpCo(COD), alkyl, Ph, alkenyl 120-130 °C R N R1 N R Et 1 R2 2 N Et Et A B N N H N N Et Problems of regioselectivity can be avoided by using diynes and nitriles or alkynyl nitriles and . The less sterically hindered orientation of the product pyridine is greatly favored under these conditions. cat. 93% Vollhardt, ACIEE, 1984, 23, 539-556.

There is a strong preference for the nucleophilic of the dienophile to add to C-3 of the . Bu Bu This is reinforced by electron withdrawing at C-3 or C-3, C-5, and C-6, but can be reversed BuCN by electron withdrawing substituents at C-3 or C-3 and C-5. The presence of alkyl groups on the N N dienophile or the use of a morpholino dienophile can degrade the extent of regioselectivity. CpCo(CO)2

A convenient method for the generation of 1,2,4- is via a Diels-Alder/Retro Diels-Alder sequence involving a 1,2,4,5- and a nitrogen-containing dienophile. This strategy was used by Boger in his 73% 4.1% synthesis of Streptonigrin. (Boger and Panek, JOC, 1983, 48, 621-623, JACS, 1985, 107, 5745-5754. Vollhardt et. al. J. Chem. Soc. Chem. Comm. 1982, 133-134.

NO 2 NO2 N TMS MeO 80 °C, 22h, 82% MeO Me TMS TMS Moderate to good yields for + OBn 5,6,7 membered rings, alkyl, NH CpCo(CO)2 N CO2Me N N TMS trialkylsilyl, substituents N N CO2Me N PhMe, reflux N on alkyne. SCH3 N OMe light, 77% N MeO2C N MeO2C N OMe Heteroatoms are tolerated in the linking chain, but N and S can interfere with catalyst turnover. This served as the basis of Vollhardt's synthesis of B6. Parnell and Vollhardt, Tetrahedron, 1985, 41, O NO2 5791-5796. SnMe3 I MeO MeO Me Me SnMe3 MeCN I NaOMe N CO Me 2 N CO2Me 2 O O O N H2N N N 99% N SnMe CpCo(CO)2, CuI2, 37% O 3 6.2 kbar, CH2Cl2, xylene, reflux, MeO C Me MeO2C Me 2 light, 48 h; Al2O3 rt, 120 h, 65% OBn OBn 44% 2.8:1 regioselectivity OMe OH OMe OMe Me Me 1. HBr, 78% HO OMe OMe O 2. H O, reflux; streptonigrin N 2 HO NH Kende intermediate AgCl, 68%

Vitamin B6 Cl Pyridine Syntheses: Cliff Notes Group Meeting O'Malley 6/9/2004

4. Electrocyclization of polyunsaturated or Reinhoudt and co-workers cyclized unsaturated oximes generated from cyclic nitrones to pyridines in moderate yield. (Reinhoudt et. al., Tetrahedron, 1989, 45, 3131-3138.

R R O R1 N (R3) 1 NO2 R NEt 1 KOtBu 3 2 N CONEt 60-85% R2 rt, 30-60% 2 R2 (R3) R2 R 3 CONEt2

R1= Alkyl or Ph, R2= Ar, R3= Ph or alkenyl

Katsumura and co-workers used two distinct electrocyclizations in their approach to the ocular age pigment A2-E. Katsumura et. al. JOC, 2001, 66, 3099-3110.

CO2Et NH2OH•HCl; TBSO AcCl,py., 53% TBSO N CO Et CHO 2


How Medicinal Chemists Do It

Lee et. al. J. Med. Chem. 2001, 44, 2133-2138.


N NH2 N N NMe2 NMe2



NMe2 Br O Br CN "a" + NC CN N N O H2N N N N O