DOI: 10.1002/chem.201001100 Recent Strategies for the Synthesis of Pyridine Derivatives Matthew D. Hill*[a] 12052 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 12052 – 12062 MINIREVIEW Abstract: Recent advances in pyridine synthesis are de- scribed. Modification of traditional condensation strat- egies continues to be a recurrent theme in contempo- rary literature. Advancements in transition-metal-cata- lyzed cyclization and cross-coupling procedures offer new routes to functionalized pyridine derivatives. These recently developed methodologies are a valuable addi- tion to azaheterocycle synthesis. Keywords: annulation · condensation · cyclization · heterocycles · pyridine Introduction Pyridine derivatives are an important class of azaheterocycle found in many natural products, active pharmaceuticals, and functional materials.[1] Diploclidine[2] and nakinadine A[3] are two examples of recently isolated and structurally diverse natural products containing the pyridine core (Scheme 1). Pyridine-derived pharmaceuticals include atazanavir[4] (Rey- ataz) and imatinib mesylate[5] (Gleevec) (Scheme 1). These drugs are prescribed for human immunodeficiency virus (HIV) and chronic myelogenous leukemia, respectively. Pyr- idine derivatives are also incorporated into polymers such as polyvinyl pyridine (PVP, Scheme 1).[6] For well over a centu- ry, chemists have developed methodologies for pyridine syn- thesis and it is unlikely that interest in the field will decrease due to the continued importance of the pyridine core in both biological and chemical fields. Scheme 1. Representative compounds containing a pyridine substructure. Ms= mesyl. Many pyridine-based alkaloid natural products are deriva- tives of nicotinic acid (also known as vitamin B3 and niacin, Scheme 1).[7] In nature, this important component of coen- 1871, respectively, marked the beginning of significant zymes nicotinamide adenine dinucleotide (NAD+) and nico- chemical research in the field.[9] Coal tar served as an initial tinamide adenine dinucleotide phosphate (NADP +) is syn- source of pyridine, however, recent commercial methods thesized from l-tryptophan by way of the kynurenine path- have been developed for its preparation from crotonalde- way in animals, or from glyceraldehyde 3-phosphate and l- hyde, formaldehyde, and ammonia in the gas phase.[1b] aspartic acid in many plants.[7] Both pathways rely on decar- Historically, many pyridine syntheses rely on condensa- boxylation of quinolinic acid as a final step, but are other- tion of amine and carbonyl compounds. These, and other wise very different. methods for the preparation of the pyridine core, are often Nicotine is formed by the incorporation of a pyrrolidine characterized by the number of atoms in each fragment con- moiety derived from l-ornithine onto the molecular frame- tributing to the six-atom azaheteroaromatic ring. Ammonia work of nicotinic acid (Scheme 1). Like nicotine, similar al- (NH3) has served as the nitrogen source in countless proto- kaloids, including anabasine, ricinine, and arecoline, all orig- cols, including [5+1] condensation with 1,5-dicarbonyls inate from nicotinic acid (Scheme 1).[7] (Scheme 2).[10] Like many condensation methods, autoxida- While picoline was isolated in 1846,[8] Kçrners and tion is necessary for aromatization. Ammonia is also fre- Dewars elucidation of the pyridine structure in 1869 and quently used in the [2+2+ 1+1] Hantzsch pyridine synthe- sis (Scheme 3).[11,12] Other pyridine syntheses rely on alkyl or vinyl amines such as the [3+3] example: 1,3-dicarbonyl [a] Dr. M. D. Hill derivative condensation with a vinylogous amide Neuroscience Chemistry, Bristol-Myers Squibb Company (Scheme 4).[13] 5 Research Parkway, Wallingford, CT 06492 (USA) Fax : (+1)203-677-7884 Methods that do not rely on condensation chemistry have E-mail: [email protected] become increasingly important. Boger et al. have developed Chem. Eur. J. 2010, 16, 12052 – 12062 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 12053 M. D. Hill Scheme 2. The [5+1] condensation route to substituted pyridines.[10] Scheme 7. The [2 +2+ 2] cobalt-mediated synthesis of substituted pyri- dines.[16] Cbz=carbobenzyloxy, cod=cyclooctadiene. Scheme 8. The Chichibabin reaction.[18] Scheme 3. The [2+2 +1+1] Hantzsch pyridine synthesis.[11] can be used with numerous transition-metal catalysts to afford a structurally diverse set of pyridine derivatives (Schemes 9 and 10).[17,19,20] Scheme 4. The [3+3] condensation of a 1,3-dicarbonyl derivative and vi- nylogous amide.[13] a[4+ 2] inverse electron demand aza-Diels–Alder reaction Scheme 9. Iron-catalyzed cross-coupling of activated pyridines.[19] acac = between enamines and 1,2,4-triazine (Scheme 5).[14] 6p-Elec- acetylacetate. trocyclization approaches are also of continuing importance (Scheme 6).[15] A well-developed [2+2+ 2] approach utilizes two alkyne equivalents and a nitrile species (Scheme 7).[16] Scheme 10. Suzuki–Miyaura cross-coupling of activated pyridines.[20] XPhos =2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, dba=di- benzylideneacetone. Scheme 5. The [4 +2] aza-Diels–Alder approach to pyridine deriva- tives.[14] MS =molecular sieves. Dr. Matthew D. Hill earned degrees in bio- chemistry, molecular biology, and legal communication from Ohio University (OU) in 2003. While at OU, Matthew got his first taste of academic research when he synthesized phorbol analogues under the supervision of Professor Mark McMills. Matthew also spent a summer at [15] Scheme 6. The [4+2] rhodium-mediated synthesis of pyridines. Columbia University where he performed research on age-related macular degenera- tion with Professor Koji Nakanishi. In 2008 he received his Ph.D. in organic Azaheterocycle substituent modification is described in chemistry from The Massachusetts Institute [17] several reviews. Some methods, including the Chichibabin of Technology (MIT). Matthew developed reaction (Scheme 8),[18] rely on the electron-deficient charac- several new methodologies for the preparation of azaheterocycles in the ter of the pyridine ring. Recent advancements in cross-cou- lab of Professor Mohammad Movassaghi. After leaving MIT, Matthew pling chemistry have increased the popularity and practicali- started his current position within the neuroscience chemistry division of drug discovery at Bristol-Myers Squibb. ty of substituent modification reactions. Activated pyridines 12054 www.chemeurj.org 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 12052 – 12062 Pyridine Derivatives MINIREVIEW Recent Advances in Pyridine Synthesis Although the literature on pyridine synthesis enjoys a rich history of versatile methodologies,[1] new approaches remain valuable to the contemporary collection of synthetic strat- egies. Some of these methodologies employ the direct con- densation of amine and carbonyl substrates, whereas other reports describe multicomponent reactions to afford substi- tuted pyridine derivatives. Recent synthetic strategies also take advantage of many transition-metal catalysts developed over the past several decades. Ring-closing metathesis (RCM) has proven to be one of the most utilized chemical breakthroughs of the twentieth [21] century. This technology has been used by Donohoe et al. Scheme 12. The [5 +1] strategy for 2,3,5-trisubstituted pyridine synthe- for the multistep synthesis of 2,6-di- and 2,3,6-trisubstituted sis.[23] pyridines with alkyl, aryl, and alkoxy substituents (Scheme 11).[22] The Hoveyda–Grubbs second generation Scheme 13. The [5+1] alternative cyclization pathway for 2,3,5-trisubsti- tuted pyridine synthesis.[23] Scheme 11. RCM strategy for pyridine synthesis.[22] KHMDS =potassium hexamethyldisilazide, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,ACHTUNGRE Bn= benzyl. Craig and Henry reported a new variation of a well-estab- lished [5+1] methodology utilizing 1,5-dicarbonyl condensa- tion with ammonia.[25] Both 2,4-di- and 2,4,6-trisubstituted ruthenium catalyst was optimal for the conversion of amide pyridines with alkyl, aryl, and ester substituents were pre- precursors to the corresponding a,b-unsaturated lactams. pared from 1,6-dienes by ozonolysis, subsequent condensa- Subsequent 1,8-diazabicyclo[5.4.0]undec-7-eneACHTUNGRE (DBU)-pro- tion with ammonia, and elimination of sulfinic acid moted benzyl alcohol elimination, and lactam trapping with (Scheme 14). This reaction sequence was demonstrated in Comins reagent afforded the pyridine products in moderate both two separate steps, and in one step from the 1,6-diene. to excellent overall yield. Post-RCM chemical manipulation [4ACHTUNGRE+2] Strategies for construction of the pyridine ring are gave access to additional substitution patterns and further prevalent in azaheterocycle literature.[1] Many of these increased the utility of this protocol. A recent report by Hu et al. describes a [5+ 1] approach to 2,3,5-trisubstituted pyridines.[23] Interestingly, the mode of cyclization was found to be temperature dependent and pro- vided two distinct classes of pyridine derivative (Schemes 12 and 13). This method relies on available 1,1-bisalkylthio-1,4- pentanedienes, prepared in one step from ketene-(S, S)-ace- tals, allylic alcohols, and ammonium acetate (NH4OAc) as an ammonia source.[24] Electron-rich arenes with alkyl thio- substitution gave the desired products in moderate to good yield, however electron-neutral and -poor aromatics gave Scheme 14. The [5+ 1] ozonolysis/condensation route to pyridines.[25] little or none