The Baran Group Meeting Synthesis of Imidazoles Alexandros Zografos

H N N H H N Ring Formation: H N N N H -Fragments C-C, N, C and N: Indroduction: 1. Combination of an alkene, carbon monoxide and ammonia -Planar, five membered heteroaromatic molecule with pyrrole type and N R Rh4(CO)12 R +CO+ pyridine type annular nitrogens. NH3 R MeOH-H2O R N H J. Org. Chem., 1971, 36, 25,. -Named first as gluoxaline (first synthesis with glyoxal and ammonia). 2. A dicarbonyl compound with aldehyde and ammonia O -Aphoteric nature, susceptible to electrophilic and nucleophilic attack. O O O NH4OAc O N -High stability to thermal, acid, base, oxidation and reduction conditions. + 1 R O 1 R R H AcOH R N -Extensive intramolecular hydrogen bonding. O H Tetr. Lett., 1994, 35, 1635 3. Hydroxycarbonyl reagent with aldehyde and ammonia

CuII CH2OH Biological Properties: H2S OH O picric acid HO H HCl N -Against fungal infections. + 2NH3 + HCHO H OH N -Treatment of hypoxic tumor cells. H OH H CH OH -Anticancer agents. 2 JACS, 1979, 101, 3983 H O -Anti-HIV agents HO HO O NaIO4 N H HO HO HN O H NH4OAc N H H COOH HCHO, Cu(II) HN Synthesis of Imidazoles: "There are no really general ways of synthesizing imidazoles and it is 4. The Maquenne synthesis O HOOC NO2 HOOC invariably necessary to consider a number of divergent methods whenever NH3 N + RCHO R a synthesis is contemplated" HOOC NO2 N HOOC H The Baran Group Meeting Synthesis of Imidazoles Alexandros Zografos

Ring Formation: -Fragments N-C-N and C-C

-Fragments a C-C-N, C and N: 4. Cyanoepoxides and amidines or guanidines OH R1 CN NC 1. Hydroxyimino ketone, aldehyde and ammonia NH2 + R3 N N 2 2 3 - R O CO2Et 4 N R O R N+ O R R3 3 4 + R NH2 + RCHO R R 3 Tetr. Lett, 1995, 36, 547 R NOH R2 N J. Org. Chem., 1963, 1620 -Fragments C-C-N and C-N R3 2. Aminonitrile, orthoformate and primary amine CONH2 1. Aminocarbonyl compounds with N-C reagents O rt,MeCN N O NC H N Et NH + CH(OEt)3 + 2 2 HCONH2 N NH2 N NHR2 2 H N 1 N R NH R heat 2 R1 J. Org. Chem., 1994, 59, 1589 -Fragments N-C-N and C-C Synthesis, 1991, 823 NHEt 2. Marckwald Synthesis. Aminocarbonyl compounds with cyanates or

cyanamide 1. Halocarbonyl or dicarbonyl compounds with guanidines 1 O R 1 NH2 DMF or R R O R X N R + NHAc + R2NCS N R2 H N NHAc MeCN 1 2 N HN R R1 R NH Cl H 3 J. Org. Chem., 1994, 59, 7299 S 2. Amidines and hydroxy or halocarbonyl compounds O 2 EtO OEt N R R 1.EtOH N + NH CN NH Cl OH 2 2 3 R + HN NH R 2. HCl 2 R NHR1 R N R1 R1 N 1 H R JACS., 1949, 71, 644 3.Ureas and thioureas with carbonyl compounds 3. Amidates and aminocarbonyl compounds

O NH O N O H H hexanol reflux OEt acid N N N R + H2N R R N EtO R R N R S OH OEt H S Synthesis, 1993, 561 The Baran Group Meeting Synthesis of Imidazoles Alexandros Zografos

Ring Formation: 3. Involving cyclization of diiminocompounds.

H -Fragments N-C-C-N and C: NC NH N N

+ + NH O 2 N 1. 1,2-Diaminoalkanes and carbon reagents NC NH O H - R R Cl R NH2 0 N O H2 alumina Pt 400 C R N NR N + HCl H2O 2 CHO HO R N J. Org. Chem., 1993, 58, 3387 NH2 H N N O - O O R R Cl R O HCl COOH MnO2 N 4. Pinner salt method N + CH(OEt)3 N H MeOH N NH 1.Et3N, rt MeO 2 N MeO HCl 2.Ph3P, DCM, rt NC N3 NH 2. Use of diaminomaleonitrile (DAMN) NH2 MeOH - N PPh3 NC H N3 Cl N RCOCl O rt RNCS N NC H rt MeO N

COCl R MeO N dioxane N NHR Synthesis, 1995, 449 H 500C S NC N N NC NH HC(OEt) H ClCN 2 3 NC N NH2 5. From 2-amino-azidoacrylates NHR N THF,500C anisole, NC 1 2 H NC NH 0 N 1 2 R N C NR 2 135 C NC R N3 R1 N R NCO H Ph3P, DCM PPh3 hv MeC(NH)(OEt)2 DCM anisole ROOC NHZ ROOC NHZ ROOC NHZ NC N NC N 1 R N N N NHR2 H2N H NC H N J. Org. Chem.,, 1974, 39, 2341 Synthesis, 1996, 1459. ROOC Z The Baran Group Meeting Synthesis of Imidazoles Alexandros Zografos

Ring Formation: Ring Transformation

-Fragment C-N-C-C-N: -Ring enlargement of azirines by reaction with nitriles

R1 1. Wallach Synthesis R1 R2 . N BF3 OEt or 3 + R3CN R HClO O PCl , POCl N 4 2 N 5 3 R H N JACS, 1967, 89, 4457. O 2 reflux N R R2 -From Dihydropyrazines 1 H NHR Cl N 1 JACS, 1967, 1259 R N N hv, MeOH 2. From acylated glycines and formamido acetamides N N O N JACS, 1967, 89, 2375. H PCl5, POCl3 R1 N -From Aminoisoxazoles N CHO reflux O H Cl N 1 O R HN H2, Pt/C NaOH HN N EtOH, rt EtOH NH O H + - EtO N N R1 Et3O BF4 , DCM N H N R2 O 2 H2N rt O O O N -From 1,2,4-oxadiazoles H J. Org. Chem., 1987, 52, 2714 R1

J. Med. Chem., 1975, 18, 90 NH2 HN COR2 -Fragment N-C-N-C-C: 1 2 N R R N N + N O 1. Cyclization of amidines R O O R O CO2R EtONa MeOH NH RO2C DMF NOH reflux heat N COR2 + CO2R O Ar Ar NH N Ar 2 H N N H R1 RCOHN N Tetr. Lett., 1971, 18, 1459. Tetrahedron, 1974, 30, 3859 H The Baran Group Meeting Synthesis of Imidazoles Alexandros Zografos

Natural Products: Dragmacydin D

Oroidin H2N Br N NH N HN N H NH N 2 N N N H H O Br O H Sceptrin N O H N OH NH2 Br N NH NH H Stevensine Br H H2N N N N

N NH2 HN H N O Br Ageliferin H Br NH H2N Br N HN N H O HN

O H Br HN N Temozolomide NH2 H O N N N N H H2N N Axinellamine O NH N H NN HN N NH N O HO NH Cl OH H Br Br H HN N N Br Br N O O H H