CHEM 330

Topics Discussed on Sept 28

Heterocycles such as pyrazole, pyrimidine, etc., as common subunits of pharmaceuticals

O O Celebrex (Pfizer) S Pyrimethamine H2N N H2N anti-inflammatory antimalarial N N N CF3 Cl R1

N NH N N

R1 R3 R2 R4 R2 R3 pyrazole pyrimidine

Imine– and enamine-type linkages in nitrogen heterocycles

R1 H imine- N N enamine- imine- N N enamine- type type 1 3 type type R R R2 R4 R2 R3 pyrazole pyrimidine

Principle: the construction of heterocyclic systems often involves the formation of imines (=Schiff bases) and / or enamines. These are produced upon the condensation of carbonyl compounds with appropriate amines (see CHEM 203 & CHEM 213 notes):

2 + 2 R cat. H R3 R2 ± H+ R3 R 3 R –NH2 + O N N 1 1 H 1 R – H2O R R primary enamine: amine ketone imine (= Schiff base): generally favored generally disfavored tautomer tautomer

4 2 + R4 2 4 R R cat. H R – H+ R R2 NH + O N N 1 3 1 R3 R – H2O R R R3 R1 secondary ketone iminium amine enamine ion

Approach to the synthesis of pyrazoles by reaction of 1,3-dicarbonyls with hydrazine: lecture of Sept 28 p. 2

H H N imine-type N N enamine-type 2 imagine the imagine O NH linkage functionality releasing imino or the R1 R3 R1 R3 iminium R2 the imine ... R2 tautomer ... pyrazole: an aromatic compound H2N NH2 hydrazine

H2N imagine O N (NH ) releasing O O "type A" 1 3 R1 R3 the imine R R 1,3-di-O functionality! (or iminum)... R2 R2

Application of the above logic to the synthesis of Celebrex

O O O O S S H2N more nucleophilic H2N N NH2 N N H CF3 O O more electrophilic due to CF3 group CF3

Preparation of diketones of the above type by a cross-Claisen-like reaction taking place under conditions of thermodynamic control:

O O H2N S O O NaH, cat. O O EtOH, then EtO CF CF + celebrex + 3 3 mild H O+ non-enolizable 3 enolizable ester HN ketone NH2

Approach to the synthesis of pyrimidines by reaction of 1,3-dicarbonyls with amidines or guanidines:

R4 R4 H2N imine-type imagine imagine linkage N N releasing O N enamine-type releasing functionality R1 R3 the imine ... R1 R3 the enamine ... pyrimidine: R2 R2 aromatic O O R4 4 "type A" 1,3-di-O amidine if R = H, alkyl 1 3 4 functionality! R R H2N NH guanidine if R = NHR R2 lecture of Sept 28 p. 3

Amidines and guanidines: compounds possessing the structures shown below

NH • R may be H or alkyl R NH R an amidine • Additional N-alkyl groups HN a guanidine may also be present NH2 NH2

Amidines as formal imines of carboxamides; guanidines as formal imines of ureas:

O imine NH R R formation acetamidine acetamide NH2 NH2

O imine NH H2N H2N guanidine NH formation NH urea 2 2

Principle: it is not possible to prepare amidines or guanidines by condensation of amides or ureas of with amines/NH3

note: this is because (i) the C=O group of amides and ureas is insufficiently electrophilic to react with amines or NH3, and (ii) if one forces the issue, other reactions tend to occur.

Preparation of amidines by addition of NH3 or amines to nitriles (under appropriate conditions not covered in CHEM 330):

2 R appropriate NH 1 + 2 R C N HN R an amidine R3 conditions R1 N a nitrile ammonia R3 primary amine secondary amine

Preparation of guanidines by addition of NH3 or amines to cyanamides:

2 R R4 NH + appropriate N C N HN R2 R4 1 R3 a guanidine R conditions N N a cyanamide: ammonia R1 R3 1 2 primary amine R , R = H secondary amine or alkyl / aryl

Application of the above logic to the synthesis of pyrimethamine

N NH2 O H1N Cl H2N + Cl N NH O NH 2 NH2 guanidine an amide... pyrimethamine

BUT: one cannot make the "imine of an amide," i.e., an amidine, by condensation of amine-type compound with an amide: a nitrile is required instead … lecture of Sept 28 p. 4

O N NH2 Cl H1N Cl H2N + N NH C NH2 N guanidine a nitrile pyrimethamine

Similarities between the chemistry of nitriles and that of esters

Preparation of ketonitriles of the above type by a cross-Claisen-like reaction taking place under conditions of kinetic control; e.g:

O O Cl LDA Cl X Cl C C C X = CN N N N X = imidazole

Kinetically controlled cross-Claisen condensations of the type above as exceptional cases in which acid chlorides (instead of acyl cyanides or acyl imidazoles) perform well:

LDA, then O Cl Cl NC EtCOCl NC

then . . .

Cl Cl

Ar Ar Et N Et NH CN N NH N N NH O 2 + NH2 NH2 N N H2N NH guanidine NH2 NH2