Pyridines

Pyridines are the most commonly encountered π- electron deficient heterocycle. Examples abound.

H O 4 N nifedipine 5 3 N NH2 (anti- angina) H CH3 6 2 MeO2C CO2Me N N 1 N NO2 nicotine niacin (nicitinamide) (in NADP)

There are many classical syntheses of pyridines; only a few can be covered in the time available.

1. Hantzsch Synthesis Probably the conceptually simples pyridine synthesis would be a simple extension based on the Paal- Knorr pyrrole synthesis. In other words…. Paal-Knorr NH3 R5 R2 5 2 R N R OO H the shouldn't a 1,5-dicarbonyl do....

NH3 [O] 6 2 6 2 R R 6 2 R N R O O R N R H This is absolutely feasible. Furthermore, as you might expect, the 1,5-dicarbonyls are readily accessible by Michael reaction chemistry (1,4-, conjugate additions). The one- pot version of this, where the unsaturated carbonyl is prepared, the Michael reaction occurs, and the pyridine formation is accomplished, is quite common. It is called the Hantzsch synthesis. 4 O O 4 R O NH3 or O R O EtO2C CO2Et R4 NH4OAc EtO + + OEt EtO OEt ∆∆∆ H2O, O O O O OO **

R4 R4 FeCl3 EtO2C CO2Et EtO2C CO2Et ∆∆∆ H2O, N N H

It’s rather forceful conditions, but the ester groups can be decarboxylated. The shown example is a symmetric case, but unsymmetrical ones can be done by doing the aldol condensation (here called a Knoevenagel) first, discretely, and then putting that compound (** ) into a separate reaction doing the subsequent steps. 2. Guareschi Synthesis A closely related synthesis a cyanoacetamide and a β-diketone, or alternatively the enamine of a β-keto nitrile. In these cases one of the ketone functions of the β-diketone is the most readily subject to nucleophilic attack. This is called the Guareschi synthesis. most readily 4 4 R attacked R R4 base, CN CN _ CN O i.e., piperidine + O O 6 R O H N O EtOH R6 O H N O 6 2 2 R O NH2

other bases/solvents include R4 R4 NaOMe/MeOH, KOtBu/DMSO, CN CN K2CO3/acetone _ O 6 R6 N O R O NH H The two ketone carbonyls are normally widely different in reactivity to give more reactive pyridine formation without regiochemical mixtures of products. Otherwise, has strong EWG symmetric diketones (R 4 = R 6) are used. CO2Et The following is an example of the modification of Guareschi that employ the O enamine of a β- keto ester. CO Et O 2 CO2Et CN K2CO3 CN O + acetone O H N 73% 2 H3C N CH3

3. By Cycloaddition Chemistry Six pyridine is a six membered ring system, there are several approaches to it that employ Diels-Alder chemistry to prepare the system. Some need a subsequent elimination, or a subsequent retro- Diels- Alder (or both) to form the pyridine. One example will be shown If one has a 1,2,4-triazene, it can participate in Diels-Alder chemistry, particularly inverse electron demand versions (i.e., electron poor diene); in this case the electron rich dienophile is an enamine. The product then undergoes elimination of the amine to give the pyridine. This is a bit unfair, in that you’ve seen no triazine chemistry to this point. These can be substituted at the 3-,5-, and 6- positions. retro N Diels-Alder N N CHCl3 N + -N≡≡≡N N N 45 o N N N N

elimination

- easily N N H It is certainly not the only type of Diels-Alder process employed, i.e., …. R1 EWG R O O R1-C≡≡≡C-R1 EWG R R1 O O N -CO N 2 N N then elimination Reactions of Pyridines Since pyridines are electron deficient species, it is possible to do nucleophilic attack reactions on carbon atoms. For the expected reasons, C-2, C-4, and C-6 are the sites susceptible to nucleophilic attack.

4 + 5 3

2 + 6 N + __N N N_ If the nucleophile is sufficiently reactive, it may attack the unactivated pyridine itself, but it must be pretty reactive. The immediate product is a ‘reduced’ pyridine; how the product gets back to a pyridine depends upon the case. It may be..

-due to spontaneous loss of H 2 from the dihydropyridine

-due to spontaneously loss of H 2 from the anion of the dihydrpyridine

-due to oxidation by air (O 2) after workup n-BuLi H2O 100 o H3C N H3C N H3C N Li This only works for the most reactive nucleophiles, such as:

RLi, RMgBr, NaNH 2 (this is the least reactive nucleophile I’ve seen, called the Chichibabin reaction)

The pK a limits is ≥ 35 under reasonable conditions Note: I have seen a report of KOH at 300 oC

Regiochemistry is normally at C-2 (or C-5); it’s reasonable that coordination of the metal counterion to the N lone pair has a role in this.

Alternatively, it is possible to employ a wider range of nucleophiles by: A. Quaternizing the nitrogen atom of pyriidine, preferably with something that can ultimately be removed. O H R R ∆∆∆,S R-M+ Cl OEt H + + N R N N +N N R N O OEt O OEt O OEt 1,2-addition 1,4-addition Pyridinium is now more reactive, but reactions often give mixtures if one position isn’t blocked.

Organometallics such as R-Li or R-MgBr give mostly 1,2- addition products Organometallics such as R-Li + CuI give almost entirely 1,4- addition products

Now, nucleophiles associated with lower pK a’s (≤ 10) can be used, and give almost entirely the 1,4- addition products. Examples of these nucleophiles include: - CH2-NO2,COMeO2C 2Me , P(OMe)3 (pKaH = 2.6) _ Another alternative is with TBDMS substituted pyridinium ion; due to the steric +N -OTf hindrance present from this group, 1,4-addition is the norm. Si

B. Put a leaving group on the pyridine, usually being Cl, but it can be F, Br, NO 2, SO 2OR, or OCH 3

Now the reaction is an addition-elimination type, and nucleophiles with pK aH ‘s down to 6. PhSH SPh Et N, 100 o N Cl 3 _N N SPh Cl - — Examples of nucleophiles include MeO , NH 3, PhLi, and Ph-CH CN The reactivity is different, depending upon the location of the Cl atom on the pyridine. In order of reactivity, it is Cl Cl > >>> N N Cl N C-4 C-2 C-3 The C-2 chloropyridine is prepared from the pyridine, by POCl 3

POCl3 O OPOCl P Cl N 2 N O + N O Cl H Cl N Cl H H - + Cl This reactivity can be extended to quinolones and isoquinolines. In quinolones, the C-2 and C-4 chloro substituted compounds are directly analogous. Cl

directly analogous reactivity C-2 C-4 N Cl N In isoquinolines, the C-1 chloro substituted case is directly analogous, whereas the C-3 chloro isomer isn’t quite as reactive. The valence bond argument supports this, in that the negative charge is not as effectively delocalized onto the electronegative N atom in this latter case. Cl C-3 C-1 not as reactive N directly analogous N

Cl

Quinoline and Isoquinolines Quinolines and isoquinolines are simply the benzo- fused homologues of pyridine. They are chemically very analogous. Quinolines are particularly important as antimalarial drugs. H

HO H NEt N 2 H N MeO quinine chloroquine N Cl N Isoquinolines are more widely encountered, usually as the reduced, 1,2,3,4-tetrahedorisoquinoline nucleus. MeO papaverine MeO emetine opium alkaloid -amoebicide N -anti spasmotic N MeO MeO OMe H Et H OMe H OMe HN

OMe Quinolines synthesis The most common quinoline synthesis is a combination that looks like an aldol condensation and a imine formation reaction. It is called the Friedländer synthesis , and can be either acid or base catalyzed. R4 R4 R3 3 O R + 2 N R NH2 O R2

It is not established with certainty which order these two processes occur in, but my bet would be that the aldol is first under basic conditions, and the imine formation is first under acidic conditions. For the regiochemistry of reaction with unsymmetric ketones, recall basic enolate/enol chemistry… base O- O kinetic - less substuted

H+ O OH more substituted

And therefore: Ph Ph O KOH , EtOH O (aq) + 0 o NH2 N Ph H2SO4(cat) AcOH, ∆∆∆ N It is reasonable to expect problems when R 4 is alkyl, as there is then a site for competing enolization. As a result, many, many of the Friedländer examples have R 4 = H or aryl, and the few examples with R 4 = alkyl have an acidic β-keto ester as the ketone partner. Note: We will not cover these reactions, but for an electrophilic substitution alternative in quinolone synthesis, see the Combes synthesis or Skraup synthesis.

Isoquinoline Synthesis The most common synthesis of the isoquinoline nucleus is based on Frielde-Crafts type chemistry, but using an imine (instead of an acid chloride). There is a separate dehydrogenation step to get the fully aromatic system. This is called the Pictet-Spengler synthesis. O MeO MeO MeO MeO R1 H HCl (aq) + NH N NH N 2 ∆∆∆ 100 o + H R1 R1 R1

must MeO dehydrogenate MeO

N NH Pd/C, DDQ, or 1 chloroanil R R1 There is a drawback to the Pictet-Spengler. The iminium ion is pretty stabilized as cations go, and consequently is not that reactive. As a result, and electron donating group, and a strong one, must be present on the carbocycle for this reaction to proceed. There is, however, a simple modification of this process which helps out with this problem. This involves working with an amide instead of an imine. (a Lewis acid) MeO MeO MeO POCl3 MeO Pd/C HN R1 NH o N N 100 100 o O R1 OH R1 R1 amide or carbamate

Lewis acid can also be PCl5, AlCl3, SOCl2, ZnCl2, Al2O3, SiCl4

This is better in terms of reactivity, because the carbocationic intermediate formed is more reactive MeO MeO (less stabilized). So, while and EDG on the carbocycle N+ N certainly speeds up the reaction, it is not absolutely + - C OPOCl C - necessary for success. For some reason, it is known by a 2 OPOCl2 1 1 different name, specifically the Bischler-Napieralski R R synthesis.

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