Heterocyclic Chemistry
Heterocyclic systems are widely important compounds, both in terms of commonness of occurrence and importance of consequence. For example, in 2010, 8 of the top 10 selling drugs contained heterocyclic systems – yet you have seen very little of heterocycle synthesis in your studies.
The Fundamental Heterocycles
We will be limited in the heterocycles we address, due to time constraints. We will only discuss….
πππ-Excessive Heterocycles πππ-Deficient Heterocycles
N N O S N N O N N H H furan thiophene pyrrole indole oxazole pyridine quinoline isoquinoline
Issue #1. Are they really aromatic?
The π-excessive heterocycles use the lone pair on the heteroatom to formally make the 6 system aromatic, but in reality they have less aromatic character than benzene. Various measures of aromaticity suggest that thiophene and pyrrole are only a bit less aromatic than benzene, while furan (and oxazole) are substantial reduced in their aromatic character. This will have consequences in their properties and reactivity.
N Aromaticity S measurement O N N O thiophene H H furan pyrrole indole oxazole
12% rel 45% 37% Baran-Richter to benzene ASE 61% 37% Homodesmotic 44% 56% 34% 91% 89% HOMA 30% not very not very pretty pretty assume it's Conclusion like pyrrole aromatic aromatic aromatic aromatic
Generalities of Reactivity
Electrophilic Aromatic Substitution – Recall, in all cases except for indole, that electrophilic substitution favours C-2 (or C-5) substitution. In indole, C-3 substitution is the first choice, and if it is blocked, then C- 2 is the 2 nd choice. 1st choice
+ + E+ E E 2nd choice S N N O H H
There are some, rare exception where C-4 or C-3 substitution is favoured. This is most often due to existing EWG groups disfavouring C-5, or due to mammoth steric effects.
E+ E m-director m-director m-director X X E X major minor
CCl 90% HNO O N 3 3 2 CCl3 o N O -50 N H O 77% H
Br (NBS) Br O Br N O again N Br N i o N Si Pr3 THF, -78 i Si Pr3 i Si Pr3 huge
Note: In some cases with furan, the reaction products look like it’s classical electrophilic substitution, but it is not really..
o Br2, 0 -HBr but one gets Br Br if rxn done OMe dioxane O O O Br O in MeOH MeO
Directed Lithiation – Once again, the predominant lithiation site is C-2
(35.0) (36.4) (27.1) (32.5) N (37.3) Li Li Li Li Li O S N O N DMG DMG
The ability to lithiate at C-3 is hit and miss at best, other than for indoles. There is irregularly successful with thiophenes, but the overall take is that it’s not generally successful. Li Li Li Li N N LiN Bu-t DMG S O N S N S O o LDA, Et O, -78 Li o o yes R 2 BuLi, -78 o BuLi, 0 to -78 THF
Li NEt2 NEt X = S, O but at least 2
Li X O S O Me3Si
The overall take home message is that C-3 and C-4 substitution is a big issue in pyrroles, thiophenes, and furans. Conversely, C-ring substitution is a big issue in indoles.
Synthesis of π-Excessive Heterocycles
Since furan, thiophenes, and even pyrroles have much in common chemically, it is no surprise that several of the syntheses of the ring system have much in common.
The Paal-Knorr Type
Furans - The most straightforward group of syntheses come from the fact that furans are really 1,4- dicarbonyls that have been dehydrated . So the key is to avoid (or remove) water.
p-TsOH(cat) 1 1 1 R R R R R R R OO PhH, ∆∆∆ OO OO 1 O + R + OH H H H H
-H+ H +H+ -H+ -H2O R R R + 1 1 O 1 O R O R OH2 R +
This reaction is known as the Paal-Knorr synthesis . Most often these 1,4-dicarbonyls are diketones, but there are examples where one or both carbonyls are aldehydes, or where one carbonyl is an ester. C-2 and C-3 substitution is well tolerated in this process, which gives furans with C-3 and/or C-4 substitution. One example is below, but there are several more on a subsequent page. p-TsOH(cat) J. Org. Chem. 1995 79% 60, 301. O O O cis
1 In principle, it should also be possible to initiate this type reaction from (Z)- γ- R R hydroxyalkenones, and this has been done. OO H Pyrroles -Fortunately, it is straightforward to make a modification of this to get pyrroles. If an “NH 3” equivalent is added to this reaction –sometimes NH 3 itself and sometimes H-N(TMS) 2 with alumina – the pyrrole is formed. Acid is often but not always present. This is also known as the Paal-Knorr (pyrrole) synthesis.
NH3 -H2O -H O 1 1 2 R R R 1 1 R R R R 1 ∆∆∆ N N R R R OO PhH, O OH H OH H N H2N HO HO H
Once again, C-2/C-3 substituted starting materials and therefore C-3/C-4 substituted pyrroles are common. Furthermore, the N can be substituted and often is, with alkyl groups, aryl groups and even acyl groups (amides).
CO2Me O CO Me CH CO H 2 3 2 R's = alkyl, aryl 1 2 R + H2N-R R1 Eur. J. Org. Chem. R (5 equiv) 150 W MW R N 2005, 5277. o O (170 ) R2
Thiophenes – For thiophenes, it might be expected that one could get the same sort of transformation to occur if only there was a reagent that could convert ketones into thioketones – and there is.
Traditionally P 4S10 was used, but reagents such as Lawesson’s reagent, or (TMS) 2S are much more common now. Acids are not additionally required for this reaction.
S
P MeO S S S S S S P4S10 P P Me3Si SiMe3 S S P P S P S S S S OMe S Lawesson's reagent This process is known by a slightly different name, as the Paal synthesis . Examples are on the following pages. Lawesson's reagent 2 1 R2 R1 R R 2 1 toluene, ∆∆∆ R S R OO SS a guess
Oxazoles – Finally, if there is an N atom in the backbone (i.e., a 2o amide) , the same type of protocol is also used to make oxazoles. The only other difference is that in this case the acid tends to be a quite strong one. Curiously, this protocol is known by a completely different name – as the Robinson-Gabriel synthesis .
H -H+ NH conc. H2SO4 N N R2 R1 2 1 -H O R2 R1 OO RT R O + R 2 O OH
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