Knorr pyrrole synthesis 6a
The Paal-Knorr pyrrole method is useful for making pyrrole rings as long as the starting 1,4-dicarbonyl
compound is readily available. For example:
Eto,C, CHs EtO.C, CH3 ° CH3
TL = H3C: CO;Et = mo NOH
H3C— XC OLEt 3 os
N 0 6 Et0,c 0
+ NH3
An alternative method, known simply as the Knorr pyrrole synthesis, involves
the reaction of an a-aminoketone with another ketone.
Et0.C, CH. Et0,€, cH; E1024 CH;
H
> ic \
CO; ne 3 COzEt
bo H3C COZEt Na
2
This retrosynthetic analysis £1026 CH3
outlines the rationale for the
method. Note the special —_—
arrows indicating this is H3c ‘CO2Et
"paper chemistry" 0 NH,Knorr pyrrole synthesis: mechanism 6b
Looking the example above we note that the oamino-f-ketoester and i-ketoester have the same
carbon skeleton. In this case the o-amino-f-ketoester can be made in situ with a second mole of the
B-ketoester to yield the pyrrole directly.
Rt
0.
pe R' =CO,Et
> pi R= CHS
R
t proton
X ‘exchange
H
RA HOUR? RL 0, UR? RL) oR? RK og UR?
L I L XL el mr i 4
R27 “n~ Rr! R27 Sn~ “Rt R27 Sn~ “Rt N* ~R
H H H HQ, H
|
Rt R? Rt R?
Ht Re R? =
— qo
R?NO”>R! R? ‘ Rt RN SR! R? (3 R!
N NO N
H HThe Knorr pyrrole synthesis: "unsymmetrical" pyrroles 7a
The Knorr pyrrole synthesis does not need to be done in “one pot". The amino ketone component
can be made separately, then condensed with another carbonyl containing compound, so giving
access to a wider range of pyrroles
Synthesis of a-aminoketones
9
9 9
Zn
HCI, NaNO, CO,Et _AcOH CO,Et
A cout ee Bifunctional
Chemistry notes,
slide 13a Non NH,
__ Bae we _NaNs Hai Pac
Chemistry notes,
slide 11a
Rt rR
Oo:
+ eo
R27 So
HN’The Knorr pyrrole synthesis: examples
Examples of pyrroles made using the Knorr method
Eto,c
1] a
HN
C4Hy
EtO,C.
A, =<
+ —>
0 HN
Ph Ph
+ ? —>
Ph
H~ No HN
7b
How would you
make this pyrrole?
Oo
[ \
xz