Baran
Heterocyclic
Chemistry
Lectures 7 + 8: Indoles
Tuesday, April 12th and Wednesday April 13th, 2011
Reading assignment: Li chapter 3; HC chapter 17; Richter indole/pyrrole handout
Background music: Johann Sebastian Bach
Partial list of concepts/transforms discussed:
Selected named indole syntheses:
Bartoli
Fischer
Gassman
Japp−Klingemann
Reissert
Bischler
Nenitzescu
Batcho−Leimgruber
Madelung
Hemetsberger
Sundberg
Heck
Syntheses discussed:
F
CN
O
F
CO2H
N
H
CO2H
N
Bn
Me
Br
Me
N
Me
N
H
N
Bn
N
N
O
RO
NMe2
2
F
O
Me
N
NHNH2
O
3
Amerge (naratriptan)
GSK, AstraZeneca
indolomorphinan
Lewis, J. Med. Chem. 2005,
48, 635
CO2Et
F
Me
Me Me
LY311727
Lilly, J. Org. Chem.
1996, 61, 9055
F
NH2
Br
5N NaOH
F
N
N
Boc
intermediate en route
to glycogen synthase
inhibitor
Lilly, J. Med. Chem.
2004, 47, 3934
NaNO2
HCl
4
F
Cl
MK-677
Merck, Tetrahedron
N
1997, 53, 10983
SO2Me
identify all 3 products formed
F
N
H
h5-HT2A-receptor agonist
Merck, J. Med. Chem. 2001,
44, 1603
P(O)(OMe)2
NH2
1. HCl
2. NaOH
N
NH
F
Ph
N
Bn
CO2Et
+
O
O
O
OBn
O
N
H
clinical candidate
from BMS
OPRD 1997, 1, 300
N
H
NH2
Maxalt (rizatriptan)
Merck
O
N
MeHNO2S
N
Bn
N
H
N
NHNH2
Br
OH
carbocyclic[g]indoles
Lilly, J. Med. Chem. 2005,
48, 893
Product and mechanism
Me
NR
OH
Me
1. THF/H2O
2. ZnCl2, heat
O
CO2H
N
H
F
MDL-103371
Aventis, OPRD 2000, 4, 477
NH2
N
N
O
N
Br
N
Cl
O
1
MeO
CO2H
Cl
melatonin
Reddy, OPRD 1999, 3, 155
O
CO2-Na+
+
N
H
CO2H
Problems of the day:
OH
Me
Lescol (fluvastatin)
Novartis, OPRD 2001, 5, 519
NH2
NHAc
MeO
OH
1-substituted
cycloalkyl[b]indoles
Merck, unpublished
pyrano[3,4-b]indoles
Wyeth, J. Med. Chem.
2004, 47, 6603
Ar
1. PhNHiPr
2. ZnCl2
N
O
Me
Me
N
H
Br
5
9
Provide at least three distinct routes to the following indole:
Provide (multiple) routes to the following indoles:
Me
F
Me2N
NC
HO
N
CO2H
N
H
N
Me2N
HN
N
H
N
from
HN
N
H
O
B
CF3
O
6 How would you prepare 14C labeled Amerge?
O
Me
N
N
H
N
H
I
NH
OBn
C
MeHNO2S
N
H
*
7 Provide routes to the following fluorinated indole isomers using the indicated sm:
I
?
Ph
F
NH2
F
Me
N
H
F
?
F
Ph
NH2
N
H
?
Ph
NH2
F
8
Propose a synthesis of MK-677
N
H
F
D
E
Me
NO2
O
A
Br
N