Heterocyclic Chemistry - Midterm
May 4, 2006
Professor Baran
Department of Chemistry
The Scripps Research Institute
Name: ______________________________________
Last 4 digits of your Social Security #: ___________
This is an “open-notes” exam designed to last 2 hours that you have 4 hours to complete
Definition of "open notes": Only handwritten notes (from lectures and any other source), no
copies allowed. Lecture summaries are the only handouts permitted during test.
Please present ONLY your FINAL answers on these sheets
Question 1
< (10 points)
Question 2
< (45 points)
Question 3
< (10 points)
Question 4
< (20 points)
Question 5
< (15 points)
Question 6
< (40 points)
Question 7
< (10 points)
Question 8
< (105 points)
Question 9
< (15 points)
Question 10
< (10 points)
Question 11
< (20 points)
Question 12
< (50 points)
Bonus Question
Total
< (25 points)
out of 350 points
Question 1 (10 points). Bipyridyls can be synthesized by the dimerization of pyridine with either
Raney nickel or sodium. Give a mechanism for this transformation and explain the difference in
the regioselectivity of the two reagents.
N
N
2,2' dimerization
Raney Ni,
Na,
then O2
THF
N
N
N
4,4' dimerization
Question 2 (45 points). Provide practical synthetic routes to the following heterocycles (15 points
each):
HO2C
Et2NOC
CO2Et
MeO
H
Me
N
Me
S
O
N
H
LSD
N
H
Cl
indomethacin
chuangxinmycin
Question 3 (10 points). Give a mechanism for the synthesis of azulene from the pyridinium salt
shown.
N
Cl
NO2
MeNH2,
pyridine, 0 °C
, NaOMe
NO2
51%
Question 4 (20 points). In the reactions shown below, identify the labeled intermediates and give
reasonable mechanisms for their formation. (10 points each)
MeO
CN
N
Cl
O
KOt-Bu, THF,
–10 °C
83%
NO2
A.
H2, Pd/C
A
MeO
EtOH, rt
81%
N
N
H
Ph
OEt
B.
Ph
O
Me
Yb(fod)3
DCE, D
97%
A
HONH2•HCl
MeCN, D
89%
B
Question 5 (15 points). Electron deficient heterocycles react with nucleophilic radicals. Provide a
mechanism and product for the following three component coupling. For full credit, label
nucleophilic and electrophilic radical species and provide a name for this reaction. Note: Only
organic intermediates need to be shown.
O
Me
Me
N
Me , H2SO4, AgNO3
(NH4)S2O8, C6H13C=CH2
?
Question 6 (40 points). Derive syntheses of the four isomers of azaindole shown below. (10
points each)
N
N
N
N
H
N
N
H
N
H
N
H
Question 7 (10 points). Using a variant of the Nenitzescu reaction, Boger and co-workers
constructed the indole core of duocarmycin SA. Give a mechanism for this transformation.
Me
Me
O
NHCOPh
O
MeO
N
OMe
OBn
NHCOPh
OH
1. Pb(OAc)4
2.
3. HCl, MeOH
(56% overall)
OH
NHCOPh
MeO
MeO
N
COPh
OBn
Question 8 (105 points). Propose total syntheses of the following products via aromatic
heterocycles (15 points each).
Cl
N
O
O
O
N
S
O
N
N
O
Me
N
O
Me
HO
O
OH
Me
angelicin
infractopicrine
EtO2C
cryptolepine
kahweofuran
N
CO2Et
Me
EtO2C
Br
Me
N
CO2H
streptopyrrole
Question 9 (15 points): Design a route I wherein R1, R2, and R3 all come from different building
blocks.
R2
R3
CO2R1
N
H
I
Question 10 (10 points): Chemists at a rival pharmaceutical company have indentified
tetrahydrothiophene A as a hot target for the treatment of numerous pathologies. While building
block B is readily available, their method for reaching A is tedious and expensive. Based on
chemistry you have learned in this class, design a one-pot method for joining thiophene B with pfluoroaniline and beat them to the market.
Me
Me
Me
F
S
NH2
A
Me
Me
S
Me
B
F
NH2
p-fluoroaniline
Question 11 (20 points). Give a mechanisms for the reactions shown below. (10 points each)
O
O
Me
Ts
Me
A.
N
C
Me
NaH, Et2O
40%
Me
N
H
CH2O, H2O,
HCl, D
O
B.
NH2
64%
OH
Me
N
Question 12 (50 points). Deduce the structures of the following heterocycles (5 points each).
A. (C8H8N2) Obtained upon treatment of 3-nitro-4-methylpyridine with vinyl magnesium bromide.
B. (C9H9N) Obtained by reacting N-acetyl-o-toluidine with sodium amide at 240 °C.
C. (C12H13NO2) Obtained by reacting p-benzoquinone and ethyl 3-aminocrotonate in boiling
acetone.
D. (C11H12N2O3) Formed upon condensation of 3-nitro-4-methyl-6-methoxypyridine with ethyl
oxalate in the presence of potassium ethoxide, followed by hydrogenolysis.
E. (C11H16O) Formed upon treatment of 1-cyclohexyl pentane-1-4-dione with TsOH.
F. (C13H19NSO4) Formed by treating a mixture of t-butyl acetoacetate, ethyl cyanoacetate, sulfur,
and EtOH with morpholine.
G. (C10H11NO4) Formed by mixing the dimethyl hydrazine of methacrylaldehyde (A) with dimethyl
acetylene dicarboxylate.
Me
CHO
A
H. (C11H10NCl) Formed from 2,3-dimethylindole after treatment with KOH in chloroform.
I. (C11H7NO4) Formed by treating isatin with 2-oxopropanoic acid and KOH at 95 °C.
J. (C10H9NO) Obtained as the major product from the treatment of N-(2-acetylphenyl)acetamide (A)
with NaOH.
O
Me
NHAc
Bonus Question (25 points). Djerassi and co-workers reported the transformation of
akuammiline to akuammicine in 1965. For extra credit towards the exam, please delineate a
mechanism for this transformation.
AcO
N
CO2Me
H
N
Me
KOt-Bu, some H2O
N
Me
H
N
H
CO2Me