Heterocyclic Chemistry Midterm Examination
3 May 2013
Professor Baran
Department of Chemistry
The Scripps Research Institute
Name: ______________________________________
Last 4 digits of your Social Security #: ___________
This is a 2-hour test that you have 4 hours to complete
Please present ONLY your FINAL answers on these sheets
Question 1
< (50 points)
Question 2
< (20 points)
Question 3
< (20 points)
Question 4
< (30 points)
Question 5
< (20 points)
Question 6
< (30 points)
Question 7
< (40 points)
Question 8
< (60 points)
Question 9
< (30 points)(15 bonus)
Bonus Question
Total
< (50 points)
< (300 points)
1
Question # 1 (5 points each, 50 points in total): Deduce the structures of the following
heterocycles based on the clues provided.
A. (C6H2ClF3IN) Obtained by treating 3-chloro-2-trifluoromethyl pyridine with LDA then
Iodine.
B. (C8H9NO2) Obtained by treating 2-methyl pyridine-N-oxide with acetic anhydride and
heating.
C. (C11H9NO) Obtained by treating pyridine-N-oxide with 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate and cesium fluoride in acetonitrile at room temperature.
D. (C17H18O6N2) Obtained by mixing methyl acetoacetate, 2-nitrobenzaldehyde, and
magnesium nitride (Mg3N2) in ethanol and water with heating.
E. (C6H7NO) Obtained by treating 2-acetyl furan with ammonia.
2
F. (C11H14BrNO4) Obtained by treating N-Boc proline methylester with Nbromosuccinimide in carbon tetrachloride with heating.
G. (C13H22Br3NSi) Obtained by treating TIPS protected pyrrole with five equivalents of Nbromosuccinimide at -78 degrees C.
H. (C6H5N3O) Obtained by dissolving methyl 1-amino-1H-pyrrole-2-carboxylate (a.k.a. 1amino-pyrrole-2-methylester) in formamide and heating to 165 degrees C.
I. (C10H9NO3) Obtained by dissolving indole-3-acetic acid in DMSO and con. aq. HCl at
room temperature.
J. (C8H8ClSON) Obtained by treating 4-chloroaniline with SOCl2 in benzene followed by
treatment with vinyl magnesium bromide in tetrahydrofuran and quenching with aq.
ammonium chloride.
3
Question # 2 (20 points): Hendrickson, eat your heart out! It's one step! It’s one pot! It starts
with dirt cheap (with the exception of the catalyst), commercially available compounds! Propose
a mechanism for how this ideal synthesis works. (Pay no attention to the solvent switch—that
doesn’t count as another step)
propargyl amine, DMF, rt;
then aniline (15 eq),
(CHO)2 (10 eq),
Yb(OTf)2 (20%),
xylene, 150 °C, 12 hours
O
O
N
H
O
(35%)
O
N
N
N
4
Question # 3 (20 points): The following common precursor was modified using reactivity and
reagents one should be very familiar with after the first half of this course. Propose a
retrosynthesis (no forward synthesis necessary) of common precursor (A) (5 points) and then
provide reagents to convert it into the following analogs (B-F) (3 points each).
A. Propose a retrosynthesis to the following molecule:
B. Provide reagents for the following transformations:
5
Question # 4 (30 points): You are the ONLY chemists at a very, very small biotech company
named “Pegasus Air Discovery.” Thus, you are acting as both a medicinal chemist and a process
chemist. To prove your worth, propose TWO retrosyntheses (no forward synthesis necessary)
for the molecule below: one retrosynthesis as a medicinal chemist looking to make many analogs
of the molecule and one retrosynthesis as a process chemist who is interested in making only this
molecules in the safest, most efficient, and most scalable way possible. For full credit, clearly
explain your disconnection logic.
O
OMe
N
Me
N
Alkyl
N
H
N
H
N
Alkyl = Me for
process route
F
Cl
Hold this group
constant in BOTH
the med. chem. and
process route.
6
Question # 5 (20 total): So you think you can dance? We discussed the synthesis of the
following natural product in class. The synthesis discussed used electrophilic aromatic
substitution, directed orthometallation, cross coupling, and halogen-metal exchange. Please
propose a route to this natural product from the given starting material featuring halogen dance
(not optional) along with any other pyridine substitution techniques you wish.
OMe
Cl
MeO
H
N
N
N
N
OH
O
N(i-Pr)2
7
Question # 6: (30 points) The following compound is needed as a potential PET radioligand for
the diagnosis of preclinal Alzheimer's disease. AZ4694 has been identified as a potential
radioligand, and your boss wants you to synthesize [3H], [18F] and [14C]AZ4694. Since you have
made it through this far in class, please propose a feasible route to the following radiolabelled
compounds.
HO
HO
HO
NHC3H
O
N
F
[3H]AZ4694
3
!
NHMe
O
N
18F
[18F]AZ4694
NHMe
O
N
F
[14C]AZ4694
8
Question # 7: (40 points) Please provide a synthesis of two (2) out of the following three (3)
heterocyclic natural products:
NH
Me
O
MeO2C
O
HN
N
O
N
CO2Me
N
HO
HO
H
N
HN
Cl
Cl
NH
9
Question # 8: (60 points) Please provide a synthesis of three (3) out of the following five (5)
heterocycles:
Me
O
N
S
O
Me
N
N
N
Me
R
O
NH2
N
H
N
NH2
O
MeN
O
N
S
N
O
N
N
10
Question # 9: (30 points) While waiting for the rotary evaporation of 4L worth of DMF, you
decided to make a report card on the synthesis of thiophenes. Below are 6 types of thiophenes,
and your goal is to evaluate each of the six methods to make each heterocycle. Please write "yes"
or "no" in each box. If you write "yes," please draw starting materials for that synthesis. Note:
there will be at least one "yes" for each heterocycle and no subsequent thiophene ring
substitutions should be used to make these thiophenes. (5 points per heterocycle, 30 points
total).
Et
Method
Et
S
Et
EtO2C
Ar2
Et
S
Ar
S
Ar3
CO2Et
C5H11
(EtO)2HC
S
CO2Me
S
S
NH2
1,4-dicarbonyl
Fiesselmann
thiophene
synthesis
Cycloaddition
Hinsberg
synthesis
Gewald
synthesis
McMurry
Coupling
11
Bonus: (5 points each) More thiophenes! Your solution on the rotary evaporator bumped, which
means you have more time to spare. Synthesize the following thiophenes:
S
S
S
S
S
S
S
Bonus Question: (5 points each, 50 points max) Congratulations! You’ve found investors to
fund your start up company despite not completing the second half of heterocycles. Your new
start up makes custom chemical building blocks. To stay competitive, you have surveyed the
local biotech companies for heterocycles they wish they could buy that are currently not offered.
Find concise syntheses for these building blocks that they requested.
O
CH3
Br
N N
N
N
N
NH2
N
HN
N
N
N
N N
N
N
HN
N
N
Br
N N
Cl
N
H3C
N
NH2
O
N N
N
N
Br
CH3
Br
CH3
Br
N
N N
NH
Cl
N
NH
N
N
N
N
H
N
CH3
12