Heterocyclic Chemistry Midterm Examination. 3 May Professor Baran Department of Chemistry The Scripps Research Institute

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1 eterocyclic Chemistry Midterm Examination 3 May 2013 Professor Baran Department of Chemistry The cripps Research Institute ame: Last 4 digits of your ocial ecurity #: This is a 2-hour test that you have 4 hours to complete Please present LY your FIAL answers on these sheets Question 1 Question 2 Question 3 Question 4 Question 5 Question 6 Question 7 Question 8 Question 9 < (50 points) < (20 points) < (20 points) < (30 points) < (20 points) < (30 points) < (40 points) < (60 points) < (30 points)(15 bonus) Bonus Question < (50 points) Total < (300 points) 1

2 Question # 1 (5 points each, 50 points in total): Deduce the structures of the following heterocycles based on the clues provided. A. (C 6 2 ClF 3 I) btained by treating 3-chloro-2-trifluoromethyl pyridine with LDA then Iodine. B. (C ) btained by treating 2-methyl pyridine--oxide with acetic anhydride and heating. C. (C 11 9 ) btained by treating pyridine--oxide with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate and cesium fluoride in acetonitrile at room temperature. D. (C ) btained by mixing methyl acetoacetate, 2-nitrobenzaldehyde, and magnesium nitride (Mg 3 2 ) in ethanol and water with heating. E. (C 6 7 ) btained by treating 2-acetyl furan with ammonia. 2

3 F. (C Br 4 ) btained by treating -Boc proline methylester with - bromosuccinimide in carbon tetrachloride with heating. G. (C Br 3 i) btained by treating TIP protected pyrrole with five equivalents of - bromosuccinimide at -78 degrees C.. (C ) btained by dissolving methyl 1-amino-1-pyrrole-2-carboxylate (a.k.a. 1- amino-pyrrole-2-methylester) in formamide and heating to 165 degrees C. I. (C ) btained by dissolving indole-3-acetic acid in DM and con. aq. Cl at room temperature. J. (C 8 8 Cl) btained by treating 4-chloroaniline with Cl 2 in benzene followed by treatment with vinyl magnesium bromide in tetrahydrofuran and quenching with aq. ammonium chloride. 3

4 Question # 2 (20 points): endrickson, 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), (C) 2 (10 eq), Yb(Tf) 2 (20%), xylene, 150 C, 12 hours (35%) 4

5 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

6 Question # 4 (30 points): You are the LY 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 TW 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. Me Cl F Alkyl old this group constant in BT the med. chem. and process route. Me Alkyl = Me for process route 6

7 Question # 5 (20 total): o 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. Me Me Cl (i-pr) 2 7

8 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 [ 3 ], [ 18 F] and [ 14 C]AZ4694. ince you have made it through this far in class, please propose a feasible route to the following radiolabelled compounds. F [ 3 ]AZ4694 C F [ 18 F]AZ4694 Me! F [ 14 C]AZ4694 Me 8

9 Question # 7: (40 points) Please provide a synthesis of two (2) out of the following three (3) heterocyclic natural products: Me Me 2 C Cl Cl C 2 Me 9

10 Question # 8: (60 points) Please provide a synthesis of three (3) out of the following five (5) heterocycles: R Me Me Me 2 2 Me 10

11 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. ote: 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 Et Et Et Ar 2 C 5 11 C 2 Et Method Et 2 C Ar Ar 3 (Et) 2 C C 2 Me 2 1,4-dicarbonyl Fiesselmann thiophene synthesis Cycloaddition insberg synthesis Gewald synthesis McMurry Coupling 11

12 Bonus: (5 points each) More thiophenes! Your solution on the rotary evaporator bumped, which means you have more time to spare. ynthesize the following thiophenes: 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. 2 C 3 Br Br C 3 Br Br C 3 Br 3 C Cl Cl 2 C 3 12