Synthetic Organic Chemistry Final Exam (6KM33) Tuesday ...

Synthetic Organic Chemistry Final Exam (6KM33)

Tuesday, 8th April, 2014, 9:00?12:00 (3 h)

This is an open-book written exam. The course textbooks (Warren & Wyatt, 2nd Ed.) with personal notes and worked exercises, one good general undergraduate textbook (e.g. Organic Chemistry, 7th Ed. Bruice) and a copy of the literature assignment with personal notes are all permitted. Additional books and material are also allowed (but

not necessary) EXCEPT access to the internet is STRICTLY FORBIDDEN. There are four questions in total including one bonus question. The first three questions are

compulsory. The bonus question is optional.

Maximum no. points per question, and recommended time are highlighted in yellow.

Maximum no. points for exam: 130 points

Explain your answers clearly.

You may write in English or in Dutch.

GOOD LUCK!

Question 1.(48 points, 1 h)

In this course you have synthesized numerous different alcohol derivatives.

a) Give examples of five different reactions, which result in the formation of an alcohol functional group (e.g. see Question 2, part b). For each reaction, you do not need to write mechanisms; simply write clearly the structures of the starting material(s), product(s) and any other necessary reagents.(15)

- 1 point starting material. - 1 point reagent. - 1 point product. - e.g (but not exclusively):

EtMgBr O

NaBH4 O

OH r ac

OH

i) BH3

ii) H2O2/KOH(aq)

OH

N2

H2O

OH

OsO4

OH OH

r ac

Alcohols are extremely versatile building blocks.

b) For the above four syntheses, each starting from alcohol 1, draw the structure of the intermediates after each step, including the most likely product(s) A and C, and suggested, B and D. Where applicable correctly assign all stereo- and geometric isomers.[Note: For B and D, more than one synthetic step may or may not be necessary.](15)

- Approximate marking scheme (at examiner's discretion): - 1 point per correct intermediate and final structure (A & C). - 1 point per reagent, 1 point per correct intermediate (B & D). - Max. 15 points. - e.g (but not exclusively):

i) (COCl)2, DMSO, NEt3

OH 1

B

i) TsCl, Py

OH 1

ii) PhMgBr O

ii) NaN3 OTs

OH chiral racemic A

N3

OH 1

i) PBr3

ii) PPh3 Br

Br

iii) KOtBu

PPh3

PPh3

Br PPh3

O

Z-isomer

C

D

i) NaCN OTs

ii) Pd/C, H2

NH2

N

iii) O

H

NH2

N

then NaBH4

Likewise, simple and inexpensive aromatic building blocks, such as benzene, methoxybenzene (anisole) and toluene are quickly elaborated into a diverse range of richly functionalized benzene AND cyclohexane derivatives. e.g. compound 2, an experimental analgesic, can be disconnected to 3 and 4. [Note: for parts 1c-e, write clearly all intermediate structures, and suggested reagents. You do not need to provide mechanisms.]

c) Propose a synthesis of methoxybenzene starting from benzene?(5)

- 1 point per correct intermediate. - 1 point per reagent. - Max. 5 points. - e.g (but not exclusively):

d) Propose a synthesis of 3 and 4 both starting from either benzene or toluene.(10)

- 1 point per correct intermediate. - 1 point per reagent. - 5 points per molecule, 3 and 4. - Max. 10 points. - e.g (but not exclusively):

e) How would you synthesize 2 from 3 and 4?(3)

- See above. - 1 point per correct intermediate. - 1 point per reagent. - Any form of carboxylic acid activation would do (HATU, DCC etc.) - Protection of alcohol is not necessary; reaction can go chemoselective

for the amine. - Max. 3 points. - e.g (but not exclusively):

Question 2.(50 points, 1 h)

,-unsaturated carbonyls are "chemical chameleons", which change their reactivity according to their chemical environment.

a) Give examples of five different ways to make an ,-unsaturated carbonyl functional group in no more than 2 steps. For each reaction sequence you do not need to write mechanisms; simply write clearly the structures of the starting material(s), product(s) and any other necessary reagents.(15)

- 1 point starting material. - 1 point reagent. - 1 point product. - e.g (but not exclusively):

,-unsaturated ketone (enone) 5 reacts with Grignard reagents at the carbonyl carbon e.g. 1,2-addition of n-BuMgBr to form alcohol 6, or with organolithium cuprates at the -carbon, e.g. 1,4-Michael addition of methylcuprate en route to ketone 7.

b) Provide a detailed curly arrow mechanism for the synthesis of 7?(3)

- 1,4-Michael addition of methyl cuprate to 5.(1 point) - Formation of thermodynamic enolate intermediate stabilized by lithium

ion.(1 point) - "Quench" enolate with BnBr, leading to alkylation to carbonyl AND to

methyl group.(1 point)

c) How could you selectively synthesize products 8-10 starting from enone 5? Suggest suitable reagents A-C.[Note: Multiple synthetic steps may be required. Write clearly all intermediate structures, and suggested reagents. You do not need to provide mechanisms.](12)

- General markign scheme: - 1 point per correct intermediate. - 1 point per reagent. - Max. 12 points distributed evenly across all three molecules. - e.g (but not exclusively):

,-unsaturated carbonyls also behave as dienophiles in Diels-Alder reactions. d) Perform Diels-Alder disconnections on the following five compounds, 11- 15, draw the corresponding diene and dienophile reagents.(10)

- 1 point per correct diene. - 1 point per correct dienophile. - Max. 2 points per molecule. 10 points in total.

e) Propose a synthesis of 16 starting from valerolactone. You do not need to provide reaction mechanisms; simply write clearly the structures of the intermediates formed and reagents used.(10)

- In general: - 1 point per correct reagent. - 1 point per correct intermediate. - Max. 10 points per molecule. 10 points in total. - Clearly, lots of ways to go about synthesizing this molecule. - Use flexible marking scheme. - One possible route could be:

Question 3. (based on literature assignment).(32 points, 45 mins) [Citation: Breitler & Carreira, Angew. Chem. Int. Ed., 2013, 52, 11168.] NOTE: for this question the compound numbers are identical to those used in the citation! With reference to Scheme 3:

a) Compounds 6 and 7 are not commercially available. Propose a synthesis of 6 and 7 from A and B, respectively?(7)

- In general: - 1 point per correct reagent. - 1 point per correct intermediate. - Max. 2 points for 6 and 5 points for 7. Max. points = 7. - Literature routes used are:

b) Draw a detailed curly arrow mechanism for the formation of 8 from 6 and 7 over two steps.(5)

- Step a - Deprotonation of 6 to ester group (1 point) and 1,4-Michael addition

at enone 7.(1 point) - Deprotonation of to ketone and 1,2-addition at aldehyde to form the

six-membered ring.(1 point) - E1cb elimination of water.(1 point) - Step b

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