CHEM 330. Final Exam December 5, 2014 ANSWERS. This a closed-notes, closed-book exam. The use of molecular models is allowed

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1 CEM 330 Final Exam December 5, 2014 Your name: ASWERS This a closed-notes, closed-book exam The use of molecular models is allowed This exam consists of 12 pages Time: 2h 30 min 1. / / / / / / / 40 TTAL / 250 = / 100 This exam counts for 50% of your CEM 330 final grade

2 Chem 330 final exam p. 2 of (30 pts.) Write a chemical equation and a brief sentence to illustrate each of the following mechanistic models: a. Principle of vinylogy the interposition of a C=C unit between the components of a functional group generates a new functional entity, which retains the chemical characteristics of the original. For instance: an enolizable carbonyl compound: deprotonation is possible because of resonance delocalization of ( ) charge on the eletronegative atom C C 2 : B B : C C=C C 2 a vinylog of the original: resonance delocalization of ( ) charge on the atom still possible through the C=C bond: can undergo deprotonation b. Fürst-Plattner rule electrophilic cyclohexene derivatives (epoxides, halonium products selectively. Example: ions,...) react with nucleophiles to form trans-diaxial Br 2 Br Br = Br Br only c. Felkin-Ahn model an α-heterosubstituted aldehyde is most reactive toward nucleophilic addition when the C α-heteroatom σ bond is approximately perpendicular to the plane of the C= group. ucleophilic attack then occurs preferentially from a conformation in which the incoming nucleophile can approach along a Dunitz-Bürgi angle from the side of the smaller α-substituent. To illustrate: Me = Me u u Me u = u Me product formed selectively

3 Chem 330 final exam p. 3 of (30 pts.) Write a chemical equation to show an example of a reaction that involves the use of the following nitrogen-containing reactants (do not write mechanisms just the reactions): a. Me 3 Si SiMe 3 TMS 2 TMS I TMS (Miller reaction) b. + CMe catalytic CMe (Baylis-illman reaction)

4 Chem 330 final exam p. 4 of 12 c. 2 (C 3 ) 2 2 Me 2 Me 2 BuLi, then C 2 Br Me d. + used, e.g., for cross-claisen condensations e. Et + C catalytic Et C strong amidine base, used, e.g., to promote Michael addition of stabilized enolates

5 Chem 330 final exam p. 5 of (30 pts.) Check the appropriate box to indicate whether the following statements are true or false: a. Reaction of A with catalytic Mea yields B: true false cat. A Mea B b. Reaction of C with maleic anhydride yields D: true false Me 3 Si Me 3 Si + Ac C Ac D c. The reactants shown below are stereochemically matched: true false Cy Cy B + Bn Mes Xc d. The copper atom undergoes oxidative addition in the course of the following reaction: true false CuCl LiCl Li 2 CuCl 4 e. The following procedure is satisfactory for the preparation of the cyclic product shown 2 equiv a Et Et I (C 2 ) 4 I true false

6 Chem 330 final exam p. 6 of 12 f. The following procedure is satisfactory for the synthesis of the triol shown true false excess C a g. The Diels-Alder reaction of furan with maleic anhydride gives the exo-adduct due to a lack of secondary orbital interactions true false + h. The process shown below is a reverse Claisen condensation: true false Et Et cat. Eta CEt + C 3 CEt i. Treatement of E with a / cat. Et, followed by mild 3 +, will produce F: true false EtC a, cat. Et CEt EtC E CEt then mild 3 + EtC F j. Treatment of G with Li in liquid 3, followed by allyl bromide and then catalytic Mea, will produce true false G 1. Li, 3 (liq), then C 2 =C-C 2 Br 2. cat. C 3 a

7 Chem 330 final exam p. 7 of (40 pts.) Provide a succinct explanation for the following experimental observations: a. Deprotonation of ketone A with 0.95 equiv of LDA, followed by reaction with TMS-Cl, produces silyl enol ether B, BECAUSE: A 1. LDA (0.95 equiv) 2. TMSCl TMS the remaining 0.05 equivalents of ketone A act a proton source ("shuttle") and induce equilibration of the initially formed kinetic enolate to the thermodynamic one B b. Reaction of compound C with Me 2 CuLi, followed by mild 3 +, selectively yields D, BECAUSE: C Me 2 CuLi then mild 3 + D the cuprate tends to attack in an axial mode, in such a way that the 6-membered ring evolves toward a chair (or half-chair) conformer. This constitutes the more energetically favorable reaction pathway c. Treatment of compound E with LDA, followed by benzyl bromide, selectively yields F, BECAUSE: EtC E LDA then -C 2 Br EtC F as expressed by the principle of least motion, atoms within a molecule tend to undergo the least possible extent of repositioning during a reaction. In the present case, compound F (the resultant of α-alkylation of the dienolate of E) forms through a process that requires the repositioning 3 out of 5 non- atoms of the substrate. The hypothetical γ-alkylation requires the repositioning of all 5 atoms. Therefore, compound F is formed preferentially d. Benzoquinone G undergoes Diels-Alder reaction selectively at the double bond bearing the CMe group, BECAUSE: MeC MeC G C 3 C 3 a CMe group lowers the LUM energy of a π bond, while a C 3 group increases it. This is a regular-demand DA reaction, so the key FM interaction is between the M of the diene and the LUM of the dienophile. The M-LUM energy gap for reaction at the CMe-substituted π bond is smaller. Therefore reaction at the CMe-substituted π bond is faster

8 Chem 330 final exam p. 8 of (40 pts.) Predict the structure of the major product expected from the following reactions. otes: (i) it is not necessary to draw mechanisms; (ii) aqueous workups at appropriate stages are understood. a. 1. a, cat. Et Et Et 2. a, Br 3. ai, aq. DMS reflux b. C TMS C 3 BF 3 C 3 c. C TMS C 3 TiCl 4 C 3 d. CMe CMe 2 CuLi CMe e. Et 1. LDA, TF MPA, 78 C 2. TBS 3. TBAF 4. TPAP / M C Et

9 Chem 330 final exam p. 9 of 12 f. 1. LDA, TF 78 C 2. Me C 3. ab(ac) 3 g. Cl C Et 4 Ac, heat cat. aet 3. 3, 4 Ac Et Cl EtC CEt h. 1. LDA, TF, 78 C DIBAL 4. 3, then Zn / + I h. Bn 1. Bu 2 BTf, Et TBSCl, Et 3 4. Me, cat. K 2 C 3 TBS CMe j. Me Me 3 P heat CMe Me Me CMe

10 Chem 330 final exam p. 10 of (40 pts.) Complete the following equations by indicating all the reagents that are necessary to effect the transformations shown. Provide your answers as a numbered list of reagents, in the correct order, written over/under the reaction arrows. ote: aqueous workups are understood and do not need to be included in your answers. a. 1. C 2 =C C=C 2 2. a, C 3 I 3. cat. s 4, M Me Me b. 1. LDA, then C 3 I 2. TMS 2, TMS-I 3. MeLi, then C 2 =C-C-Et 4. ame 5. LDA, then SeBr 6. MCPBA, then heat Me c. 1. CDI 2. add to enolate of C 2 CEt (prepared by deprotonation with LDA) Et d. Me 2 CuLi, then C 2 =C-C 2 Br TMEDA

11 Chem 330 final exam p. 11 of (40 pts.) Propose a method to achieve the enantioselective synthesis of the molecules shown below starting with the suggested compounds plus any additional building blocks that might be required (simple carbonyl compounds, alkyl halides, ). Be careful about protecting groups and configurations of stereocenters. Assume the availability of all needed reagents, auxiliaries, etc. Present your answer as a clear flowchart. It is not necessary to draw mechanisms or to indicate aqueous workups. a. TBS Et 2 BMe ab 4 starting with + Bu Bu B TBS Xc DIBAL Li TBS, cat. + Pyr S 3 DMS TBAF TBS then Et 3

12 Chem 330 final exam p. 12 of 12 b. TBS cat. acid or base starting with TBS I t-buli TBS (Bu 3 P) 2 CuBr Li Cu(PBu 3 ) 2 CEt TBS TBS TBS TES TBAF (1 equiv) CEt Li TBS Bn C 2 =C-C 2 Br TMEDA Xc TES Et TBS Xc TBS DIBAL CDI TES TBS TBS TBS TES aq. Li, then mild + Xc Bu Bu B Bn pyr S 3 DMS then Et 3 TBS appy olidays!