Section 2 - Cross-coupling reactions - Answer key1

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Section 2: Transition metal-catalyzed cross-coupling reactions 1. Propose the product of the following reactions

2. a) B. Oxidative insertion involves transferring two electrons from Pd to the substrate. Ligands that donate electron density to Pd promote oxidative addition by giving Pd extra electron density to transfer. NMe 2 is a good electron-donating group, so ligand B will make Pd more electron rich and thus better at oxidative addition. b) D. The C – Cl bond is fairly strong and not easy to cleave. The C – N 2 + bond is expected to be much weaker because it liberates N 2 gas as a very stable leaving group c) F. Oxidative insertion involves transferring two electrons from Pd to the substrate. It is easier to transfer electrons to F because it is electron deficient. d) G. In general, the more s character the transferring carbon fragment has, the better it is at transmetallation. Thus, the sp-hybridized alkyne will be most quick to transfer.

3. The following is an unusual example of the Mizoroki-Heck reaction because the double bond of the starting material appears to disappear. (a) Draw a mechanism for the reaction. Hint: Remember that enols tend to tautomerize to the more thermodynamical favoured ketone. (b) Propose why the Pd catalyst preferentially reacts at the carbon – iodine bond instead of the carbon – chlorine bond of the starting material. a)

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b) Carbon – iodine bonds are weaker than carbon – chlorine bonds, primarily due to the differing size and poor orbital overlap between carbon (2 nd row of periodic table) and iodine (5 th row of the periodic table). The Pd catalyst will preferentially cleavage the weaker bond. 4. The following Buchwald-Hartwig amination was reported by chemists at Pfizer. (a) Propose a mechanism for the formation of the desired product. (b) Propose how the two possible byproducts shown in the box may be formed.

5. The following intramolecular cross-coupling did not go as planned for De Borggraeve and co-workers, who were trying to make analogues of the podophyllotoxin family of natural products. Explain what must have gone wrong.

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6. When attempting the following Buchwald-Hartwig amination, the labelled chirality center was found to ‘scramble.’ I.e. the starting material was a pure sample of the R enantiomer, but the product was a mixture of R and S enantiomers. Propose a mechanism for this reaction, including a hypothesis for how the stereocenter scrambling occurred. Hint: A reversible  -hydride elimination is likely involved.

7. Consider the following Suzuki-Miyaura reaction. (a) The starting catalyst, Pd(OAc) 2 , is a Pd(II) salt. However, the active catalyst in Suzuki-Miyaura reactions is believed to be Pd(0). Propose how Pd(OAc) 2 the corresponding boronic ester might react to make Pd(0) in situ. What is the by- product of this reaction? (b) Propose why the basic additive K 3 PO 4 is required for the reaction’s success? (c) There are three halogens present in the two starting materials. Propose why only one of them reacts.

8. Consider the following intramolecular Mizoroki-Heck reactions. When the reaction on top was tried, the illustrated reaction product was formed. For the reaction on bottom, which differs only in the stereochemistry of the methyl-containing carbon, the reaction failed to produce the same product. Use a mechanism to illustrate why.

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9. Many diverse nucleophiles can participate in cross-coupling chemistry. For instance, cyanide anion can act as a nucleophilic coupling partner. Propose a mechanism for the following reaction.

10. Pd-catalyzed cross-coupling with alcohol nucleophiles is possible but challenging. One of the main by-products involves reduction of the corresponding aryl bromide to the arene – i.e. the C – Br bond is replaced with C – H. This is proposed to occur by b-hydride elimination of the Pd alkoxide intermediate followed by reductive elimination to form the C – H bond. Illustrate this with a mechanism.

11. The synthesis of anilines from aryl chlorides and ammonia is a challenging but useful reaction. Propose what the major side products are.

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12. The following is a so- called ‘domino’ reaction that likely proceeds by oxidative addition,  -bond insertion of the alkyne, and C – N coupling.

13. When 3-bromo-5-iodopyridine is reacted with phenylacetylene under the conditions given below, product A is primarily formed. If A isn’t isolated, and another alkyne was instead added to the reaction mixture (1-heptyne), product B is isolated instead. Propose structures for both A and B: 14. Draw a mechanism for the following intramolecular Mizoroki-Heck reaction. The Pd catalyst can be abbreviated as [Pd].

15. Which phosphine ligand L is most likely to support oxidative insertion of Pd(0)L 2 into an aryl chloride C-Cl bond: PPh 3 or P(4-OMeC 6 H 4 ) 3 ? Explain. P(4-OMeC 6 H 4 ) 3 is a more electron-rich ligand than PPh 3 due to the presence of electron- donating methoxy groups on the aromatic ring. Consequently, the Pd catalyst will be more electron rich, which makes it more capable of giving electrons to the substrate (Pd gets oxidized; the substrate gets reduced). 16. Use resonance to explain the differing regiochemistry of carbopalladation of an electron- poor alkene and an electron-rich alkene. 17. Explain the role of CuI in the Sonogashira reaction. CuI facilitates the Sonogashira reaction by making the terminal alkyne coupling partner more acidic. After deprotonation, the resulting organocopper species becomes the nucleophile that undergoes transmetallation with Pd. 18. Suggest a reason why one would use a Stille coupling or Suzuki coupling when the organotin reagents and organoboron reagents that are used in these reactions can be

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made from Grignard reagents, and Grignard reagents can by used directly in Kumada couplings. Grignard reagents are very nucleophilic. They can attack many functional groups such as esters, aldehydes, ketones, and nitriles. They are also very basic, and readily deprotonate acidic O-H and N-H bonds in a molecule. Consequently, they are also very sensitive to moisture, and can decompose when exposed to air. Organotin coupling partners thus serve as a milder and more stable alternative to Grignard reagents, particularly when performing cross-coupling on a molecule with many potential sites of reactivity. 19. Propose an intermediate and product for the following reaction, the first involves mixing the substrate, catalyst, and base together, mixing for a few hours, then adding iodobenzene and heat. 20. Propose what the intermediate in the following reaction is.

21. Propose a mechanism for the following reaction.