The Williamson ether synthesis cannot be used to prepare tert-butyl phenyl ether. (a)

Provide an IUPAC name for each of the following compounds: (a) O O (b) Cl O Cl Cl (c) OH OEt (d) O (e)

Draw the structure of each of the following compounds: (a) (R)-2-Ethoxy-1,1-dimethylcyclobutane (b) Cyclopropyl isopropyl ether

There are six ethers with molecular formula C5H12O that are constitutional isomers. (a) Draw all six constitutional isomers. (b) Provide a systematic name for each of the six compounds. (c) Provide a common name for each of the six compounds. (d) Only one of these compounds has a chirality center. Identify that compound.

Identify the missing reagent needed to achieve each of the following transformations: Br F KF benzene (a) ? Br F (b) NaF benzene ? Br F (c) LiF benzene ? OH OH (d) KMnO4 benzene

Show what reagents you would use to prepare each of the following ethers via a Williamson ether synthesis and explain your reasoning: O (a) O (b) OMe (c)

The following cyclic ether can be prepared via an intramolecular Williamson ether synthesis. Show what reagents you would use to make this ether. O O

Can the following compound be prepared via a Williamson ether synthesis? Explain your answer. O

Show what reagents you would use to prepare each of the following ethers via an alkoxymercuration-demercuration: OEt (a) O (b) OMe (c) O (d)

How would you use an alkoxymercuration-demercuration to prepare dicyclopentyl ether using cyclopentene as your only source of carbon?

Show how you would use an alkoxymercuration-demercuration to prepare isopropyl propyl ether using propene as your only source of carbon and any other reagents of your choosing.

Predict the products for each of the following reactions: (a) O ? Excess HBr Heat O (b) ? Excess HI Heat O (c) ? Excess HBr Heat O (d) ? Excess HI Heat O (e) ? Excess HI Heat O (f) ? Excess HBr Heat

Assign a name for each of the following compounds: O (a) O (b) O (c)

Assign a name for each of the following compounds. Be sure to assign the configuration of each chirality center and indicate the configuration(s) at the beginning of the name. O Me (a) O (b) O (c)

Identify the reactants you would use to form a racemic mixture of each of the following epoxides: O H H (d) O Me H (a) O H H Me (b) O H Me O (c)

Consider the following two compounds. When treated with NaOH, one of these compounds forms an epoxide quite rapidly, while the other forms an epoxide very slowly. Identify which compound reacts more rapidly and explain the difference in rate between the two reactions. (Hint: You may find it helpful to review the conformations of substituted cyclohexanes in Section 4.13.) OH Br Compound A OH Br Compound B

Predict the products for each of the following reactions: OH O O H Ti[OCH(CH3)2]4 (+)-DET (a) ? (b) OH ? O O H Ti[OCH(CH3)2]4 ()-DET (c) OH ? O O H Ti[OCH(CH3)2]4 (+)-DET (d) OH ? O O H Ti[OCH(CH3)2]4 ()-DET

For each of the following reactions, predict the product and draw a mechanism for its formation: O Me 2) H2O 1) PhMgBr (a) ? (b) O Me ? 1) NaCN 2) H2O O (c) Me ? 1) NaSH 2) H2O (d) O Me ? 1) LAH 2) H2O (e) O Me Et ? 1) NaSH 2) H2O (f) O Me Et ? 1) LAH 2) H2O

When the following chiral epoxide is treated with aqueous sodium hydroxide, only one product is obtained, and that product is achiral. Draw the product and explain why only one product is formed. O Me Me ? NaOH H2O

When meso-2,3-epoxybutane is treated with aqueous sodium hydroxide, two products are obtained. Draw both products and describe their relationship.

For each reaction, predict the product and draw a mechanism for its formation: O (a) HCl ? O (b) Me ? HBr O Me Et EtOH [H2SO4] ? (c) O Me Et Me H2O [H2SO4] ? (d) O Me MeOH [H2SO4] ? (e) O Me Et ? (f) HBr

Propose a mechanism for the following transformation: O Me Et H OH O OH Me Et [H2SO4]

What reagents would you use to prepare each of the following thiols? SH (a) SH (b) SH (c)

Predict the products for each of the following reactions: SH 1) NaOH (a) 2) Br ? (b) Br ? SNa (c) S ? NaIO4 (d) S ? 2 H2O2

Propose an efficient synthesis for each of the following transformations: CN HO (a) OH OH + En (b) OH SH (c) SH OH (d) O O

In the previous chapter, we saw that ethylene glycol is one of the main components of automobile antifreeze. Using iodoethane as your starting material, show how you could prepare ethylene glycol.

Propose an efficient synthesis for each of the following transformations: Br OH (b) Br OH (a) Br O (d) Br OH (c) Cl Cl (f) Cl Cl (e) Cl OH (h) Cl OH (g) OH (i)

Propose an efficient synthesis for 1,4-dioxane using acetylene as your only source of carbon atoms. O O 1,4-Dioxane

Dimethoxyethane (DME) is a polar aprotic solvent often used for SN2 reactions. Propose an efficient synthesis for DME using acetylene and methyl iodide as your only sources of carbon atoms. O O Dimethoxyethane

Using compounds that possess no more than two carbon atoms, propose an efficient synthesis for the following compound: O

Assign an IUPAC name for each of the following compounds: O (a) (b) O SH (c) S O (d) O (e) OMe OMe (f) (g) S

Predict the products that are expected when each of the following compounds is heated with concentrated HBr: O (a) O (b) (c) O O (d)

Draw all constitutionally isomeric ethers with molecular formula C4H10O. Provide a common name and a systematic name for each isomer.

Starting with cyclohexene and using any other reagents of your choice, show how you would prepare each of the following compounds: O (a) OH (b) OMe O (c)

When 1,4-dioxane is heated in the presence of HI, compound A is obtained: O O Compound A 2 H2O Heat HI Excess + (a) Draw the structure of compound A. (b) If one mole of dioxane is used, how many moles of compound A are formed? (c) Show a plausible mechanism for the conversion of dioxane into compound A.

Tetrahydrofuran (THF) can be formed by treating 1,4-butanediol with sulfuric acid. Propose a mechanism for this transformation: 1,4-Butanediol HO OH O Tetrahydrofuran (THF) H2SO4

When ethylene glycol is treated with sulfuric acid, 1,4-dioxane is obtained. Propose a mechanism for this transformation: HO OH Ethylene glycol 1,4-Dioxane O O H2SO4

The Williamson ether synthesis cannot be used to prepare tert-butyl phenyl ether. (a) Explain why this method cannot be used in this case. (b) Suggest an alternative method for preparing tert-butyl phenyl ether.

Methylmagnesium bromide reacts rapidly with ethylene oxide, it reacts slowly with oxetane, and it does not react at all with tetrahydrofuran. O Tetrahydrofuran (THF) Ethylene oxide O O Oxetane Explain this difference in reactivity.

Identify the reagents necessary to accomplish each of the following transformations: O O

When 5-bromo-2,2-dimethyl-1-pentanol is treated with sodium hydride, a compound with molecular formula C7H14O is obtained. Identify the structure of this compound. HO Br C7H14O

Problem 14.39 outlines a general method for the preparation of cis- or trans-disubstituted epoxides. Using that method, identify what reagents you would use to prepare a racemic mixture of each of the following epoxides from acetylene: O Me H H (a) O H H Et (b) O Et Me H H (c) O Et H H Et (d

Predict the products for each of the following: 2) MeMgBr 3) H2O 1) RCO3H (a) ? 2) NaBH4 1) Hg(OAc)2, MeOH (b) ? (c) 2) NaSH 3) H ? 2O 1) MCPBA OH (d) 2) EtCl ? 1) Na OH ? (e) 1) Na 2) O 3) H2O Cl 1) Mg, diethyl ether ? (f) 2) O 3) H2O OH ? (g) 1) Na O 2) 3) H2O Cl 1) Mg, diethyl ether ? (h) O 2) 3) H2O

Propose a plausible mechanism for each of the following transformations: O OH 1) EtMgBr 2) H2O (a) OH OEt (b) 1) NaH 2) EtI (c) O HO 2) H2O 1) H C C Na @ ! O MeS OH (d) [H2SO4] MeSH Cl OH O (e) NaH O Cl Cl O O (f) NaOH (excess)

What product do you expect when tetrahydrofuran is heated in the presence of excess HBr?

Compound B has molecular formula C6H10O and does not possess any p bonds. When treated with concentrated HBr, cis-1,4- dibromocyclohexane is produced. Identify the structure of compound B.

Propose a stepwise mechanism for the following transformation: O Cl Me Et OH Me Et 1) Excess EtMgBr 2) H2O

Predict the products for each of the following: 2) NaBH4 1) Hg(OAc)2, MeOH (a) ? 2) NaBH4 1) Hg(OAc)2, MeOH (b) ? 2) NaBH4 1) Hg(OAc)2, OH (c) ? 2) NaBH4 1) Hg(OAc)2, OH (d)

Using acetylene and ethylene oxide as your only sources of carbon atoms, propose a synthesis for each of the following compounds: HO OH (a) (b) O O H H

Fill in the missing reagents below. OH OH O Me OH O OEt OH Br OH SH OMe O Me OEt OEt OH OH CN ? ?? ?? ? ? ?? ?

Fill in the missing products below. MCPBA 2) NaBH4 1) Hg(OAc)2, EtOH 2) H2O 1) NaSH HI Heat Excess ? ? ? HBr ? ? ? H C C Na @ !

Propose an efficient synthesis for each transformation. (a) OH (b) O (c) Cl Cl Cl Cl (d) (e) OH O OH O OH (f) (g) O (h) O O (i) O (j) O + En (k) (l) OH O O (m) O OH (n) OH O (o) OH (p) Cl OH Cl H O (q) OH O OH (r) OH O OH (s) O + En (t) OH OMe + En (u)

Propose a structure for an ether with molecular formula C7H8O that exhibits the following 13C NMR spectrum: Chemical shift (ppm) Carbon NMR 160 140 120 100 80 60 40 55.1 129.5 120.7 114.

Propose a structure for a compound with molecular formula C8H18O that exhibits the following 1 H NMR and 13C NMR spectra: 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Proton NMR Carbon NMR 3 2 2 2 70 60 50 40 30 20 10 0 Chemical shift (ppm) Chemical shift (ppm) 19.3 13.7 70.5 31.6

Propose a structure for a compound with molecular formula C4H8O that exhibits the following 13C NMR and FTIR spectra: Carbon NMR 67.7 25.4 Chemical shift (ppm) 100 90 80 60 50 40 30 20 10 70 0 Wavenumbers (cm1) 4000 3500 3000 2500 2000 1500 1000 % Transmittance 0 20 40 60 80 100

Propose a structure for a compound with molecular formula C4H10O that exhibits the following 1 H NMR spectrum: Chemical shift (ppm) Proton NMR 4.0 3.5 3.0 2.5 2.0 1.5 1.0

Propose a structure for a compound with molecular formula C4H10O that exhibits the following 1 H NMR spectrum: Chemical shift (ppm) Proton NMR 4.0 3.5 3.0 2.5 2.0 1.5 1.0

Epoxides can be formed by treating a-haloketones with sodium borohydride. Propose a mechanism for formation of the following epoxide: O X O NaBH4

When methyloxirane is treated with HBr, the bromide ion attacks the less substituted position. However, when phenyloxirane is treated with HBr, the bromide ion attacks the more substituted position. O Me HO Me Br HBr O Ph OH Br Ph HBr Explain the difference in regiochemistry in terms of a competition between steric effects and electronic effects. (Hint: It may help to draw out the structure of the phenyl group.)

Propose an efficient synthesis for the following transformation: OH OH + Enantiomer

Using bromobenzene and ethylene oxide as your only sources of carbon, show how you could prepare trans-2,3-diphenyloxirane (a racemic mixture of enantiomers). O + Enantiomer

The SN2 reaction between a Grignard reagent and an epoxide works reasonably well when the epoxide is ethylene oxide. However, when the epoxide is substituted with groups that provide steric hindrance, a competing reaction can dominate, in which an allylic alcohol is produced. Propose a mechanism for this transformation and use the principles discussed in Section 8.13 to justify why the allylic alcohol would be the major product in this case below. O OH Major product 1) EtMgBr 2) H2O HO Et Minor product

The following sequence of reactions was employed during synthetic studies on reidispongiolide A, a cytotoxic marine natural product (Tetrahedron Lett. 2009, 50, 50125014). Draw the structures of compounds A, B, and C. O O Ph Ph Ph A B C 1) NaH 2) CH3I OsO4 2) H2O NMO 1) CH2 CHMgBr

Sphingolipids are a class of compounds that play an important role in signal transmission and cell recognition. Fumonisin B1 is a potent sphingolipid biosynthesis inhibitor. OHOH NH2 OH O O O CO2H O CO2H HO2C CO2H 5 9 Fumonisin B1 6 7 8 A recent synthesis of fumonisin B1 employed the following transformation, involving the incorporation of carbons 79 via the formation of alkyne 2 from epoxide 1, shown below (Tetrahedron Lett. 2012, 53, 32333236). Starting with 3-bromo-1-propyne, show a synthesis of alkyne 2 from epoxide 1. O O O OR O O OR OH 1 2 5 6 9 7 8

The following procedure (J. Am. Chem. Soc. 1982, 104, 35153516) is part of a synthetic strategy for the enantioselective preparation of carbohydrates (Chapter 24): OH O O O S O O OH OH Ph NaOH / H2O Ph S H (a) Propose a plausible mechanism that explains the stereochemical outcome of this transformation. (b) Predict the product of the following process: OH Ph O Ph ? 2) NaOH / H2O, PhSH Ti[OCH(CH3) 2] 4 (+)-DET 1) t-BuOO

In Section 14.11, we learned that 1 is a strong methyl transfer agent. However, when treated with a strong base (e.g., NaH), 1 is converted into a special type of carbanion, called a sulfur ylide, which can function as a methylene (CH2) transfer agent. Specifically, treating the sulfur ylide with a ketone affords an epoxide, with dimethyl sulfide (DMS) being generated as a by-product (Synth. Commun. 2003, 33, 21352143). Propose a plausible mechanism for this process, known as the Corey-Chaykovsky reaction. S CH3 H3C H3C 1) NaH Ph CH3 O + S H3C H3C 1 O CH3 2) Ph

Guggul is an herbal extract from the resin of the mukul myrrh tree, and it shows potential for treating high cholesterol. In a recent synthesis of (+)-myrrhanol A (a compound present in guggul), compound 1 was treated with MCPBA, followed by LAH to afford compound 2 as the only diastereomer detected (J. Org. Chem. 2009, 74, 61516156). Draw a mechanism for the transformation of 1 to 2 and explain the stereochemical outcome with respect to the newly formed chirality center. Your explanation should include (i) a bond-line drawing that clearly shows the chair conformation adopted by each six-membered ring in the trans-decalin system and (ii) a Newman projection that clearly shows the source of the observed stereochemical preference. TMSO H OH TMSO H OH 1) MCPBA OH 2) LAH 3) H2O 1 2

Reboxetine mesylate is used in the treatment of depression and is currently marketed as the racemate. The (S,S)-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain. The following synthetic scheme was part of the synthesis of (S,S)- reboxetine completed by a research group at Pfizer (Org. Proc. Res. & Devel. 2007, 11, 354358): 2 OH OEt NaOH O HO OH OEt 3 3) H3O+ 2) MsCI, Et3N 1) TMSCI, Et3N O H OEt 5 H O Ti[OCH(CH3) 2] 4 ()-DIPT t-BuOOH NaOH 4 OH 1 (a) In the conversion of 1 to 2, (-)-DIPT serves the same function as (-)-DET. Provide the structure of 2. (b) Propose a plausible mechanism for the transformation of 2 to 3 and draw the expected configuration at each of the chirality centers in 3. (c) TMSCl is used to selectively protect the less hindered, primary OH group in 3. MsCl functions very much like TsCl by converting an OH group into a good leaving group, called a mesylate (OMs) group (see Figure 7.28). Aqueous acid then removes the protecting group to give 4. Draw the structure of 4. (d) Draw a plausible mechanism for the transformation of 4 to 5.

Laureatin is a natural product isolated from the marine algae Laurencia nipponica that exhibits potent insecticidal activity against mosquitos. During an investigation toward the synthesis of laureatin, an interesting skeletal rearrangement was observed. When compound 1 was treated with a source of electrophilic bromine (e.g., Br2), the product isolated was epoxide 2 (J. Org. Chem. 2012, 77, 78837890). Propose a plausible mechanism. OSiR3 O OH Br2 O OSiR3 Br O 1 2 OR OR

Oxymercuration-demercuration of compound 1 affords the expected hydration product 2 in 96% yield. In contrast, oxymercuration-demercuration of compound 3 results in only a minor amount of the normal hydration product. Instead, compounds 7 and 8 are formed (J. Org. Chem. 1981, 46, 930939). It is believed that the initial product of oxymercuration (compound 4) undergoes an intramolecular epoxide-opening step, giving two possible cyclic compounds, 5 and 6. This step is likely catalyzed by the interaction between the epoxide group and Hg(OAc)2, which functions as a Lewis acid. (a) Draw the structure of 2. (b) Draw the structures of 4, 5, and 6 and show a mechanism for the conversion of 4 S 5 as well as 4 S 6. (c) Explain why the product distribution is so different for epoxyalkenes 1 and 3. 1 O 3 O 1) Hg(OAc)2, H2O 2) NaBH4 2 Hg(OAc)2 H2O 4 NaBH4 O OH O OH 5 6 7

The following electrophile-induced, ether transfer reaction was utilized in the synthesis of several structurally related natural products (J. Org. Chem. 2008, 73, 55925594). Provide a plausible mechanism for this transformation. Ph O OMe Ph O I SPh OMe 1) I2 2) PhSH, Et3N

During a total synthesis of 2-methyl-d-erythritol (a sugar of importance to isoprenoid biosynthesis), epoxide 2 was required (J. Org. Chem. 2002, 67, 48564859). (a) Identify the reagents you would use to achieve a stereoselective synthesis of epoxide 2 from allylic alcohol 1. (b) Propose a plausible mechanism for the formation of orthoester 4 from epoxide 3 upon treatment with a catalytic amount of aqueous acid. (Hint: The O in the CRO bond of the ester group can function as a nucleophilic center.) OH Ph O O OH H O Ph O H O Ph O O [H3O+] O O Ph O O 1 2 4

Artemisinin (also known as Qinghaosu) is a peroxide-containing compound that has been used in traditional Chinese medicine as a treatment for malaria. Today, synthetic derivatives of artemisinin are standard treatments to fight against Plasmodium falciparum infections, the parasite which causes the most dangerous form of malaria. Epoxide 1 is a synthetic derivative of artemisinin; when treated with hexafluoro2-propanol and catalytic acid, it undergoes a ring-opening reaction for which the regiochemical outcome and stereochemical outcome are both contrary to what you might have expected (J. Org. Chem. 2002, 67, 12531260). Explain these observations with a plausible mechanism. O O O O H H O O O O O H H O cat. H3O+ F3C OH CF3 CH(CF3)2