Protecting Groups

In his book, Protecting Groups, Philip J. Kocieński stated that there are three things that cannot be avoided: death, taxes, and protecting groups. Indeed, protecting groups mask functionality that would otherwise be compromised or interfere with a given reaction, making them a necessity in organic synthesis. In this chapter, for each protecting group showcased, only the most widely used methods for protection and cleavage are shown. Also, this section is not comprehensive and only addresses some of the most common blocking groups in organic synthesis. For a thorough review of protecting groups, the reader should consult the following references: (a) Wuts, P. G. M.; Greene, T. W.; Protective Groups in Organic Synthesis, 4th ed.; Wiley: Hoboken, NJ, 2007; (b) Kocienski, P. J. Protecting Groups, 3rd edition.; Thieme: Stuggart, 2004. In this section, the formation and cleavage of eight protecting groups for alcohols and phenols are presented: acetate; acetonides for diols; benzyl ether; para-methoxybenzyl (PMB) ether; methyl ether; methoxymethylene (MOM) ether; tert-butyldiphenylsilyl (TBDPS) silyl ether; and tetrahydropyran (THP). Acetate is a convenient protecting group for alcohols—easy on and easy off. Selective protection of a primary alcohol in the presence of a secondary alcohol can be achieved at low temperature. The drawback of this protecting group is its incompatibility with hydrolysis and reductive conditions.

Functional Group Manipulations

CBr4–Ph3P is very straightforward and widely used. Workup and purification can be messy at times because of the by-product, Ph3PO. To a mixture of the alcohol (0.800 g, 3.36 mmol) and carbon tetrabromide (1.337 g, 4.03 mmol) in CH2Cl2 at 0 ºC was added a solution of PPh3 (1.319 g, 5.03 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, and purified by column chromatography to afford the bromide (0.941 g, 93% yield). Reference: Hu, T.-S.; Yu, Q.; Wu, Y.-L.; Wu, Y. J. Org. Chem. 2001, 66, 853–861. A two-step sequence consisting of mesylate formation followed by treatment with LiBr can also be used. This procedure involves two steps, but workup and purification are very straightforward. The bromide can be carried out to the next step without further purification in many cases. To a solution of 5-hydroxymethyl-1-methylcyclopentene (3.8 g, 34 mmol) in CH2 Cl2 (50 mL) at 0 ºC was added triethylamine (5.2 mL, 37 mmol) followed by methanesulfonyl chloride (2.9 mL, 37 mmol). The mixture was stirred at 0 ºC for 5 h and then water was added. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give 6.4 g (98%) of (2-methylcyclopent-2- enyl)methyl methanesulfonate, which was used in the next step without further purification. A solution containing the mesylate (6.4 g, 34 mmol) in acetone (70 mL) was treated with lithium bromide (8.89 g, 102 mmol). The mixture was heated at reflux for 6 h, cooled to room temperature, diluted with water, extracted with ether, and the combined ethereal extracts were dried over MgSO4. Removal of the solvent under reduced pressure gave 4.6 g (78%) of 5-bromomethyl-1-methylcyclopentene, which was used in the next step without further purification.

Fundamental Techniques

What we do in a modern organic chemistry laboratory is serious business. While it can provide social benefit, basic scientific discoveries, and intellectual satisfaction, chemical experiment is not just fun, it can also be very hazardous, some experiments inherently so. Complacency is often observed by veterans and novices alike. One often forgets that chemistry is a potentially dangerous enterprise; a cavalier attitude often results in disastrous consequences. Therefore, extreme caution should be exercised at all time, especially when one handles large-scale reactions that are exothermic or when dealing with toxic chemicals. If a chemical splashes into your eyes, it could do serious and sometimes permanent damage to your vision. The most common forms of eye protection include safety glasses (with sideshields), goggles, and face shields. Prescription eye glasses are acceptable provided that the lenses are impact resistant and they are equipped with side shields. While at the Massachusetts Institute of Technology, Professor K. Barry Sharpless, the 2001 chemistry Nobel laureate, experienced an event that forever changed his life. Professor Sharpless normally wore his safety glasses, but one evening in 1970 he was examining a sealed nuclear magnetic resonance (NMR) tube without safety glasses. Unfortunately for Professor Sharpless, the tube exploded, spraying glass fragments into one of his eyes. The damage was so severe that he lost functional vision in the injured eye. Professor Sharpless’s own words summarize the importance of eye protection, “The lesson to be learned from my experience is straightforward: there’s simply never an adequate excuse for not wearing safety glasses in the laboratory at all times” (Scripps Research Institutes’ Environmental Health and Safety Department Safety Gram, 2000 (2nd quarter), www.scripps.edu/researchservices/ehs/ News/safetygram/). Laboratory gloves are an essential part of safe laboratory practice and must be worn while handling chemicals. Despite practicing good safety techniques, tragedy may still strike.

Carbon−Carbon Bond Formation

Reviews: (a) Vicarion, J. L.; Badia, D.; Carillo, L.; Reyes, E.; Etxebarria, J. Curr. Org. Chem. 2005, 9, 219-235. (b) Mahrwald, R. Ed. In Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004; Vol. 1., pp. 1-335 (c) Mahrwald, R. Ed. In Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004; Vol. 2., pp. 1-345.(d) Machajewski, T. D.; Wong, C.-H. Angew. Chem. Int. Ed. 2000, 39, 1352-1375. (e) Carriera, E. M. In Modern Carbonyl Chemistry; Otera, J.; Wiley-VCH: Weinheim, 2000; Chapter 8: Aldol Reaction: Methodology and Stereochemistry, 227-248. (f) Paterson, I.; Cowden, C. J.; Wallace, D. J. In Modern Carbonyl Chemistry; Otera, J.; Wiley-VCH: Weinheim, 2000; Chapter 9: Stereoselective Aldol Reactions in the Synthesis of Polyketide Natural Products, pp. 249-298. (g) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1 317-338. (h) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, Fl.; 1984; Vol. 3., Chapter 2: The Aldol Addition Reaction, pp. 111-212. (i) Mukaiyama, T. Org. React. 1982, 28, 203-331. Since the early 1980s, aldol condensations involving boron enolates have gain great importance in asymmetric synthesis, particularly the synthesis of natural products with adjacent stereogenic centers bearing hydroxyl and methyl groups. (Z)-Boron enolates tend to give a high diastereoslectivity preference for the syn-stereochemistry while (E)-boron enolates favor the anti-stereochemistry. Because the B-O and B-C bonds are shorter than other metals with oxygen and carbon, the six membered Zimmerman–Traxler transition state in the aldol condensation tends to be more compact which accentuates steric interactions, thus leading to higher diastereoselectivity. When this feature is coupled with a boron enolate bearing a chiral auxillary, high enantioselectivity is achieved. Boron enolates are generated from a ketone and boron triflate in the presence of an organic base such as triethylamine. Reviews: (a) Abiko, A. Acc. Chem. Res. 2004, 37, 387-395. (b) Cowden, C. J. Org. React. 1997, 51, 1-200.

Reductions

The Barton deoxygenation (or Barton–McCombie deoxygenation) is a two-step reaction sequence for the reduction of an alcohol to an alkane. The alcohol is first converted to a methyl xanthate or thioimidazoyl carbamate. Then, the xanthate or thioimidazoyl carbamate is reduced with a tin hydride reagent under radical conditions to afford the alkane. Trialkylsilanes have also been used as the hydride source. Reviews: (a) McCombie, S. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, U. K., 1991; Vol. 8, Chapter 4.2: Reduction of Saturated Alcohols and Amines to Alkanes, pp. 818–824. (b) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413–1432. To a solution of the â-hydroxy-N-methyl-O-methylamide (0.272 g, 1.55 mol) in tetrahydrofuran (THF) (30 mL) were added carbon disulfide (6.75 mL, 112 mmol) and iodomethane (6.70 mL, 108 mmol) at 0 °C. The mixture was stirred at this temperature for 0.25 h, and then sodium hydride (60% suspension in mineral, 136.3 mg, 3.4 mmol) was added. After 20 min at 0 °C, the reaction was quenched by slow addition to 60 g of crushed ice. (Caution: hydrogen gas evolution!). The mixture was raised to room temperature and separated, and the aqueous layer was extracted with CH2Cl2 (4 × 15 mL). The combined organic extracts were dried (Na2SO4</aub>), concentrated in vacuo, and purified (SiO2, 5% EtOAc in hexanes) to afford 0.354 g (86%) of the xanthate. To a solution of the xanthate (2.95 g, 11.1 mmol) in toluene (100 mL) was added tributyltin hydride (15.2 mL, 56.6 mmol) and 2,2´-azobisisobutyronitrile (AIBN, 0.109 g, 0.664 mmol). The reaction mixture was then heated to reflux for 1 h. The mixture was cooled, concentrated in vacuo, and purified (SiO2, 100% hexanes to remove tin byproducts, followed by 10% EtOAc in hexanes to elute product) to afford 1.69 g (96%) of the N-methyl-O-methylamide.

Oxidation

Activated manganese dioxide (MnO2) reliably oxidizes acetylenic, allylic, and benzylic alcohols to aldehydes and ketones. Saturated primary and secondary alcohols are also oxidized, albeit more slowly. The two main concerns are the activity of the manganese dioxide and the slow filtration of salts after the reaction. Activated MnO2 is available commercially or may be prepared. To a solution of 15.3 g (37.5 mmol) of the alcohol in 150 mL of hexanes was added 60 g of activated MnO2. The reaction mixture was stirred at 22 °C overnight and filtered, and the solid residue was washed with 30% EtOAc in hexanes solution. The combined filtrates were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on SiO2 (EtOAc:hexanes, 1:10) to give 13.7 g (90%) of the ketone as a colorless oil. Reference: Wipf, P.; Xu, W. J. Org. Chem. 1996, 61, 6556–6562. Chromium-based oxidations are reliable and well established, but the toxicity associated with chromium salts have meant that they are generally considered the second choice. For a review of chromium–amine complex oxidations, see Luzzio, F. A. Org. React. 1998, 53, 1-221. To a mixture of pyridinium chlorochromate (PCC 339 mg, 1.57 mmol), ammonium acetate (215 mg, 2.62 mmol), and 4 Å molecular sieves (610 mg) in CH2Cl2 (33 mL) was added a solution of the alcohol (208 mg, 1.05 mmol) in CH2Cl2 (14 mL) under argon at 0 °C over a period of 10 min. After the mixture had been stirred at room temperature for 3 h, diethyl ether (200 mL) was added and the mixture was filtered through a short pad of Florisil. The filtrate was washed successively with water (100 mL) and brine (100 mL), dried with Na2SO4, and concentrated. The residue was purified by chromatography on silica gel (hexane 70%, Et2O 30%) followed by distillation to give the aldehyde as a colorless oil (132 mg, 63%).