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Protection and Deprotection
Two of the most important steps in synthetic organic chemistry routes are protection and deprotection of important functional groups. Protecting groups are needed to temporarily block a certain reactive site on a molecule. The protective group is then chemically removed (deprotected) in a later step and that particular reactive functional group is regenerated. There are many different methods of both protection and deprotection. Traditionally, protection has selectivity problems, while harsh conditions are needed for deprotection. Microwave irradiation has been shown to be quite effective in both of these areas, as well as decreasing reaction times immensely. Trifluoroacetylation of amines and esterification of alcohols were both briefly discussed in Section IV of this chapter. In addition, research has been performed on the protection of amino acids653, etherification of alcohols654-656 and diols657, and both oxathiolane/dithiolane62,150,658,659 and ketal/ acetal62,150,660-667 protection of carbonyl compounds.
Hydroxyl groups are present in a large number of compounds that are of pharmaceutical interest, including nucleosides, carbohydrates, steroids, and macrolides. They are susceptible to oxidation, acetylation, and halogenation, and therefore, must be protected occasionally in synthetic routes. Etherification is one of the most widely used alcohol protection methods available. Traditionally, the selective protection of one of two identical hydroxyls in a symmetrical molecule is quite limited. Successful monotetrahydropyranylation has been effected on symmetrical diols in less than three minutes with microwave irradiation (Scheme 122).654 Acetals and ketals are used to protect 1,2- and 1,3-diols. Scheme 123 shows acetalization effected on clay in a solvent-free environment with ten minutes of microwave heating.657
Scheme 122
Scheme 123
Carbonyls are very susceptible to nucleophilic attack. Acyclic and cyclic acetals or ketals are the most widely used protection method for carbonyl-containing compounds. Classically, this reaction is usually acid catalyzed and requires high temperatures for the azeotropic removal of water with a Dean-Stark trap. Successful acetalization resulted on aldehydes and ketones by using a catalytic amount of p-toluenesulfonic acid coupled with microwave irradiation (Scheme 124).660
Scheme 124
Extensive work has been done on deprotection methods that have required harsh conventional reaction conditions. Successful research on deprotection methods to alcohols or diols include demethylation668, deacetylation669,670, and oxidative deprotection of ethers83,671-682. Cleavage of oxathiolanes683, thioacetals684,685, acetals82,123,686-689, hydrazones690-692, semicarbazones692-694, and oximes69,76,79,80,146,170,695-700 with microwave irradiation provides carbonyl-containing compounds readily. Lastly, deprotection of esters yields carboxylic acids.701-706
To reiterate, ethers are the most widely used protective group in synthetic chemistry. Their high stability against a variety of reaction conditions makes them very effective. Deprotection of methylated phenolic derivatives is hard to accomplish mildly, and therefore, requires acidic reagents and high temperatures. Use of pyridine hydrochloride and microwave irradiation successfully regenerates phenols in 15 minutes (Scheme 125).668 Varma et al. show how both deacetylation669 (Scheme 126) and cleavage of t-butyldimethylsilyl ethers679 (Scheme 127) can easily be achieved directly on alumina in solvent-free reaction conditions. Traditionally, deprotection of THP ethers to their respective alcohols is achieved with toxic chromium(VI) reagents. Heravi and co-workers have used iron(III) nitrate on clay for direct oxidation of THP ethers to their carbonyl compounds (Scheme 128).676
Scheme 125
Scheme 126
Scheme 127
Scheme 128
Dithioacetals and acetals, both cyclic and acyclic, are superb carbonyl protecting groups and are used extensively in synthetic routes. The sulfur-containing acetals are very effective, as they are highly stable against strong acids and bases. Conventional deprotection methods usually require toxic heavy metals. Successful dethioacetalization of thioacetals/ketals, utilizing iron(III) nitrate on clay (clayfen) and very little microwave irradiation, occurred with 87-98% product yields (Scheme 129).684 Diacetyl acetals are very efficient as protectors of the aldehyde moiety. Geminal diacetates are quite stable in acidic conditions and are cleaved by strong bases. Traditionally, deprotection is executed by either overnight stirring with sodium hydroxide or refluxing in alcoholic sulfuric acid. Scheme 130 exhibits deacetalization of benzaldehyde diacetate derivatives on neutral alumina in 30-40 seconds, 88-98% yields.689
Scheme 129
Scheme 130
Semicarbazones, hydrazones, and oximes are essentially functional group equivalents of carbonyl compounds, and thus, are useful protecting groups. Conventional deprotection of these derivatives usually requires long reaction times with very high temperatures. Semicarbazones and hydrazones can be deprotected to regenerate the carbonyl with ammonium persulfate on clay coupled with microwave irradiation (Scheme 131).692 Microwave-enhanced regeneration of the carbonyl by deoximation can be achieved by use of either ammonium persulfate698 or sodium periodate699 on silica, or even pyridinium chlorochromate700 (Scheme 132).
Scheme 131
Scheme 132
Carboxylic acids mainly need to be protected in order to mask the acidic proton in base-catalyzed reactions. Esters are a useful protecting group for the carboxyl moiety, as they remove the acidic proton and provide for easier handling of the molecule. Deesterification traditionally provides moderate yields and poor chemoselectivity. Varma and co-workers have successfully deprotected benzyl esters in solvent-free conditions on alumina (Schemes 133 and 134).702
Scheme 133
Scheme 134
Instruments
69. Balalaie, S.; Salimi, S.H.; Sharifi, A. “Solid state deoximation with zinc chlorochromate: regeneration of carbonyl compounds.” Indian J. Chem., Sect. B 2001, 40, pp. 1251-52.
76. Hajipour, A.R.; Mallakpour, S.E.; Mohammadpoor-Baltork, I.; Khoee, S. “An efficient and selective method for conversion of oximes and semicarbazones to the corresponding carbonyl compounds under solvent-free conditions.” Synth. Commun. 2001, 31, pp. 1187-94.
79. Heravi, M.M.; Tajbakhsh, M. “Solid state deoximation with clay supported potassium ferrate under microwave irradiation.” Phosphorus Sulfur Silicon Relat. Elem. 2001, 176, pp. 195-99.
80. Heravi, M.M.; Ajami, D.; Mohajerani, B.; Tajbakhsh, M.; Ghassemzadeh, M.; Tabar-Hydar, K. “Solid state desemicarbazonation on clayfen under microwave irradiation.” Monatsh. Chem. 2001, 132, pp. 881-83.
82. Tajbakhsh, M.; Heravi, M.M.; Habibzadeh, S.; Ghassemzadeh, M. “Microwave-assisted eco-friendly cleavage of acetals using supported potassium ferrate.” Phosphorus Sulfur Silicon Relat. Elem. 2001, 176, pp. 151-55.
83. Tajbakhsh, M.; Heravi, M.M.; Habibzadeh, S. “Potassium ferrate supported on silica gel: a mild, efficient, and inexpensive reagent for oxidative deprotection of tetrahydropyranyl ethers in nonaqueous conditions.” Phosphorus Sulfur Silicon Relat. Elem. 2001, 176, pp. 191-94.
146. Bandgar, B.P.; Makone, S.S. “Rapid and selective regeneration of carbonyl compounds from their oximes under mild, neutral and solvent-free conditions.” Org. Prep. Proced. Intl. 2000, 32, pp. 391-94.
170. Tamami, B.; Kiasat, A.R. “Microwave promoted rapid oxidative deoximation of oximes under solvent-free conditions.” Synth. Commun. 2000, 30, pp. 4129-35.
653. Cros, E.; Planas, M.; Bardaji, E. “Synthesis of N-α-tetrachlorophthaloyl (TCP)-protected amino acids under microwave irradiation (MWI).” Synthesis 2001, pp. 1313-20.
654. Deka, N.; Sarma, J.C. “Microwave-mediated selective monotetrahydropyranylation of symmetrical diols catalyzed by iodine.” J. Org. Chem. 2001, 66, pp. 1947-48.
655. Khalafi-Nezhad, A.; Alamdari, R.F.; Zekri, N. “Efficient and selective protection of alcohols and phenols with triisopropylsilyl chloride/imidazole using microwave irradiation.” Tetrahedron 2000, 56, pp. 7503-06.
656. Heravi, M.M.; Ajami, D.; Ghassemzadeh, M. “Solvent free tetrahydropyranylation of alcohols and phenols over sulfuric acid adsorbed on silica gel.” Synth. Commun. 1999, 29, pp. 1013-16.
657. Csiba, M.; Cleophax, J.; Loupy, A.; Malthete, J.; Gero, S.D. “Liquid crystalline 5,6-O-acetals of L-galactono-1,4-lactone prepared by microwave irradiation on montmorillonite.” Tetrahedron Lett. 1993, 34, pp. 1787-90.
658. Perio, B.; Hamelin, J. “Oxathiolane and dithiolane exchange reaction for carbonyl group protection: a new, fast and efficient procedure without solvent under microwave irradiation.” Green Chem. 2000, 2, pp. 252-55.
659. Kad, G.L.; Singh, V.; Kaur, K.P.; Singh, J. “Microwave assisted preparation of 1,3-dithiolanes under solvent free conditions.” Indian J. Chem. 1998, 37B, pp. 172-73.
660. Pourjavadi, A.; Mirjalili, B.F. “Microwave-assisted rapid ketalization/acetalization of aromatic aldehydes and ketones in aqueous media.” J. Chem. Res. (S) 1999, pp. 562-63.
661. Beregszaszi, T.; Molnar, A. “Microwave-assisted acetalization of carbonyl compounds catalyzed by reusable Envirocat supported reagents.” Synth. Commun. 1997, 27, pp. 3705-09.
662. Moghaddam, F.M.; Sharifi, A. “Microwave promoted acetalization of aldehydes and ketones.” Synth. Commun. 1995, 25, pp. 2457-61.
663. Kalita, D.J.; Borah, R.; Sarma, J.C. “A new selective catalytic acetalization method promoted by microwave irradiation.” Tetrahedron Lett. 1998, 39, pp. 4573-74.
664. Wang, C.D.; Shi, X.Z.; Xie, R.J. “Synthesis of diacetals from 2,2-bis(hydroxymethyl)-1,3-propanediol under microwave irraditation.” Synth. Commun. 1997, 27, pp. 2517-20.
665. Perio, B.; Dozias, M.J.; Jacquault, P.; Hamelin, J. “Solvent free protection of carbonyl group under microwave irradiation.” Tetrahedron Lett. 1997, 38, pp. 7867-70.
666. Nahar, P. “Microwaves - a powerful tool for the base protection of cytidine.” Tetrahedron Lett. 1997, 38, pp. 7253-54.
667. Yadav, J.S.; Reddy, B.V.S.; Srinivas, R.; Ramalingam, T. “Silica gel-supported metallic sulfates catalyzed chemoselective acetalization of aldehydes under microwave irradiation.” Synlett. 2000, 5, pp. 701-03.
668. Kulkarni, P.P.; Kadam, A.J.; Mane, R.B.; Desai, U.V.; Wadgaonkar, P.P. “Demethylation of methyl aryl ethers using pyridine hydrochloride in solvent-free conditions under microwave irradiation.” J. Chem. Res. (S) 1999, pp. 394-95.
669. Varma, R.S.; Varma, M.; Chatterjee, A.K. “Microwave-assisted deacetylation on alumina: a simple deprotection method.” J. Chem. Soc., Perkin Trans. 1 1993, pp. 999-1000.
670. Perez, E.R.; Marrero, A.L.; Perez, R.; Autie, M.A. “An efficient microwave-assisted method to obtain 5-nitrofurfural without solvents on mineral solid supports.” Tetrahedron Lett. 1995, 36, pp. 1779-82.
671. Heravi, M.M.; Ajami, D.; Ghassemzadeh, M. “Wet alumina supported chromium(VI) oxide: a mild, efficient, and inexpensive reagent for oxidative deprotection of trimethylsilyl and tetrahydropyranyl ethers in solventless systems.” Synth. Commun. 1999, 29, pp. 781-84.
672. Heravi, M.M.; Ajami, D. “Clay-supported bis(trimethylsilyl)-chromate. Oxidative deprotection of tetrahydropyranyl ethers under solvent-free conditions using microwaves.” Monatsh. Chem. 1999, 130, pp. 709-12.
673. Oussaid, A.; Thach, L.N.; Loupy, A. “Selective dealkylation of alkyl aryl ethers in heterogeneous basic media under microwave irradiation.” Tetrahedron Lett. 1997, 38, pp. 2451-54.
674. Yadav, J.S.; Meshram, H.M.; Reddy, G.S.; Sumithra, G. “Microwave thermolysis. Part 4: Selective deprotection of MPM ethers using clay supported ammonium nitrate ‘clayan’ in dry media.” Tetrahedron Lett. 1998, 39, pp. 3043-46.
675. Heravi, M.M.; Hekmatshoar, R.; Beheshtiha, Y.S.; Ghassemzadeh, M. “Ammonium chlorochromate adsorbed on montmorillonite K-10: oxidative deprotection of tetrahydropyranyl ethers using microwaves in a solventless system.” Monatsh. Chem. 2001, 132, pp. 651-54.
676. Heravi, M.M.; Ajami, D.; Mojtahedi, M.M.; Ghassemzadeh, M. “A convenient oxidative deprotection of tetrahydropyranyl ethers with iron(III) nitrate and clay under microwave irradiation in solvent free conditions.” Tetrahedron Lett. 1999, 40, pp. 561-62.
677. Heravi, M.M.; Beheshtiha, Y.S.; Oskooi, S.H.A.; Shoar, R.H.; Khalilpoor, M. “Direct oxidative deprotection using montmorillonite supported ammonium chlorochromate under conventional heating and microwave irradiation in solventless system.” Phosphorus Sulfur Silicon Rel. Elem. 2000, 161, pp. 251-55.
678. Heravi, M.M.; Ajami, D.; Ghassemzadeh, M.; Tabar-Hydar, K. “Zeofen, an efficient reagent for oxidative deprotection of trimethylsilyl ethers under microwave irradiation in solventless system.” Synth. Commun. 2001, 31, pp. 2097-100.
679. Varma, R.S.; Lamture, J.B.; Varma, M. “Alumina-mediated cleavage of t-butyldimethyl-silyl ethers.” Tetrahedron Lett. 1993, 34, pp. 3029-32.
680. Hajipour, A.R.; Mallakpour, S.E.; Baltork, I.M.; Adibi, H. “Oxidative deprotection of trimethylsilyl ethers, tetrahydropyranyl ethers, and ethylene acetals with benzyltriphenylphosphonium peroxymonosulfate under microwave irradiation.” Synth. Commun. 2001, 31, pp. 1625-31.
681. Mojtahedi, M.M.; Saidi, M.R.; Heravi, M.M.; Bolourtchian, M. “Microwave assisted deprotection of trimethylsilyl ethers under solvent-free conditions catalyzed by clay or a palladium complex.” Monatsh. Chem. 1999, 130, pp. 1175-78.
682. Mojtahedi, M.M.; Saidi, M.R.; Bolourtchian, M.; Heravi, M.M. “Solid state oxidative deprotection of trimethylsilyl ethers with iron(III)nitrate and montmorillonite under microwave irradiation.” Synth. Commun. 1999, 29, pp. 3283-87.
683. Chavan, S.P.; Soni, P.; Kamat, S.K. “Chemoselective deprotection of 1,3-oxathiolanes using Amberlyst 15 and glyoxylic acid under solvent free conditions.” Synlett. 2001, pp. 1251-52.
684. Varma, R.S.; Saini, R.K. “Solid state dethioacetalization using clayfen.” Tetrahedron Lett. 1997, 38, pp. 2623-24.
685. Meshram, H.M.; Reddy, G.S.; Sumitra, G.; Yadav, J.S. “Microwave thermolysis. VI. A rapid and general method for dethioacetalization using “Clayan” in dry media.” Synth. Commun. 1999, 29, pp. 1113-19.
686. Meshram, H.M.; Sumitra, G.; Reddy, G.S.; Ganesh, Y.S.S.; Yadav, J.S. “Microwave thermolysis. V. A rapid and selective method for the cleavage of THP ethers, acetals, and acetonides using clay supported ammonium nitrate “Clayan” in dry media.” Synth. Commun. 1999, 29, pp. 2807-15.
687. Bose, D.S.; Jayalakshmi, B.; Narsaiah, A.V. “Efficient method for selective cleavage of acetals and ketals using peroxymonosulfate on alumina under solvent-free conditions.” Synthesis 2000, 1, pp. 67-68.
688. Ballini, R.; Bordoni, M.; Bosica, G.; Maggi, R.; Sartori, G. “Solvent free synthesis and deprotection of 1,1-diacetates over a commercially available zeolite Y as a reusable catalyst.” Tetrahedron Lett. 1998, 39, p. 7587.
689. Varma, R.S.; Chatterjee, A.K.; Varma, M. “Alumina-mediated deacetylation of benzaldehyde diacetates. A simple deprotection method.” Tetrahedron Lett. 1993, 34, pp. 3207-10.
690. Boruah, A.; Baruah, B.; Prajapati, D.; Sandhu, J.S. “Bi(III)-catalyzed regeneration of carbonyl compounds from hydrazones under microwave irradiation.” Synlett. 1997, 11, pp. 1251-52.
691. Mitra, A.K.; De, A.; Karchaudhuri, N. “Regeneration of ketones from semicarbazones in the solid state on wet silica supported sodium bismuthate under microwave irradiation.” J. Chem. Res. (S) 1999, pp. 320-21.
692. Varma, R.S.; Meshram, H.M. “Solid state cleavage of semicarbazones and phenylhydrazones with ammonium persulfate-clay using microwave or ultrasonic irradiation.” Tetrahedron Lett. 1997, 38, pp. 7973-76.
693. Baruah, B.; Prajapati, D.; Sandhu, J.S. “Regeneration of carbonyl compounds from semicarbazones under microwave irradiations.” Synth. Commun. 1998, 28, pp. 4157-63.
694. Meshram, H.M.; Srinivas, D.; Reddy, G.S.; Yadav, J.S. “Clay supported ammonium nitrate, “Clayan”: a rapid and convenient regeneration of carbonyls in dry media.” Synth. Commun. 1998, 28, pp. 4401-08.
695. Mitra, A.K.; De, A.; Karchaudhuri, N. “Regeneration of ketones from oximes in the solid state on wet silica supported sodium bismuthate under microwave irradiation.” Synlett. 1998, 12, pp. 1345-46.
696. Bendale, P.M.; Khadilkar, B.M. “Microwave promoted regeneration of carbonyl compounds from oximes using silica supported chromium trioxide.” Tetrahedron Lett. 1998, 39, pp. 5867-68.
697. Boruah, A.; Baruah, B.; Prajapati, D.; Sandhu, J.S. “Regeneration of carbonyl compounds from oximes under microwave irradiation.” Tetrahedron Lett. 1997, 38, pp. 4267-68.
698. Varma, R.S.; Meshram, H.M. “Solid state deoximation with ammonium persulfate-silica gel: regeneration of carbonyl compounds using microwaves.” Tetrahedron Lett. 1997, 38, pp. 5427-28.
699. Varma, R.S.; Dahiya, R.; Saini, R.K. “Solid state regeneration of ketones from oximes on wet silica supported sodium periodate using microwaves.” Tetrahedron Lett. 1997, 38, pp. 8819-20.
700. Chakraborty, V.; Bordoloi, M. “Deoximation by pyridinium chlorochromate under microwave irradiation.” J. Chem. Res. (S) 1999, pp. 120-21.
701. Gajare, A.S.; Shaikh, N.S.; Bonde, B.K.; Deshpande, V.H. “Microwave accelerated selective and facile deprotection of allyl esters catalyzed by montmorillonite K-10.” J. Chem. Soc., Perkin Trans. 1 2000, pp. 639-40.
702. Varma, R.S.; Chatterjee, A.K.; Varma, M. “Alumina-mediated microwave thermolysis: a new approach to deprotection of benzyl esters.” Tetrahedron Lett. 1993, 34, pp. 4603-06.
703. Loupy, A.; Pigeon, P.; Ramdani, M.; Jacquault, P. “Solid-liquid phase-transfer catalysis without solvent coupled with microwave irradiation: a quick and efficient method for saponification of esters.” Synth. Commun. 1994, 24, pp. 159-65.
704. Fabis, F.; Jolivet-Fouchet, S.; Robba, M.; Landelle, H.; Rault, S. “Thiasatoic anhydrides: efficient synthesis under microwave heating conditions and study of their reactivity.” Tetrahedron Lett. 1998, 39, pp. 10789-800.
705. Vass, A.; Tapolcsanyi, P.; Wolfling, J.; Schneider, G. “Microwave-induced selective deacetylation and stereospecific acyl migration of steroid acetates on alumina.” J. Chem. Soc., Perkin Trans. 1 1998, pp. 2873-75.
706. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C.R.; Trainor, R.W. “Applications of high-temperature aqueous media for synthetic organic reactions.” J. Org. Chem. 1997, 62, pp. 2505-11.