Chem 35: Protecting Groups Handout Most of the time a compound has more than one functional group that will react to a given reagent. If the desired reaction only needs one functional group to react with the reagent you need to protect the other functional group.
A protecting A protecting group (PG) is a group that protects a functional group from a synthetic operation that it would not otherwise survive.
In using PGs you add additional steps to carry out your desired reactions. o The first step is to convert the functional group to another group that does not interfere with the reaction by protecting or the adding of a PG. o The second step is to carry out the desired reaction. o The third and final step is deprotection or deprotection or the removal of a PG.
Fig. 2. Protection of Alcohol group with TBDMS ether
Deprotection: silyl Deprotection: silyl ethers are usually removed with a fluoride salt, usually tert -butylammonium -butylammonium fluoride.
Fig. 3. Deprotection of the Alcohol group with tert -butylammonium -butylammonium fluoride
Ethers Methyl Ether (ROMe) Note that there are many ways to form ROMe w ith –OH but we will only give 3
Protection: o Me2SO4, NaOH, Bu4NI, organic solvent, 6090% yield. This is an excellent and general method that can easily be scaled up
MeI or Me2SO4, NaH or KH, THF. This is the standard method for introducing methyl ether onto hindered and unhindered alcohols. o Me2SO4, DMSO, DMF, Ba(OH) 2, BaO, rt, 18h, 88% yield. Deprotection: o Me3SiI, CHCl 3, 25 C, 6h, 95% yield. This o
Fig. 1. General strategy in using protecting groups
IMPORTANT: The reaction in removing the PG must not affect the other groups in the molecule.
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reagent also cleaves many other ether type protective groups, but selectivity can be maintained ntained by control of the reaction conditions and inherent rate differences between functional groups.
Note that protecting groups can also be used to react less reactive functional groups in a molecule by protecting the more reactive functional group and carrying out the re action.
PGs must only be used if necessary since the addition of two more steps reduces the overall yield.
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the most commonly used method for the cleavage of methyl ethers because it generally gives e xcellent yields with a variety of structural types. The solid complex BBr 3∙Me2 S that is more easily handled can a lso be used. BBr 3 will cleave ketals.
Note: there are varying literatures about protecting groups and the list provided below are a compilation compilation of these various literature literature
Hydroxyl (-OH) Protecting Groups -OH functional groups can be protected by using ethers, silyl ethers, esters, acetals etc.
Protection: The PG will react with the molecule to form a new O-X bond, wherein X is a group in the PG, in place of the O-H bond of the alcohol. o An example would be tert- butyldimethylsilyl ether (TBDMS ether). ether). The functional group is protected by reacting the alcohol with TBDMS chloride and an amine base, usually imidazole, as seen in Fig. 2. Formed via SN2 rxn
BBr 3, CH2Cl2, high yields. This method is probably
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t-BuCOCl t-BuCOCl or AcCl, NaI, CH 3CN, 37h, rt, 84% yield. In this case the methyl ether is replaced by a pivalate or acetate group that can be hydrolyzed with base.
Substituted Methyl Ethers Methoxymethyl Ether (MOM Ether)
Protection: o CH3OCH2Cl, i -Pr -Pr 2Net, 0 C, 1h 25 C, 8h, 86% yield. Most commonly employed procedure for MOM °
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introduction, choloromethyl methyl ether is carcinog enic, its byproduct: dicholoromethyl methyl ether is even more toxic. A procedure that does not produce both both has been reported .
CH3OCH2Cl, NaH, THF, 80% o MOMCl, NaI, DIPEA, DME, reflux, 12h, 88% yield. NaI increases the reactivity of MOMCl Deprotection: o
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Trace conc. HCl, MeOH, 62 C, 15 min. Ac2O, BF3∙Et2O, 4 C, 89% yield. This reagent combination converts MOM ethers to the AcOCH2OR ether which is cleavable with base. 1,3-dithiane, BF3∙Et2O, 84% yield. °
0.5 N HCl, THF, 0 C, 100% yield. The °
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ethoxyethyl ether is more readily cleaved by acidic hydrolysis than THP ether, but it is more stable than 1 -methoxyethyl ether. TBDMS ether are not affected by these conditions.
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PPTS, n-PrOH, 80-85% yield. Acetonide was not affected by these conditions
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p-Methoxyphenyl Ether (PMP Ether) This group is stable to 3 N HCl, 100 C; 3 N NaOH, 100 C; H 2 , 1200 psi; O 3, MeOH, -78 C; RaNi, 100 C; LiAlH 4; Jones reagent and pyridinium chlorochromate (PCC). °
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Fig. 4. Example of protection via 1,3-dithiane
Protection: o NaH, DME, CH 3SCH2Cl, NaI, 0 C, 1h to 25 C, 1.5h, >86% yield. o CH3SCH2I, DMSO, Ac 2O, 20 C, 12h, 8090% yield. o DMSO, Ac2O, AcOH, 20 C, 1-2 days, 80% Deprotection: o HgCl2, CH3CN, H 2O, 25 C, 1-2h, 88-95% yield. If water 2-methoxyethanol MTM becomes MEM, if °
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Protection: o From an alcohol: MeOC6H4I, CuI, Cs 2CO3, 1,10-phenanthroline, 18-24h, 110 C, 6493% yield. o From a tosylate: p-MeOC6H4OH, DMF, NaH, 60 C, 14h. Deprotection: o Ceric ammonium nitrate, CH 3CN, H2O (4:1), 0 C, 10 min, 80-85% yield or CAN, Pyr, CH3CN, H2O, 0 C, 0.5h, 96% yield. o Treatment of PMP ether with Na/NH3 results in the formation of an enol ether which can be hydrolyzed to release the alcohol. °
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Methylthiomethyl Ether (MTM Ether)
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water methanol, MTM becomes MOM. If MTM ether has adjacent hydroxyl, it is possible to form the formylidene acetal
Benzyl Ether (Bn Ether) one of the most robust pgs, orthogonal to a h ost of
as a by-product .
unwanted side rxns.
HgCl2, CaCO3, MeCN, H2O. The CaCO3, is used as an acid scavenger for acid sensitive substrates.
others making it and its variants one o f the most used pgs, but it can p articipate in
Protection: o BnCl, powdered KOH, 130-140 C, 86% yield. o BnX (X=Cl, Br), Ag 2O, DMF, 25 C, good yields. This method is very effective for monobenzylation of diols. o BnOH, BiBr 3, CCl4, rt, 76-95% yield. Deprotection: o H2/Pd—C, EtOH, 95% yield. (Reductively: Hydrogenolysis) o Na/NH3, or EtOH (Reductively: Single Electron) o Me3SiI, CH2Cl2, 25 C, 15 min, 100% yield. (Lewis Acid-Based) This reagent also cleaves most °
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Methoxyethoxymethyl Ether (MEM Ether)
Protection: o NaH or KH, MEMCl, THF or DME, 0 C. 1060 min, >95% yield. o MEMN+Et3Cl-, CH3CN, reflux, 30 min, >90% yield. o MEMCl, CHCl 3, DIPEA, 0 C Deprotection: o ZnBr 2, CH2Cl2, 25 C, 2-10h, 90% yield. o TiCl4, CH2Cl2, 0 C, 20 min, 95% yield. o Me2BBr, CH2Cl2, -78 C; NaHCO 3, H2O, 8795% yield. This method also cleaves MTM and MOM °
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ethers and ketals.
other ethers and esters, selectivity can be a chieved with proper choice of conditions.
Methoxy-Substituted Benzyl Ethers More readily cleaved oxidatively than the unsubstituted benzyl ethers
p-Methoxybenzyl ether (MPM/MPB Ether)
Substituted Ethyl Ethers
Most commonly used method for simple alcohol.
Ethoxyethyl Ether (EE Ether)
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Protection: o Ethyl vinyl ether, HCl (anhydrous) o Ethyl vinyl ether, TsOH, 25 C, 1h o Ethyl vinyl ether, pyridinium tosylate (PPTS), CH2Cl2, rt, 0.5h Deprotection: o 5% AcOH, 20 C, 2h, 100% yield °
p-MeOC6H4CH2Br (freshly distilled), THF, TEA, KHMDS, -78 C, 1h then rt 2h. The method °
was used to protect a secondary neopentyl alcohol. o
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Protection: o NaH, p-MeOC6H4CH2Cl, THF, 81% yield.
n-BuLi, Ph2PCl; p-MeOC6H4CH2OH, fluoranil, CH2Cl2, rt, 3h, 30-94% yield. method works for a variety of ethers.
Deprotection:
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Electrolytic oxidation: Ar 3N, CH3CN, LiClO4, 20 C, 1.4-1.7V, 80-90% yield. Benzyl ethers are
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not affected by these conditions. o
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Dichlorodicyanoquinone (DDQ), CH2Cl2, H2O, 40 min, rt, 84-93% yield. SnCl4, PhSH, CH 2Cl2, -78 C to 50 C, 5 min to 1h, 88-93% yield. Benzyl, allyl, TBDMS ether are °
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stable along with various esters.
Silyl Ethers most frequently used hydroxyl protecting group Trimethylsilyl Ether (TMS Ether)
Protection: o Me3SiCl, Et3N, THF, 25 C, 8h, 90% yield. o Me3SiCl, Li2S, CH3CN, 25 C, 12h, 75-95% yield. Silylation occurs under neutral conditions with this °
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Me3SiCl, Mg, DMF, rt, 70-99% yield . Tertiary alcohols are readily silylated,
Deprotection: TMS are quite susceptible to acid hydrolysis, but acid stability is quite dependent on the local steric en vironment. o o o
Bu4NF, THF, aprotic conditions BF3∙Et2O K2CO3, anhydrous MeOH, 0 C, 45 min, 100% yield.
Bu4NCl, KF∙H2O, CH3CN, 25 C, 4 h, 95% yield. Generates in situ TBAF, suitable for rxns that normally requires anhydrous conditions. °
Carbonyl Protecting Groups In a synthetic sequence a carbonyl group may have to be protected against attack by various reagents (e.g. Nu including organometallic reagents, reducing agents). Because of the order of reactivity of the carbonyl group (aldehydes>acyclic ketones, cyclohexanones> cyclopentatnone> α, β -unsaturated ketone, α,α-disubstituted ketones>> aromatic ketones) it may be possible to protect a re active carbonyl group selectively in the presence of a less reactive one.
In the protection of a carbonyl group, it reacts with diols to form five or six-membered ring ketals or acetals. Protection: The mechanism for the protection of the carbonyl group is the same as that of the acetal formation, except that instead of interacting with two separate molecules of alcohol, the carbonyl group reacts with the two alcohol group of a single molecule diol. Deprotection: The PGs can be removed via Raney Ni and Na/NH3 or via acid-catalyzed hydrolysis.
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Triethylsilyl Ether (TES Ether)
Protection: o Triethylsilyl triflate, pyridine or 2,6-lutidine, CH2Cl2 or CH3CN o Triethylsilane, catalytic B(C 6H5)3, hexane or CH2Cl2, 86-95% yield. Primary alcohols can be reduced, alcohols and phenols: readily silylated, under suitable condition can reduce some alcohol and ether
Fig. 5. Example of protection and deprotection of a carbonyl group.
Acyclic Acetals and Ketals Dimethyl Acetals and Ketals: R 2C (OCH 3 )2
N-Methyl-N -triethylsilyltrifluoroacetamide Deprotection: ~10-100 x more stable than TMS, shows much greater o
stability to many reagents, methods used to cleave TBDMS can be use d to cleave TES o
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H2SiF6, IPA, -40 C, 88% yield. Primary TES group was removed in the presence of TBS and TIPS DDQ, CH3CN or THF, H 2O, 86-100% yield. TBDMS not usually cleaved Ph3P∙HBr , MeOH, CH2Cl2, 0 C, 80% yield.
ketals of diaryl ketones.
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Diisopropyl Acetal (i-PrO)2 CHR
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alcohol with low steric demands, also silylates phenols
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TBDMSCl, Li2S, CH3CN, 25 C, 5-8h, 7595% yield. Rxn occurs under nearly neutral conditions TBDMSCl, DMAP, Et 3N, DMF, 25 C, 12h. °
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Used to selectively silylate primary over secondary alcohol .
Deprotection: o Bu4NF, THF, 25 C, 1h, >90% yield. F ion is very
TBAF, NH4F, THF, rt, 30 min, 63% yield,
Protection: CH(Oi -Pr)3, CSA, IPA, removal of i -PrOH by distillation, 68-92% yield. Deprotection: Formic Acid, THF, H 2O, 20 C, 100% yield. °
Cyclic Acetals and Ketals
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basic to moderate the basicity acetic acid can be added to the soln o
Deprotection: o TsOH, acetone o Oxalic acid, THF, H 2O, rt, 12 min, 72% yield. o HCO2H, pentane, 1 h, 20 C. Under these conditions β -γ-double bond does not migrate into conjugation
Protection: o TBDMSCl, imidazole, DMF, 25 C, 10h, high yields. Most common method for TBDMS introduction on o
LiBF4, ROH, (MeO) 3CH, reflux, 72-100% yield. Aromatic ketones and aldehydes react more slowly but are efficiently derivatized
t-Butyldimethylsilyl Ether (TBS/TBDMS Ether)
Protection: o MeOH, dry HCl, 2min. o CH(OMe)3, MeNO2, CF3COOH, reflux, 4 h, 81-93% yield. Particularly effective for preparation of
Protection: HOCH2C(CH3)2CH2OH > HO(CH2)2OH > HO(CH2)3OH Deprotection: acid-catalyzed hydrolysis
1,3 Dioxanes
Ammonium fluoride was used to buffer the basic TBAF
Protection:
HO(CH2)3OH, TsOH, benzene, reflux o HOCH2C(CH3)2CH2OH, Sc(NTf 2)3, toluene, 0 C, 3h, 87-92% yield. Deprotection: o For the most part, some form of aqueous acid will cleave this ketals and acetals. o TMSCl, SmCl 3, THF, 71-99% yield. Ketals are cleaved faster than acetals. o
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1,3-Dioxolanes
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A molecule containing two similar ketones can be selectively protected at the less hindered carbonyl.
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carbamate is cleved preferentially o
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Protection: o HO(CH2)2OH, C5H5N∙TsOH, C6H6, reflux, 13h, 90-95% yield. This is a commonly used mild and general method for dioxolane formation.
HO(CH2)2OH, Tetrabutylammonium tribromide, triethylorthoformate, 21-97% yield. This method produces HBr in situ and can be used to
HO(CH2)2OH, Me3SiCl, MeOH or CH 2Cl2. HCl is produced insitu.
Deprotection: can be cleaved via acid-catalyzed exchange dioxolanation, acid-catalyzed hydrolysis or oxidation o
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PPTS, acetone, H2O, heat, 100% yield. Microwaves have been used to accelerate cleavage. 5% HCl, THF, 25 C, 20h. 80% AcOH, 65 C, 5min, 85% yield
Amino Protecting Groups One of the many ways an amino group can be protected is by being converted into an amide. The acetyl group can then be subsequently removed via acid-catalyzed hydrolysis.
Protection: o CH2=CHCH 2OCOCl, Pyr o (CH2=CHCH 2OCO)2O, dioxane, H2O, reflux or CH2Cl2, 1h, rt, 67-96% yield. Deprotection: o I2, CH3CN, H 2O, 60 C, 8-16h, 83-93% yield Pd(Ph3P)4, Me2NTMS, 89-100% yield as the TMS carbamate that is easily hydrolyzed. This °
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Protection: o Cl3CCH2OCOCl, Pyr or aq. NaOH, 25 C, 12h o Silylate with Me 3SiN=C(OSiMe3)CH3 then treat with Cl3CCH2OCOCl Deprotection: o Zn, THF, H2O, pH 4.2, 30 min, 86% yield o Cd-Pb, AcOH, 89-94% yield
Allyl Carbamates (Alloc-NR 2 or Aloc-NR 2 ): CH 2= CHCH 2- OC(O)NR 2
prepare both cyclic and acylic acetals.
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Aldehydes are generally protected over ketones
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KOH, H2O, ethylene glycol, 100 C, 12h, 88% yield. HBr, AcOH, 25 C, 18h
Ex: 2,2,2-Trichloroethyl Carbamate (Troc-NR 2 )
If one carbonyl is conjugated with a double bond, the unconjugated carbonyl is selectively protected.
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Deprotection: o Me3SiI, 50 C, 70% yield. The most electron rich
Substituted Ethyl Carbamates
Protection of carbonyls containing other acid-sensitive functionality use acids of low acidity or pyridinium salts.
CO, O2, MeOH, HCl, PdCl 2, CuCl 2
method was developed to suppress allylamine formation
Amides Acetamide the simplest method for acetamide preparation is to react amine w/ acetic anhydride or acetyl chloride w/ or w/o added base. This method is quite reactive thus are not usually selective. Below are some that tends to be more selective.
Protection: C6F5OAc, DMF, 25 C, 1-12h, 78-91% yield. °
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These conditions allow selective acylation of amines in the presence of alcohols. If triethylamine is used instead of DMF alcohols are also acylated. o
Fig. 6. Example of protection and deprotection of an amino group.
also be used to transfer o ther acyl groups and is selective for primary amines in the presence of secondary amines.
Deprotection: acetamides as well as other alkyl and aryl amides are difficult to hydrolyze so you often need forcing co nditions to achieve it
Carbamates
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Methyl and Ethyl Carbamate (CH 3OC(O)NR 2 )
CH3SO2NHAc, heat, 90% yield. This method can
Protection: o CH3OCOCl, K2CO3, reflux 12 h. Methyl chloroformate is the most common reagent used for the introduction of a methyl carbamate. Pyridine and TEA are the most frequently used bases.
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1.2 N HCl, reflux, 9h, 61-77% yield 85% Hydrazine, 70 C, 15h, 68% yield °
Trifluoroacetamide (TFA) R 2N COCF 3 considered as one of the more useful amides since it can be removed under mildly basic conditions.
Protection:
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CF3CO2Et, Et3N, CH 3OH, 25 C, 15-45h, 7595% yield. Selectively protects a primary amine in the °
Protection:
presence of a secondary amine. With DMAP catalysis primary anilines are efficiently acylated with 75-98% yield o
TFA, Ph3P, NBS, CH 2Cl2, Pyr, 81-99% yield. This method can be used to prepare other amides from carboxylic acid
Deprotection: o K2CO3 or Na2CO3, MeOH, H2O, rt, 55-95% yield. TFA has been cleaved in the presence of methyl
t-Butyldimethylsilylalkyne and Thexyldimethylsilylalkyne (TBDMS- and TDS- alkyne)
ester which illustrates the ease of hydrolysis of the TFA group. o
Protection: o KHMDS, THF, TBDMSOTf, -78 C, 98% yield °
LiOH∙H2O, THF, MeOH, H 2O, rt, 24h, 100% yield
for the TBDMS group, the TDS group behaves similarly except that it is slightly more hindered, LHMDS can also be used as base.
Benzamide R 2N COC 6H 5 o
Protection: o PhCOCl, Pyr, 0 C, high yield PhCOCN, CH2Cl2, -10 C, 92% yield. This °
reagent readily acylates amines in the presence of alcohols
Deprotection: o 6 N HCl, reflux, 48h or HBr, AcOH, 25 C, 72h, 80% yield o Ph3P, Cl2, TEA, CH 2Cl2, -30 C, then ethylene glycol, 90% yield. This is a general
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Alkyne Protecting Groups Alkynes can be protected by adding a Grignard or lithium reagent to the compound and forming an alkynyl Grignard or alkynyl lithium reagent. Once you have an alkynyl Grignard or alkynyl lithium reagent, you can react it with carbonyls, OTs, TMS, etc.
Fig. 7. Example of protection and reaction of alkyne
Trialkylsilylacetylenes Acetylenic hydrogen is often necessary bc of its acidity. The bulk of a silane can protect acetylene against catalytic hydrogenation bc of the rate of difference bet olefin and more hindered alkyne Trialkylsilanes are usually formed by reacting silyl chlorides with Grignard or lithium reagent.often used asa convenient method for introduction of acetylenic unit bc they tend to be easily handled by solids or liquids compared to gaseous acetylene Silyl acetylenes are prepared from alkynyl copper(I) rea gents
Deprotection: o Bu4NF, THF, -23 C, 75% yield o Bu4NF, 2-nitrophenol, THF, 0-23 C, 87% yield. The 2-nitrophenol was added as a weak acid to prevent the elimination of a vinyl bromide. °
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method applicable for a variety of amides
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ethers ex. TES derivative, but hydrosilylation occurs sometimes to form vinylsilanes.
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TBDMSH, Ir 4(CO)12, Ph3P, 120 C, 40h, 95% yield. This method works for the introduction of other silyl
Hydroxymethylalkyne (alkyne-CH 2O H)
Protection: o 2-methyl-2-hydroxy-3-butyne (source of acetylyne) Deprotection: o NaOH, benzene, reflux, >96% yield o For the hydroxymethyl derivative: MnO 2, KOH, Et2O, rt, 88% yield.