Current Organic Synthesis, 2012, 9, 137-148

137

Recent Developments on the Synthesis and Cleavage of tert-Butyl Ethers and Esters for Synthetic Purposes and Fuel Additive Uses
Letizia Sambri*,1, Giuseppe Bartoli1, Giorgio Bencivenni1 and Renato Dalpozzo2
1 2

Universit di Bologna, Dipartimento di Chimica Organica A. Mangini, viale Risorgimento 4, I-40136 Bologna, Italy Universit della Calabria, Dipartimento di Chimica, ponte Bucci cubo 12/c, I-87036 Arcavacata di Rende (Cs), Italy Abstract: tert-Butyl esters are frequently employed in multi-step synthesis, especially with amino acid derivatives, and their importance is well established. On the contrary, tert-butyl ethers received less attention owing to the difficulties in their preparation and cleavage. Recently the tert-butyl ethers found employment also as fuel additives thus their synthesis became important and various protocols were developed. The present article will cover the developments of the synthesis and cleavage of the tert-butyl esters and the tert-butyl ethers in the new millennium. Dedicated to Professor Saverio Florio in the University of Bari on the occasion of his 70th birthday.

Keywords: Oxygenate fuel additive, protecting groups, tert-butyl esters cleavage, tert-butyl esters synthesis, tert-butyl ethers cleavage, tertbutyl ethers synthesis. 1. INTRODUCTION In spite of its very simple hydrocarbon structure, the tert-butyl group shows unique properties due to its steric hindrance and/or stability of the associated carbocation [1]. Hence, the tert-butyl moiety plays an outstanding role in affecting the regio- and stereoselectivity of many organic reactions and affords solutions for orthogonality in protection and deprotection sequences, especially in peptide synthesis [2-4]. Since the tert-butoxy group is extremely stable to strongly basic conditions [2], it could be one of the most versatile alcohol protecting groups. However, the earlier syntheses of tert-butyl ethers involved isobutylene bubbling or difficult chromatographic purification from the crude material when other tert-butyl donors are used. Moreover, the involvement of tert-butyl carbocation in these syntheses as well as in the classical Williamsons ether synthesis limits the application of these methodologies to the protection of aromatic alcohols, which predominantly undergo a Friedel-Crafts alkylation. Furthermore, a protecting group is considered valuable when, together with a valid method for its introduction, a mild deprotection procedure is available, but for a long time all the methods involving the tert-butyl group suffered from drastic conditions or showed restricted applications [2, 4]. The tert-butyl ether, therefore, was one of the most underused alcohol protecting groups [4], owing to the conditions required for its formation and deprotection. The knowledge of the good antiknock properties of some oxygenated compounds dates back to the 1930s, when improvements in aircraft performance resulted in demand for fuels of increasingly higher antiknock performance [5]. In spite of this, however, no industrial development of oxygenated compounds was started until removal of alkyl
lead compounds from gasoline in the early 1970s, when ANIC in Italy in 1973 and Chemische Werke Huels in Germany in 1976 produced industrial quantities of methyl tert-butyl ether (MTBE). Industrial production of MTBE and other tert-butyl ethers is, however, beyond this review scope, but in the last years chemical researches have addressed the synthesis of less volatile tert-butyl ethers and the results will be covered by this review,
*Address correspondence to this author at the Universit di Bologna, Dipartimento di Chimica Organica A. Mangini, viale Risorgimento 4, I-40136 Bologna, Italy; Tel: 051-2093614; Fax : 051-2093654, E-mail: letizia.sambri@unibo.it

Also tert-butyl esters can be widely used in multistep synthesis. In fact they are resistant to attack by strong basic reagents such as butyl lithium and, taking advantage of the encumbering of the tertbutoxy group, by a wide range of nucleophiles. Moreover, tertbutyl moiety takes advantage from the chance to be cleaved with both the mechanisms universally accepted for ester hydrolysis (see section 3.2). Recent literature has described new methodologies for the synthesis and cleavage of both tert-butyl ethers and esters and they are overviewed in this review. 2. TERT-BUTYL ETHERS As stated above, recent research on tert-butyl ethers has addressed the need to find clean and easy methods for their synthesis in order to increase their importance both as protecting group and as fuel additive. The present part is therefore divided into two main sections. When tert-butyl is used as a hydroxyl protecting group, an easy cleavage method is also aimed for by chemists; therefore the first section will be further divided into two sub-sections: protection and deprotection methodologies. 2.1. Protecting Group Traditionally, alcohols had been transformed in tert-butyl ethers by reaction with isobutylene or tert-butyl-trichloroacetimidate, in the presence of a strong acid [2, 4]. However, gas bubbling through substrate solutions for long periods of time in the former reaction and difficult chromatographic purification from residual trichloroacetamide in the latter are unattractive options. Moreover, the involvement of a tert-butyl carbocation often causes undesired side-reactions. In the last decade new methodologies appeared in the literature both for the synthesis and the cleavage of tert-butyl ether to overcome these drawbacks. 2.1.1. Synthesis The new protocols appeared in this new millennium for the synthesis of tert-butyl ethers involve the unusual decomposition of Boc2O in the presence of magnesium perchlorate [6, 7], or iodine [8], the nucleophilic substitution of 2-bromo-2-methylpropane induced by lead salts [9, 10] and the cleavage of tert-butyl esters by perchloric acid [11], the palladium catalyzed cross-coupling reac 2012 Bentham Science Publishers

1570-1794/12 $58.00+.00

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Mg(ClO)4 (10 mol %) 40 C Boc2O + ROH ROCMe3 (65-95 % yields) R= n-C8H17, c-C5H9, menthyl, PhCH2, 4-MeOC6H4, 4-FC6H4, 3-ClC6H4, 1-naphthyl, 2-naphthyl,
-methylcinnamyl, (Z)-3-nonenyl, 2-NO2C2H4, 9-BrC9H18, 4-PhCH2OC4H8, (i-C3H7)3SiOC4H8, 2-(BocNH)C2H4 Me Me Ph O Ph Me , EtO2C Me , Me Me

Mg2+ Mg2+ Boc2O Me3CO O O 1 O OCMe3 ROH (2) Me3CO R O

Mg2+ O O H 3 path b Mg2+ O O O OCMe3 Me3C O H O O R Mg2+ O OCMe3 RO 4 CO2 + t-BuOH (6) O OCMe3 OCMe3 path a Me3CO R O Mg2+ O O O H OCMe3

ROCMe3

O O

Mg2+ CMe3 O TS R2 RO

O 5 2 CO2 O

Scheme 1.

tion of aryl halides and alcohols [13, 14, 15]. All these reaction will be discussed in detail in this section. Our research group reported an interesting synthesis of tertbutyl ether as an alternative to the procedures mentioned above [6]. In our approach, Boc2O (Scheme 1) was used as a tert-butyl source and anhydrous Mg(ClO4)2 as the catalyst. Under these conditions, primary, secondary, benzylic, allylic and homoallylic alcohols, and notably a large variety of phenols can be easily converted into the corresponding tert-butyl ether (65-95% yields). Only, tertiary alcohols failed to give the desired ether. Moreover both Mg(ClO4)2 and Sc(OTf)3 behave as comparably efficient catalysts in the synthesis of aromatic tert-butyl ethers, but the former allows decomposition of the product for long reaction times [7]. During this study, we found that Boc-alcohols or tert-butyl ethers formation is mainly controlled by the anionic part of the Lewis acid catalyst [7]. Perchlorates and triflates, anions with highly delocalized negative charge, give prevalent or exclusive ether formation. On the other hand, Boc-alcohols are the main or exclusive products with undelocalized isopropoxide or low-delocalized acetate ions. The proposed explanation (see Scheme 1) is that highly nucleophilic anions do not dissociate from their metal counterpart, and, as a consequence, the intermediate 3 has high anionic character, so it is more prone to restore the carbon-oxygen double bond (path a), favoring elimination of the good leaving group carbonate monoester and leading to the exclusive formation of carbonate 4. On the other hand, naked metal ions, such as those of perchlorates and triflates, tightly bind to the oxygen anion of 3 and allow the reaction to follow path b,

where the tert-butyl alcohol becomes the better leaving group, leading to a mixed carbonate carbonic anhydride, that decomposes through a synchronous mechanism in a six-ring transition state (TS) to form the tert-butyl ether 5. The absence of free tert-butyl carbocation formation in this mechanism is consistent with the very good yields in tert-butyl aryl ether synthesis. An analogous behavior was observed by Chakraborti [8] in the organocatalyzed reaction of phenols with Boc2O. In fact, in the reaction of 4-nitrophenol, I2, an organocatalyst with high Lewis acidic character, allowed the generation of the ether 5 (30% yields as the only isolable product), while CBr4, which involves a charge transfer complex formation to give a radical-cation-radical-anion pair, led to formation of 4 (93% yields). Rai [9] and Rajus [10] groups published two similar etherification reactions in the same period (Scheme 2). Both groups employed an excess of tert-butyl bromide in the presence of basic lead carbonate (10 mol%). Very surprising they obtained the same identical yields (75-96% yields) on the same range of substrates, with the same excess of bromide. The only appreciable differences were the reaction times, considerably shorter with MW irradiation [10], but at higher temperature with respect to the reaction without irradiation [9]. No mechanistic considerations were reported, but the features of the reagents seem to exclude that the basic medium allows the formation of alcoholate intermediates followed by SN2 pathway on bromide. More likely, the redox characteristics of lead(II) ion allow

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ROH + Me3CBr

2PbCO3Pb(OH)2 (10 mol %) solvent free (75-96 % yields)

ROCMe3 Ph O

R= allyl, propargyl, Ph, 4-MeOC6H4, 4-FC6H4, 3-ClC6H4, n-C5H11, n-C8H17, PhCH2, Ph 3-HOC6H4CH2, 1-naphthyl, 2-naphthyl, c-C5H9
Scheme 2.

ROH ROCMe3 O Me 7 AcOH MeCOOR HClO4 (10 mol %) ROH ROH2+ R+ elimination products
Scheme 3.

HClO4 (10 mol %) OCMe3

O O AcOH 8 9 10

(eq 1)

Me

(eq 2)

ROH + CH3CO2CMe3 7

HClO4 (10 mol %) ROCMe3 (70-100 %)

R= 3-(FmocNH)propyl, 4-ClC6H4(CH2)2, 2-octyl, c-C6H11, menthyl, c-C12H23, 2-hexynyl, hex-3-yn-2-yl Ph EtO2C Me Me , Me . , Me Me MeO2C Me CO2Me , Me Me , Me Me Me Me CbzHN CO2Et , NC CO2Et Me , Ph

, Me

Scheme 4.

to envisage an electron transfer on the tert-butyl bromide with cleavage of the bromine-carbon bond. Very recently [11], the generation of the tert-butyl ether was easily performed by applying the experimental conditions known to lead to the cleavage of carboxylic acid tert-butyl esters (Scheme 3, eq 1). Thus, the addition of HClO4 (10 mol%) to a solution of an alcohol in tert-butyl acetate at 25 C led to the corresponding tbutyl ether (Scheme 4 ). The acidic medium, however, can induce the competitive protonation of the alcohol (eq 2), generating a carbocation and a series of competitive reactions that can prevail over the one described in eq 1, depending on the relative stability of the carbocations. As a consequence, good results (70-100% yields) were obtained with primary, secondary and cyclic alkyl alcohols, also in the presence of many functional and protecting groups, but elimination is the main pathway followed by tertiary alcohols. In the reaction with aromatic substrates, the formation of tertbutyl carbocation 9 should be prevented by the palladium-catalyzed

cross-coupling reaction of aryl halides with alcohols, as an alternative method for the formation of the aryl-oxygen bond. Watanabe has provided examples of aryl tert-butyl ether formation (13, Scheme 5) in 60-94% yields and high selectivity in the presence of tri-tert-butylphosphine/palladium(II) acetate (3/1, 3 mol%) in xylene at 120 C [12]. Only strong electron donor substituents (such as p -methoxy and 3,4-methylenedioxy groups) gave low yields and significant de-halogenation. On the contrary, Hartwig used tri-tertbutylphosphine [13] or di-tert-butylphosphinoferrocene / bis(dibenzylideneacetone)palladium as the catalyst (2-5 % mol) in toluene [14], respectively. In the former reaction yields are lower (6284% vs 77-98%) and temperature higher (85-110 C vs room). Once more, low yields are obtained with strong electron donor substituents. These phosphine ligands are, however, air sensitive and thus require special handling techniques. More recently [15], palladium-catalyzed synthesis of aryl tert-butyl ethers was performed in the presence of commercially available or readily prepared airstable dialkylphosphinobiphenyl ligands and palladium(II) acetate

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X + Me3CONa R 11 ligand/Pd(II) 12 Conditions

ligand/Pd(II) R 13 yields (%)

OCMe3

P(CMe3)3/Pd(OAc)2 ArP(CMe3)2/Pd(OAc)2

3 mol%, xilene, 120 C

60-94

4-CHO, 4-PhCO, 4-CF3, 4-CMe3, 3-MeO, 4-MeO, 2-Me-3-Cl, 3,4-OCH2O 4-CMe3, 4-C4H9, 3,5-Me2, 2,5-Me2, 3-MeO, 4-MeO H, 2-Me, 3-MeO, 4-MeO, 4-PhCO, 4-NO2, 2-(CH2)2OH, 2-CH2CH(Me)OH, 2-(CH2)2CH(Me)OH 2-(CH2)2C(Me)2OH, 2-CH2C(Me)2OH

2 mol%, toluene, 100C

62-84

5 mol%, toluene, rt

77-98

Scheme 5.

acid ROCMe3

CMe3 O H

Nu ROH + CMe3Nu

Acid Amberlist SiO2/TsOH H3PO4 (85%)

Nu H2O H2O H2O

Yields (%) 83 87 74-97 4-BrC6H4 NHCbz CbzHN O Me

R vanillin vanillin CO2H N

CO2CH2Ph

CO2CH2Ph

CeCl3/NaI

I-

92-99

1-octyl, 2-octyl, menthyl, 2-NO2C2H4, (Z)-3-nonenyl, 6-HOC6H12, Ph, 1-naphthyl, 2-naphthyl, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 2-CNC6H4, 4-CHOC6H4, 4-NO2C6H4, 3-ClC6H4

EtO2C

Me

, Ph O

Ph

Scheme 6.

(1-2.5 mol%) in 65-90% yields. It is noteworthy that both 4methoxy chloro and bromobenzene were converted into the corresponding ether 13 in about 85 % yields contrary to previous reports. 2.1.2. Deprotection In order to avoid strong acid conditions for the deprotection of tert-butyl ethers, recently Lewis acids or milder Brnsted acids have been introduced to cleave the C-O bond (Scheme 6). Some procedures were applied both to ethers and esters and they both will be collected in the proper section. Experiments on the selectivity between ether and ester cleavage were reported in section 3.2, where ester deprotection will be described. Brnsted acids, such as Amberlyst-15 at 80C or p-TsOH immobilized on silica at room temperature, were found to cleave tertbutyl ethers of vanillin employing 0.6 equiv of catalyst in 83 and 87 % yields, respectively (Scheme 6) [16]. The tert-butyl group is removed easier than other aromatic ethers reflecting the stability of the corresponding carbocation, but the application of the method has not been extended to other aryl ethers, so at the present the method appears of scarce interest. Recently, aqueous phosphoric acid (85 wt %) was reported for the deprotection of the tert-butyl groups in esters, carbonates carbamates and ethers, (Scheme 6). The tert-butyl ether cleavage is the slowest reaction among them, so ester and Boc protection did not

survive, whereas Cbz did. Yields ranged from 74 to 97%, but 5 equivs of aqueous H3PO4 were typically required [17]. Among Lewis acids, zinc bromide promoted deprotection of unfunctionalized tert-butyl ethers give alcohols in 78-82% yields under mild conditions within 1224 h, but once more a large amount (5 equivs.) of promoter is required [18]. We have developed a simple and general method for the cleavage of tert-butyl ethers, by treatment with equimolecular amounts of anhydrous CeCl3 and NaI in CH3CN [19]. The procedure can be successfully applied (92-99% yields) to a large variety of aliphatic and aromatic substrates, in the presence of both various functional groups and/or other alcohol protecting groups, (Scheme 6 ). Group 5 and 6 metal chlorides such as MoCl5, WCl6, NbCl5 and TaCl5 were found as very efficient catalysts for acylative cleavage of the CO bond of ethers [20]. In particular, the C-O bond cleavage reflects the stability of the cation species, so tert-butyl alkyl ethers always led to alkyl ester and tert-butyl chloride (Scheme 7). Very recently, the cleavage of the CO bond of O-tert-Bu groups in esters, carbonates, carbamates and ethers has been accomplished by PhMe2SiH (1.2 equiv.) activated by a triruthenium cluster (3 mol%) (Scheme 8) [21]. The method works under neutral conditions, and it will be further discussed in section 3.2, where ester cleavage will be discussed. Only a few examples of ether cleavage are reported and aromatic ethers seem to be cleaved more

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MoCl5 (1 mol %) 80 C, DCE ROCMe3 + PhCOCl R=Me, PhCH2 ( 61-99% yields) PhCO2R + Me3CCl

PhCO2R

MoCl5

ROCMe3

Ph O Cl O

R R MoCl4 O CMe3

Cl4Mo-Cl

ROMoCl4 PhCOCl
Scheme 7.

Me3CCl

R'3Si ROCMe3 SiR'3 Ru3H R R= Ph(CH2)3, 4-PhC6H4

Scheme 8.

Ru3-H H ROSiR3' + H2 + (70-95% yields)

OH

OCMe3 R 13

h
MeOH

OH R + 10

(>80% yields) R= H, 4MeO, 3-MeO, 4-Me, 3-Me, 4-F, 3-F, 4-CF3, 3-CF3, 4-CN

a h
13 R O b H

a R

OH + 10

O b R H CMe3 R

OH

CMe3 (Fries products)

Scheme 9.

efficiently than aliphatic ones. In particular, selective deprotection of the O-tert-Bu group occurred in the reaction of bisphenol A tertbutyl methyl ether to exclusively afford bisphenol monomethyl ether in 84% yields. However, the reaction is actually a transetherification reaction and the removal of PhMe2Si group is required in a second reaction step to obtain the free hydroxy group. Finally, the reactant is rather complex and expensive and the reaction limited in scope.

Pickock introduced a completely different approach to cleave aromatic tert-butyl ethers [22]. His group found that aromatic ethers could be cleaved in more than 80% yields (Scheme 9 ), when irradiated at 254 nm, in methanol, at 25 C. This wavelength results in excitation of the molecule into an upper vibrational level with formation of in-cage radical pairs. However, ion pairs cannot be excluded, in particular with strong electron withdrawing substituents, (Scheme 9, path a). Unfortunately, significant amounts of the Fries rearrangement products were obtained in all cases (path b).

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Table 1. ETBE Synthesis Under Heterogeneous Catalysis

Catalyst H-Beta Zeolite B25t Reaction Conditions ethanol/isobutene ratio = 1/1, He carrier, WHSV = 2 h , 45 C, vapour-phase ethanol/isobutene ratio = 1/1, N2 carrier, 11.8 g cat per feed mole, 60 C, vapour-phase ethanolb/isobutene ratio = 1.4/1, He carrier, WHSVa = 5 h-1, 40 C, vapour-phase ethanol/isobutene ratio = 1.5/1, He carrier, LHSVd = 1 h-1, 140 C, vapour-phase ethanol/tert-butyl alcohol ratio = 2/1, 10 mol %, 70 C, liquid-phase ethanol /isobutene ratio = 1.5/1, He carrier, LHSV = 1 h , 80 C, vapour-phase ethanolb/isobutene ratio = 1.5/1, He carrier, LHSVd = 1 h-1, 120 C, vapour-phase
b d -1 a -1

Yields (%) 32

Ref. [27]

membrane-like H3PMo12O40-polymer H6P2 W18O 62
8H2O

18 43c

[28, 29]

[30]

natural zeolites Purolite CT-145H inorganic organic sulfonated cation exchange resin polymer-based phosphorus-containing carbon

23 60 16

[31] [32] [33]

48

[34]

a WHSV: Weight Hourly Space Velocity, that is hourly weight of mixture processed to the weight of catalyst. b Azeotropic mixture containing 4.43 wt % of water. c The excess of alcohol prevents the formation of isobutene oligomers at the catalysts surface. d LHSV, Liquid Hourly Space Velocity, that is the same of WHST but expressed as volumes.

2.2. Fuel Additive MTBE became the fastest growing chemical of the 1980s as octane supplier, since it is the most economical oxygenated compound that refiners could use and also it is completely miscible with gasoline, low susceptible to phase separation in the storage and distribution system and it has low tendency to undergo peroxidation. However, its volatility opened a controversial discussion on its employment as a clean air additive and the International Agency of Research on Cancer and Environmental Protection Agency consider it health threat. Therefore researches have addressed the synthesis of less volatile tert-butyl ethers, in order to maintain the role of octane supplier, but to decrease levels of Volatile Organic Compounds. Among them, ethyl tert-butyl ether (ETBE) and tert-butyl ethers of glycerol (GTBEs) found consideration since they degrade faster in soils and water and, moreover, ethanol or glycerol may result from renewable sources, only isobutene exclusively arising from oil cracking. The reaction of isobutene with glycerol produces GTBEs as a mixture of different molecules, being di-ethers the more desirable compounds for economic and practical reasons. In fact, monoethers are less soluble in fuels, while tri-ethers dissolve high amounts of isobutene, which is the most expensive reagent. The synthesis of GTBEs is generally performed under moderate pressure at 60-100 C to have isobutene in the liquid phase. However, this is a complex multiphase system, because isobutene is insoluble in the glycerol phase, but highly soluble in di- and tri-ethers of glycerol produced by the reaction. Moreover oligomers of isobutene are generally formed as by-products in the acid reaction conditions. The development of GTBEs production until 2008 has been very recently reviewed in a wide contribution on the use of glycerol as fuel additive and we address the reader there for more information [23]. A new process for the production of GTBE has been appeared in the literature, by using Amberlyst 15 at 92 C, 15 bar in 480 min and 2:1 isobutene/glycerol molecular ratio [24], and it is not covered in the above mentioned review [23]. The performances of this process on the basis of a preliminary kinetic analysis, seems to show that it is simpler than the previous ones proposed in the literature and the product is a mixture of biodiesel and GTBE that can be used directly as diesel additives. tert-Butyl alcohol as both the reactant and the solvent (4-fold excess) has been proposed recently in order to overcome the com-

plex multi-phase systems involved in the classical glycerol etherification reactions [25]. Very low amounts of Amberlyst 15 (1.2 wt %) as the catalyst can be charged, but water, produced by in situ dehydration of tert-butyl alcohol, inhibits the glycerol etherification and its removal from the reaction medium is necessary for the formation of di- and tri-ethers. On the other hand, the tert-butyl cation concentration in the liquid phase is negligible, owing to both a dynamic equilibrium existing between tert-butyl alcohol and isobutene and the scavenger action of water, so that no isobutene oligomers form during the reaction. However, the vapour-phase ETBE synthesis from isobutene and ethanol in heterogeneous acid catalysis, such as sulfonated ionexchange resin, zeolite or inorganicorganic hybrid acid catalysts, is undoubtedly the most studied reaction. It is mostly conducted in flow reactors with a fixed bed of catalyst in the vapour-phase and kinetics at different temperatures and catalysts are made. For earlier papers we refer the reader to earlier reviews on this topic [5, 26], while more recent results are collected in Table 1, where the reported data refer to the best reaction conditions and the products between the limiting-reagent conversion and ETBE selectivity are reported as yields. 3. tert-BUTYL ESTERS Last century researches on tert-butyl esters have been addressed to find clean and easy methods for their synthesis and cleavage in order to increase their importance as protecting groups. The present section as well as that on ethers is therefore divided into two main sections: synthesis and cleavage. 3.1. Synthesis Several methods had been reported for the synthesis of tertbutyl esters, including either reaction of acyl chlorides with tertbutoxide salts or tert-butanol in basic medium, or reactions of carboxylic acids and tert-butanol in the presence of dehydrating reagents [2, 4]. Some years ago [35], Karmakar suggested a synthesis in heterogeneous phase (acidic alumina, sulphur and zinc dust) between carboxylic acid and tert-butanol at room temperature. Yields ranged from 68% to 90% in 1.5-2 h, but large amounts of tert-butanol were required. The authors emphasized the role of alumina as a water scavenger; no other mechanistic details were furnished, but an electron transfer reaction could be envisaged.

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BuLi + 2 n-BuMgBr MgBr2 Br n-Bu3MgLi (0.4 equiv) PhMe, -10 C, 1 h Br Br 1) Boc2O (1.2 equiv) 2h Li Br 2) H+ Br

Mg

CO2CMe3

Br 14
Scheme 10.

15

A X B

EWG

1) LDA (1.1 equiv), -78 C, THF 2) Boc2O (1.1 equiv) X (68-93% yields)

CO2CMe3 A B EWG

A, B = N,C EWG= H, Me, CN, CO2Me X= H, Cl, Br, F, F2, Me, Me2, CN, NO2, MeO, (MeO)2, CF3, CF3O

EWG=H 1) LDA (2.2 equiv), -78 C, THF 2) Boc2O (2.2 equiv) X (81-93% yields)

CO2CMe3 A B CO2CMe3

A X

Y 1) LDA, -78 C, THF 2) Boc2O X (84-91% yields) Z A=N, X=H, Y=Br, Z=F A=CH, X=4-Br, Y=Z=F A=CH, X=3-Br, Y=Z=MeO

CO2CMe3 Z

Scheme 11.

A quite different procedure involves the addition of organometallic reagents to Boc2O. The reaction of haloarenes bearing multiple halogen substituents with lithium tri-n-butylmagnesium ate complex occurs with high selectivities for metalhalogen exchange of bromine in the presence of other halogens and for the mono exchange in the presence of more than one bromine with preference for ortho-selectivity [36]. Then triarylmagnesium ate complex intermediates (like 14, Scheme 10) are trapped with Boc2O to give tert-butylbenzoates (like 15) in good to high yields (66-99%) except for 3,5- and 2,6-dibromopyridine that gave complex mixtures. The reaction was then extended to arenes substituted with a methyl or an active methylene group, by using the non-nucleophilic base LDA (1.1 equiv) as metalating agent and Boc-anhydride (1.1 equiv) as carbanion trapping in THF at -78 C (68-93% yields) [37]. The reaction of methyl arenes in the presence of an excess of LDA and Boc2O (2.2 equiv) led to double addition affording malonates, whereas active methylene substituted arenes did not. Finally substrates particularly prone to ortho-metalation gave benzoates under these conditions (Scheme 11). Goossen introduced the decarboxylative esterification of carboxylic acids with carbonic anhydrides with Mg(ClO4)2 (1 mol %) as the Lewis acids catalyst, for the synthesis of esters in nitromethane at room temperature [38]. Among dicarbonates, Boc2 O was found to lead to tert-butyl esters in 91-96% yields (three examples). The two major limitations of this reaction protocol were the

instability of Boc2O under strong Lewis acid conditions [7] that required high excess of this reagent and the instability of tert-butyl esters of
-amino acids, that decomposed forming isobutene, and the carboxylic acids were recovered. On the other hand the major advantage was the fact that only volatile or water-soluble byproducts are released. From our study on the synthesis of tert-butyl ethers [7], we proposed a rationale for this reaction based on the influence of the Lewis acid power, that could overcome all the drawbacks of the previously reported protocols, (Scheme 12) [39]. This methodology ought to be based on acid catalysis with weak Lewis acids from environmentally benign metals, which are unable to decompose dicarbonates, especially Boc2O. On this basis, tert-butyl esters were synthesized (55-97% yields, 9 examples) from carboxylic acids, Boc2O (1.3 equiv) in tert-BuOH (2 equiv) in the presence of MgCl2 (10 mol%) as the catalyst at 40 C. It is worth noting that a N protected
-amino acid was easily converted into its tert-butyl ester. The synthesis of amino acid esters in which the ester moiety is sterically demanding and orthogonal to Fmoc- or Boc-N -protection often requires harsh conditions, but it is of basic importance in solid phase peptide synthesis. Recently the synthesis of esters has been performed by the use of the cross-linked enzyme aggregates of the industrial protease Alcalase in neat tert-butyl alcohol [40]. A series of amino acids and peptide were converted into their tert-butyl ester in 72-92% yields in the presence of 4 molecular sieves as

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MgCl2 (10 mol %) Boc2O (1.3 equiv) CMe3OH (2 equiv) 40 C RCOOH (55-97% yields) 16 17 (CH2)3 , (CH2)2 R=Ph(CH2)2, MeCO(CH2)5, EtCH=CHCH2, MeO2C(CH2)3, Br(CH2)7, C5H11, PhCONHCH2, 1 16 CO2 + CMe3OH RCO2CMe3

17 Mg2+ O Me3CO CMe3OH Mg2+ O R

Scheme 12.

O O R

16

O O R CO2 + CMe3OH

O O 18

O O

1) RCHO, H2O 2) NaBH4 O

O O R

[MeN=CH2]+I- (19) tert-BuOH R (50-96% yields) 20 COOCMe3

R= 2-thienyl, 3-thienyl, 3-Me-2-thienyl, 3-MeO-4-OHC6H3, 4-MeOC6H4, 2-MeOC6H4, 2,3,4-(MeO)3C6H2, 2-F-4-MeOC6H3, 3-Cl-4-MeOC6H3, 4-FC6H4, 2,6-F2C6H3, 4-MeSC6H4, 4-MeC6H4, 2,6-Me2C6H3, i-Pr, 1-naphthyl, 1,3-benzodioxol-4-yl, 1,3-bezodioxol-5-yl,
Scheme 13.

water scavenger. Many protections on the amino group are tolerated and inter-peptide linkage remains unaffected. The chance to esterify with complete selectivity for the
-carboxylic moiety in glutamic and aspartic acid derivatives was also exploited, but not with tertbutanol. Scale-up can be performed since water could also efficiently be removed by azeotropic distillation and the protease can be recycled with minimal loss of activity.
-Substituted acrylates (20), compounds of increasing importance in the design and synthesis of new polymer-based materials, are often difficult to be synthesized. A practical synthesis of tertbutyl derivatives from commercially available aldehydes, Meldrums acid (18) and Eschenmoser's iodide salt (19) appeared recently in the literature (Scheme 13) [41]. The reaction conditions are mild and many functional groups are tolerated. Esters 20 can be recovered in 50-96% overall yields. 3.2. Cleavage The tert-butyl moiety can be cleaved via both the mechanisms universally accepted for ester hydrolysis [3] (Scheme 14) either involving the carbonyl group (both under acidic or basic conditions)

in the classical additionelimination mechanism (path i) or by cleavage of the oxygenalkyl bond owing to the particular stability of the tert-buyl carbocation (path ii). This versatility made tert-butyl esters valuable protecting group for their orthogonality with many other protecting groups, and they are particularly useful in peptide chemistry. In recent years some interesting deprotection reactions had been set up and they are reviewed in this section. Brnsted acids efficiently catalyse the hydrolysis of tert-butyl esters via path ii, (Scheme 14). For example, the in situ generation of tert-butyl carbocation 9 during the cleavage promoted by a Brnsted acid has found a very smart application in the synthesis of tertbutyl ethers proposed by Venturello and co-workers described in section 2.1.1 [cfr Scheme 3 (eq. 2) with Scheme 14 (path ii)] [11]. Aqueous phosphoric acid (85 wt %) is able to deprotect esters in good to excellent yields (73-100%) as well as tert-butyl ethers (see section 2.1.2) [17]. Acid-labile N-Cbz, benzyl and acetate ester protecting groups as well as glycosidic bonds remain intact in the reaction. However, formation of gummy phosphates during reaction workup represents a serious drawback of this method.

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145

OH i H+ O ii O i H2O ii RCOOH + Me3C+ 9 H2O

Scheme 14.

R OH 21

RCOOH + Me3COH

H H+ RCO2CMe3 R

+ H+ Me3COH

Nitric acid (3-4 equiv.) smoothly deprotects tert-butyl esters of benzyloxycarbonyl protected amino acids in CH2Cl2 at 0 C during 2 h in 82-96% yields [42]. However tyrosine, as well as other amino acids with activated benzene rings, undergoes quantitative alkylation by electrophilic aromatic substitution. Moreover, sulphur-containing amino acids, like methionine, are fully oxidized to sulphoxides. On the other hand, the case of the tert-butyl derivative of aspartame is significant, since only the tert-butyl is cleaved and no nitration occurred on the benzene ring. Also stoichiometric amounts of commercial 96% H2SO4 in CH2Cl2 at ambient temperature for 6 h are reported to easy hydrolyze four simple tert-butyl carboxylates in 89-98% yields [43]. The reaction, however, is too restricted in its application to be considered a valuable alternative to other methods. Simple aromatic tert-butyl esters smoothly furnish carboxylic acids in 73-96% yields under microwave irradiation for 3-4 min and solvent-free conditions with p -toluenesulfonic acid monohydrate (2.0 equiv.) at room temperature [44]. Yields become almost quantitatively in the presence of standard flash chromatography grade silica gel at 120 C [45]. No selective experiments or aliphatic examples were given in both papers, but single-mode MW irradiation is found slightly more effective than the multi-mode MW irradiation, which could be ascribed to the focused irradiation that increases local micro-heating [45]. Standard flash chromatography grade silica gel was also used in refluxing toluene for 0.57 h, giving the free acids in 68-94% yields and high purities [46]. Solvents with lower reflux temperature are less efficient. Interestingly, polar substrates, having higher affinities for the silica gel than hydrophobic ones, tend to be hydrolyzed faster. The higher reaction times are offset by selectivity. In fact, Fmoc-protected amines, CONH bonds and trimethylsilyethyl and ethyl esters were unaffected under these reaction conditions. The cleavage of tert-butyl esters over tert-butyl ethers appears to be substrate dependent with the ester cleavage potentially being a prime determinant, since variable mixtures of ether-acid and fully deprotected substrates were always obtained, while traces of esteralcohol were never detected. Actually, in the literature, examples of the selective removal of tert-butyl esters in the presence of tertbutyl ethers are sporadic and applied to specific substrates [47, 48] and the opposite completely missing. A Lewis acid can coordinate the carbonyl group allowing hydrolysis via path i, (Scheme 14) and ZnBr2 was used even if in large excess (5 equivs.) under reaction conditions similar to those above reported for ether cleavage (section 2.1.2) [18]. Both aromatic esters and aliphatic esters are deprotected as well (62-91% yields in 648 h). Electron donating groups favor the cleavage of tert-butyl benzoates, while electron withdrawing ones disfavor the cleavage; the longest reaction times and the lowest yields are obtained with tert-butyl 4-nitrobenzoate. Boc and Fmoc protecting groups on

primary amines are described as unaffected, but a subsequent study by Lubell and co-workers found N-Boc as well as N-trityl groups to be labile under these experimental conditions and N-Fmoc group stable only if it is in a remote position [49]. Only 9-(9phenylfluorenyl) amino protecting group was found to be really stable under these conditions. Lubell showed also that Lewis basic functionalities such as alcohols and amides inhibit the reaction. Wu and co-workers [18] attempted the selective cleavage of the tertbutyl ester over the tert-butyl ether, but with little success. In fact, after two hours 47% of mono-deprotected acid was recovered, and prolonged exposure to the Lewis acid resulted in complete cleavage at both sites. Remarkably Lubell stated that tert-butyl ethers were unaffected [49]. Finally Lubells claimed the chance of almost selective deprotection (18:1) of , -di-tert-butyl ester of N- [9-(9phenylfluorenyl)] glutamate at the -position with 1000 mol % of ZnBr2 in CH2Cl2 for 24 h. Clays can act as Bronsted as well as Lewis acids in their natural or ion-exchanged forms. Actually, montmorillonite KSF, an example of ion-exchanged clay, deprotected tert-butyl esters in refluxing acetonitrile in 3-5.5 h yielding 80-95% of the parent carboxylic acids [50]. Benzyl, methyl and allyl esters and acetate were intact as well as olefins, carbamates (Boc, Cbz), ethers and halides. Finally, tert-butyl 4-tert-butoxybenzoate is selectively cleaved to 4-tertbutoxybenzoic acid in 80% yields. A mixture of 1.5 equiv of CeCl37H2O and 1.3 equiv of NaI were found to give the best results (86-91% yields) for the hydrolysis of simple carboxylic acids and selectivity was observed towards other ester function but not with N-Boc and the tert-butyl ether protecting groups. In order to maintain the N-Boc protecting group intact, the experimental conditions were partially modified to increase the solubility of CeCl37H2O in acetonitrile by refluxing it for 24 h. When this mixture was added to N -Boc-O-tert-butyl amino acids the selective deprotection of the tert-butyl ester moiety was accomplished in 75-99% yields. Also the N-Cbz protecting group survived these reaction conditions (Scheme 15, eq 1) [51]. tert-Butyl esters were also cleaved in the presence of iodine (30 mol %) and water (40
L) in refluxing acetonitrile within 45 h in 82-92% yields (Scheme 15, eq 2) [52]. Also this procedure allowed the survival of the N-Boc-protection in amino acids besides the classical acid labile groups, (esters and double bonds). It is worth noting in the latter two procedures that hydrogen iodide, which is supposed to be released in situ , is not actually formed, because it is known to remove tert-butoxycarbonyl groups from amines [53]. The actual mechanism of Marcantonis reaction can be supposed through the coordination of cerium with both oxygen atoms of the ester function. The chelate liberates the tert-butyl carbocation (Scheme 14, eq 1, path i), which is trapped by nucleophilic attack of iodide ion to afford tert-butyl iodide. Alternatively iodide ion can participate in a SN2 displacement reaction on the

146 Current Organic Synthesis, 2012, Vol. 9, No. 1

Sambri et al.

H2O i CeIII O R i and ii ii Iii 22 + 23 H2O RCOOH O RCOOCeIII 23 + CMe3+ IMe3I 22 (eq 1) RCOOH

R= N-Boc-aminoacid I I O H O H I2 RCOOH + Me3COH (eq 2)

O R

R= 2-NO2-4-PhCH2O-5-MeOC6H2, 3-MeO-4AllOC6H3, 2-ClC6H4, 3,4,5-(MeO)3C6H2, 4-PhCH2O-3-MeOC6H3, 4-pyridyl, PhCH2OCO(CH2)2, 4-MeOC6H4CH=CH, AcNHCH2,

Scheme 15.

1) Ru catalyst (1-3 mol %), PhMe2SiH, (MeOCH2)2 2) MeOH RCO2CMe3 RCOOH

R=Ph(CH2)2, 4-MeC6H4

(CO)2 Ru Ru(CO)2 Ru (CO)2 24 H SiR'3 RCO2CMe3 R'3Si O + H2

Scheme 16.

+ PhMe2SiH

CO

H-Ru3 R

O MeOH OSiR'3 RCOOH

Ru3H

weakened carbon-oxygen bond (Scheme 14, eq 1, path ii). In a similar manner Yadavs reaction could occur, via Lewis acid coordination of iodine, followed by synchronous cleavage of iodineiodine and carbon-oxygen bonds (Scheme 15, eq 2). However, Chandrasekaran and co-workers published the first true catalytic method for the hydrolysis of tert-butyl esters in 2002 [54]. Ytterbium triflate (5 mol %) deprotected tert-butyl esters selectively in the presence of other esters, Fmoc and Cbz nitrogen protecting groups under mild conditions (45- 50 C in nitromethane) in 90-99% yields. The reactions are carried out in ni-

tromethane using 5 mol percent of the catalyst. No ester-ether selectivity was instead observed and tert-butyl 4-tert-butoxybenzoate was hydrolyzed to 4-hydroxybenzoic acid in 6 h at 50 C. Moreover, also the reaction of PhMe2SiH (1.2 equiv.) activated by a triruthenium cluster (24, 1-3 mol %, Scheme 16) is able to cleave esters and ethers at 40 C during 7 h (see Scheme 7, for tertbutyl ethers) [21]. In this reaction (Scheme 15), no carbocation is formed, since isobutene release is obtained by hydrogen evolution from a proton of the tert-butyl group and the hydride of the hydrosilane complexed with the catalyst. The ester is activated by the in-

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147

tervention of a [R3Si]+ species. Notably the reaction conditions are neutral conversely from classical reactions producing [R3Si]+ species from Me3SiI and Me3SiOTf, which can decompose in contact with moisture to HI or triflic acid. Actually the few examples (only two with 95 and 93% yields) remain the major drawback of this methodology. The deprotection of six aryl, and heteroaromatic t-butyl esters and carbonates was performed in fluorinated alcohols in particular hexafluoro-isopropanol at 100 C under microwave irradiation [55]. Owing to their unique properties, that are high ionizing powers, strong hydrogen bond donor abilities and low nucleophilicity, fluorinated alcohols are envisaged as ideal solvents to cleave tertbutyl esters without any catalyst. The corresponding carboxylic acids were obtained in 82-96 % yields. Malonates and substituted 2cyanoacetates readily undergo decarboxylation under the reaction conditions. Esters are hydrolyzed when simply heated in hexafluoro-isopropanol, but the reactions are significantly accelerated when microwave-assisted. A true advantage of this procedure is the simple workup, since only evaporation of the solvent is required for obtaining pure acids; therefore the opportunity of expanding this method to a wider range of substrates would be welcomed. Finally, an enzymatic approach to the hydrolysis of tert-butyl esters has been reported when it was discovered that a certain amino acid motif [GlyGlyGly(Ala)X-motif, where X is any amino acid], located in the oxyanion binding pocket of lipases and esterases determines activity toward tertiary alcohols [56]. In particular, an esterase from Bacillus subtilis and lipase A from Candida Antarctica were identified as the most active enzymes, which hydrolyzed a range of tert-butyl esters in 54-80 % yields leaving Boc, Cbz, and Fmoc-protecting groups intact. B. subtilis esterase was ineffective against tert-butyl ethers. Hydrolysis of protected amino acids was found dependant on the side chain. In fact, the enzymatic hydrolysis of phenylalanine and tyrosine moieties occurred to a higher extent (62 and 74% respectively) than alanine and valine (16 and 29 %, respectively), thus indicating that B. subtilis esterase prefers aromatic side chains. Actually, the dipeptide substrate (BocVal-Gly-OtBu) that remained unaffected under these conditions confirmed the evidence. 4. CONCLUSION The claimed versatility of the tert-butyl group as protecting groups is enhanced by the recently discovered methodologies for its introduction and removal both on alcohols and acids. The use of an appropriate Lewis acids, the aid of microwave irradiation or the use of heterogeneous catalysis made these protocols operatively simpler and under milder and more environmentally benign conditions, so enlarging their application to sensitive molecules. Therefore the statement that tert-butyl ether was one of the most underused alcohol protecting groups, owing to the conditions required for its formation and deprotection, that was stated at the beginning of this review, now seems less appropriate. Also recently introduced ester cleavage protocols have overcome the classical drawbacks that these reactions suffered from. However, this research field is not yet complete and further contributions from chemists are expected in the future. LIST OF ABBREVIATIONS ANIC MTBE Boc2O Boc MW Cbz = = = = = = Azienda Nazionale Idrogenazione Carburanti methyl tert-butyl ether di-tert-butyldicarbonate tert-butoxycarbonyl (CMe3OC=O) microwave benzyloxycarbonyl (PhCH2OC=O)

GTBE ETBE WHSV LHSV LDA EWG Fmoc TfO Gly Ala Val

= = = = = = = = = = =

glycerol tert-butyl ether ethyl tert-butyl ether Weight Hourly Space Velocity Liquid Hourly Space Velocity lihium diisopropylamide electron withdrawing group 9-fluorenylmethoxycarbonyl Trifluoromethanesulfonate (triflate) glycine alanine valine

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Received: July 27, 2010

Revised: November 06, 2010

Accepted: December 13, 2010