Di-t-butyl Dicarbonate

[24424-99-5]  · C10H18O5  · Di-t-butyl Dicarbonate  · (MW 218.25)

(efficient t-butoxycarbonylating agent for amines,1,2 phenols, and thiols; t-butoxycarbonylation of alcohols, amides,3 lactams, carbamates4 and NH-pyrroles5 occurs in the presence of 4-dimethylaminopyridine)

Alternate Names: di-t-butyl pyrocarbonate; Boc anhydride; Boc2O.

Physical Data: mp 22-24 °C; bp 56-57 °C/0.5 mm Hg; fp 37 °C; d 0.950 g cm-3; nD20 1.4103.

Solubility: insol cold H2O; sol most organic solvents such as decalin, toluene, CCl4, THF, dioxane, alcohols, acetone, MeCN, DMF.

Form Supplied in: colorless liquid; widely available.

Analysis of Reagent Purity: IR 1810 and 1765 cm-1; NMR 1.50 (CCl4).

Preparative Method: prepared by the action of Phosgene on potassium t-butyl carbonate, followed by conversion of the obtained di-t-butyl tricarbonate under the action of basic catalysts such as 1,4-Diazabicyclo[2.2.2]octane.6

Handling, Storage, and Precautions: the liquid is flammable and must be stored in a refrigerator in the absence of moisture. Do not heat above 80 °C.

t-Butoxycarbonylation of Amines.

Owing to the instability of the corresponding chloride (t-Butyl Chloroformate), the Boc2O reagent is widely used for the introduction of the t-butoxycarbonyl amino protecting group (Boc). This group is easily removed under moderately acidic conditions such as treatment with Trifluoroacetic Acid, or by thermolysis. The Boc-NHR group is not hydrolyzed under basic conditions and is inert to many other nucleophiles.1 Therefore the use of this amino protecting group is not limited to amino acid and peptide synthesis; it has been extended to the synthesis of amino sugars, alkaloids, etc. The great importance of the t-butyl carbamate function in peptide synthesis is not only due to the ease of its cleavage, but also to the fact that the oxazolones formed from the activated N-alkoxycarbonyl amino acids do not usually epimerize (racemize) during coupling with amines.7

Boc2O reacts smoothly and rapidly with amino compounds in organic solvents, or aqueous organic solvent mixtures, to form pure derivatives in high yields, the only byproducts being the innocuous and easily removable t-butanol and carbon dioxide (eq 1). Innumerable examples are available.8-11 Hydroxylamine slightly accelerates the reaction through the in situ formation of the Boc-ONH2 intermediate.12 The reaction is also accelerated by sonication of the amine salts.13

Aliphatic,14 alicyclic,15 aromatic,16,17 and heterocyclic amines18,19 have been t-butoxycarbonylated under a variety of conditions. Anilines are sometimes heated at reflux in THF to obtain the corresponding Boc derivatives in good yields. However, t-butoxycarbonylation also occurs at rt,17 and 4-aminobenzoic acid reacts in DMF/aq NaOH at rt.20 The Boc-NHR substituent is an ortho-directing group in heteroatom-facilitated lithiations of aromatic and heterocyclic amines.16,18,19,21 Reaction of the resultant carbanions (eq 2), as well as that of the analogous benzylic carbanions, with electrophiles is a powerful method for the synthesis of substituted anilines and heterocycles.16,22

Asymmetric deprotonation of Boc-pyrrolidine with s-Butyllithium/(-)-Sparteine gives a chiral organolithium reagent, which undergoes reaction with electrophiles to give enantiomerically enriched products.23 The sequence of equatorial a-lithiation followed by an electrophilic substitution of a series of N-Boc cyclic amines provides amines which are substituted adjacent to the nitrogen atom.15

A suspension of 4-dimethylaminopyridinium fluoroborate in ethyl acetate reacts with Boc2O to give the corresponding 1-t-butoxycarbonyl-4-dimethylaminopyridinium salt, which is an efficient water-soluble agent for the t-butoxycarbonylation of amines (eq 3).24

Interesting chemo- and regioselective alkoxycarbonylation of polyfunctional substrates, e.g. diamines, amino alcohols, and amino acids, can be achieved under mild conditions. Treatment of a,o-alkanediamines (6-10 molar excess) with the reagent in dioxane or acetone as solvent leads to the corresponding mono-Boc diamines in 75-90% yields (eq 4).25,26

Nε-Boc-L-lysine has been selectively prepared from the copper complex of lysine.27 This complex, as well as that of Nd-Boc-L-ornithine, has been directly benzyloxycarbonylated to give the corresponding a-Cbz-ε-Boc amino acids (eq 5).28

In CH2Cl2 at low temperature, selective t-butoxycarbonylation of a b-amino- in the presence of an a-amino-ester function has been recently realized (eq 6).29

The substitution of a secondary amino group in the presence of a primary amine has been performed by an indirect route: formation of the labile Schiff base of the primary amine and then t-butoxycarbonylation of the secondary nitrogen (eq 7).30 Selective protection of polyamines may also be achieved by an indirect route in the presence of DMAP (see below).

The Boc2O reagent has been widely used for the N-protection of amino acids and peptides. When a carboxylic acid function is present in the molecule, 1 equiv of base (NaOH, Et3N, Triton B) is necessary (eq 8).10,11,31

To avoid loss of the O-labeling, trialkylammonium salts of amino acids have been t-butoxycarbonylated in dry methanol or DMF.32 N-t-butoxycarbonylation of an alkaline labile and hindered 2,2-dimethylthiazolidine-4-carboxylic acid has been performed in acetonitrile (eq 9).33

In the presence of pyridine, a free carboxylic function reacts with the reagent to give a mixed anhydride (see below). This reaction also occurs during the acylation of an amino acid salt with Boc2O and is responsible for the formation of small amounts of dipeptide byproducts by aminolysis of the mixed anhydride intermediate (eq 10).34

t-Butoxycarbonylation of phenolic amino acids in aqueous Potassium Hydroxide gives the N,O-bis-Boc derivatives.35 Under phase-transfer conditions, selective N-t-butoxycarbonylation of tyrosine ethyl ester has been observed (see below). The SH group of cysteine,36 the imidazole of histidine,37 and even the guanidine function of arginine38 have been acylated. Boc2O has been used for the chemical modification of histidine residues of proteins.39 For the t-butoxycarbonylation of insulin, Boc2O is much more reactive than the corresponding succinimidyl and p-nitrophenyl esters.40 Bamberger ring-cleavage of the imidazole nucleus slowly occurs in the presence of Potassium t-Butoxide.41 Selective N-protection of amino alcohols is also easily performed (eq 11).42

At pH 10.3, hydroxylamine itself gives the O-substituted product,12 whereas treatment of N-alkylhydroxylamines in dioxane furnishes the N-Boc derivatives (eq 12).43 The O-Boc hydroxylamine12,44 as well as O-Boc oximes45 are themselves efficient t-butoxycarbonylating agents.

Hydrazines and hydrazides are acylated by the reagent.46 The mono-Boc derivatives of hydrazine or phenylhydrazine, obtained in isopropanol, react further with Boc2O in benzene or dioxane to give the (Boc-NR)2 diacylated derivatives. Regioselective Na-protection of ethyl hydrazinoacetate is performed at 0 °C and the product used for the synthesis of hydrazino peptides (eq 13).47

Boc-amines can also be prepared directly from azides by hydrogenation in the presence of Boc2O (eq 14).48

The alkylation of Boc-amines, particularly that of the more acidic Boc-anilines17 and the selective alkylation of N-Boc amino acids,49-51 has been done by using an alkylating agent and Sodium Hydride or Silver(II) Oxide as a base. For the N-perbenzylation of N-Boc peptides a P4-phosphazene base (see Phosphazene Base P4-t-Bu) has been used at -100 °C.52

Exchange of Amino-Protecting Groups.

N-Benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc) amino protecting groups are also widely used in peptide synthesis.2 The choice of protecting groups, and hence of the conditions for their cleavage (Cbz: hydrogenolysis or HBr/HOAc; Fmoc: piperidine or F-)1 plays a key role in the planning of a synthesis. For instance, orthogonal protection (Boc/Cbz or Fmoc/Boc or Cbz) is of crucial importance in the case of the trifunctional amino acids. For a given peptide segment, chemoselective transformation of an amino protecting group into another one under neutral conditions may be very useful for the synthesis.

In the presence of a slight excess of Boc2O, conversion of a benzyl carbamate into a t-butyl carbamate has been achieved by catalytic hydrogenation,53 or by the use of cyclohexadiene as an hydrogen donor (eq 15).54 The catalytic transfer hydrogenation is the more selective: benzyl and BOM ethers are stable under the reaction conditions. The Cbz -> Boc transformation can also be performed using triethylsilane and a palladium catalyst.53 The replacement of a Fmoc group by a Boc group has recently been achieved by the in situ cleavage of the Fmoc group with Potassium Fluoride in DMF (eq 15).55

t-Butoxycarbonylation of Phenols, Alcohols, Enols, and Thiols.

In alkaline media the nucleophilic phenolate salts are easily t-butoxycarbonylated.35,56 Acylation of p-dimethylsulfoniophenol gives a sulfonium salt which is a new water-soluble t-butoxycarbonylating agent for amino acids.57 Under anhydrous conditions, thiolate salts are also substituted in good yields using the Boc2O reagent.56 Under phase-transfer conditions, t-butoxycarbonylation of phenols as well as enols, thiols, or alcohols can be realized. For phenols, enols, and thiols, K2CO3 (powder)/18-crown-6/THF are the best experimental conditions. Biphasic conditions (Bu4NHSO4/CH2Cl2/aq. NaOH) are also effective with sluggish alcoholic groups.56 Using 1 equiv of Boc2O, selective N-t-butoxycarbonylation of tyrosine ethyl ester can be achieved. N,S-Bis(Boc)-cysteine ethyl ester has also been prepared.56 The t-butoxycarbonylation of alcohols to give alkyl t-butyl carbonates is efficiently catalyzed by DMAP.58

t-Butoxycarbonylation of Amides, Lactams, and Carbamates.

In the presence of 4-Dimethylaminopyridine, Boc2O is a strong acylating agent able to react with the weakly nucleophilic amide and carbamate groups under anhydrous conditions. The reaction probably involves a 1-t-butoxycarbonyl-4-dimethylaminopyridinium ion intermediate (eq 3).24 This enhanced reactivity has led to numerous interesting synthetic applications. A wide range of amides, lactams, and urethanes have been converted to the corresponding Boc derivatives using Boc2O as reagent and DMAP as catalyst.

Secondary amides and lactams react with Boc2O in the presence of both Triethylamine and DMAP in CH2Cl2 to give stable N-t-butoxycarbonylated products (eq 16).3 In the reaction of disubstituted pyrrolidones, the yields are much higher using THF as solvent than with dichloromethane.59

Exhaustive acylation of a series of secondary amides has also been performed with Boc2O in dry acetonitrile at ambient temperature using DMAP as catalyst. The method has some steric limitations. For instance, it is retarded in the case of the ortho-substituted benzamides. The reaction has been extended to the acylation of carbamates and other amide type functions: sulfonamides, sulfenamides, and phosphinamides.60 b-Lactams are also N-protected in good yields (eq 17).61

Primary carboxamides react with 2 equiv of Boc2O and 1 equiv of DMAP to give isolable N-acylimidodicarbonates which are acylating agents for amines (eq 18).62 Formamide itself furnishes the unstable di-t-butyl N-formylimidodicarbonate (eq 19).63

Grieco has shown that the regioselective hydrolysis or methanolysis of N-t-butoxycarbonyl derivatives of amides and lactams affords the corresponding carboxylic acids or methyl esters, respectively (eq 16).3 1,1,3,3-Tetramethylguanidine efficiently catalyzes the methanolic cleavage.64 Grieco's method has been applied to a formal synthesis of gabaculine, in which Lithium Hydroxide treatment induces both sulfoxide elimination and lactam cleavage (eq 20).65

Other regioselective attacks at the acyl function are known. Aminolysis of substituted pyrrolidones gives the corresponding N-Boc g-amino acid amides.59 The N-Boc five- to eight-membered lactams are cleaved with Grignard reagents at the endocyclic carbonyl group to give o-Boc-amino ketones,66-68 which can be deprotected with TFA and cyclized with NaOH to yield cyclic imines.67 Regioselective ring opening of the N-Boc-pyroglutamate ethyl ester with the lithium enolates of carboxylic esters, dithiane anion, alcohols, amines, and thiols occurs without epimerization.69-71 Selective cleavage of cyclic carbamates gives N-protected amino alcohols (eq 21). In this reaction, methyl ester substituents are not transformed into acids by using Cesium Carbonate as a base.72

The selective deacylation of N-Boc carboxamides has also been achieved by aminolysis to give N-Boc amines. 2-Diethylaminoethylamine in acetonitrile is particularly convenient, but other conditions such as hydrazine in methanol can also be used.64,73 Aminolysis of di-t-butyl N-formylimidodicarbonate affords di-t-butyl imidodicarbonate, HN(Boc)2 (eq 19).63 This compound, as well as the unsymmetrical benzyl t-butyl imidocarbonate, has been used as a substitute for Phthalimide in the Gabriel and Mitsunobu reactions to give primary amines. Compared to the classical method, which requires the hydrazinolysis of the phthaloyl protecting group, the main advantage of these novel Gabriel reagents is the much milder and rather specific conditions for the final deprotection step.74 The lithium salt of HN(Boc)2 has also been used in a palladium-catalyzed allylic amination.75 Labeled di-t-butyl imidodicarbonate leads to 13C and 15N glycine derivatives.76 Alkylation with triflates prepared from a-hydroxy acid esters gives 15N-labeled chiral Boc-amino acids suitable for the synthesis of labeled peptides.77

t-Butoxycarbonylation of benzyl or allyl N-Boc or N-Cbz amino acid esters using Boc2O/DMAP gives N-bis(alkoxycarbonyl) amino acid esters. Specific cleavage of the allyl protecting group with Chlorotris(triphenylphosphine)rhodium(I), or hydrogenolysis of the benzyl ester function, respectively, gives Na-benzyloxycarbonyl, Na-t-butoxycarbonyl or Na-di-t-butoxycarbonyl amino acids (eq 22).78,79

The di-t-butoxycarbonyl amino acids have been applied to solution peptide synthesis using the 1,3-Dicyclohexylcarbodiimide or p-nitrophenyl ester method in DMF for coupling79

Reaction of a bis(alkoxycarbonyl)amino acid pyridinium salt with cyanuric fluoride at -30 °C gives a N-bis(alkoxycarbonyl)amino acid fluoride (eq 23). Owing to the high electronegativity and small size of the fluorine atom, this derivative is an efficient acylating agent for amines and pyrrole anions.80 Use of the Vilsmeier reagent instead of cyanuric fluoride leads to a chemically and optically pure N-Boc or N-Cbz amino acid N-carboxy anhydride (Boc- or Cbz-NCA) without the use of phosgene and the unstable t-butyl chlorocarbonate (eq 23).80 Peptide synthesis with these urethane protected amino acid N-carboxy anhydrides (U-NCAs) is a very clean reaction which liberates only CO2 as a byproduct.81

Treatment with Boc2O/DMAPcat allows exhaustive N-t-butoxycarbonylation of some peptides.82 The t-butoxycarbonylation of the internal amide bonds favors the cyclization of the peptides.83 Interestingly, one Boc group can be selectively removed from a bis(Boc)-amine75,76 with a slight excess of trifluoroacetic acid. Use of the Boc2O/DMAPcat/MeCN conditions also allows selective protection of mixed primary-secondary diamines. t-Butoxycarbonylation of a N,N-bis(benzyloxycarbonyl)diamine followed by hydrogenolysis of the Cbz groups furnishes the t-butoxycarbonylated derivative of the primary amino function (eq 24).84 Analogous strategies have been used for the selective indirect acylation of polyamines such as spermidine.85,86

The t-butoxycarbonylation of the sodium salt of thiourea does not require DMAP catalysis. The resulting N,N-bis(t-butoxycarbonyl)thiourea reacts with amines to give bis(t-butoxycarbonyl)guanidines (eq 25).87

Sequential diacylation of 1-guanidinylpyrazole gives the N,N-bis(Boc)-guanidinylpyrazole, which is also an efficient reagent for the conversion of amines to protected monosubstituted guanidines and therefore for the synthesis of arginine-containing peptides from their ornithine counterparts (eq 26).88

N-t-Butoxycarbonylation of Pyrroles and Indoles.

A series of substituted pyrroles and indoles89-92 react smoothly with Boc2O in the presence of catalytic amounts of DMAP in CH2Cl2 or acetonitrile to give the corresponding N-Boc pyrrole or indole derivatives. The N-t-butoxycarbonylation allows direct lithiation a to the indole and pyrrole nitrogen at low temperature. Alternatively, lithium-halogen exchange of N-Boc-2-bromopyrroles generates the N-protected 2-lithiopyrroles (eq 27).91 After reaction with an electrophile, the Boc protecting group is easily removed either by methoxide ion in methanol or by thermolysis.90,93

In the reaction with Boc2O/DMAP, Na-Boc-tryptophan methyl ester affords the Na,Nin-di-Boc derivative in almost quantitative yield. This product has been used in peptide synthesis. Moreover, selective cleavage of the Na-Boc group is possible in the presence of the Nin-Boc function by using 2.7 N HCl in dioxane.94

Activation of the Carboxyl Group. Formation of Esters and Anhydrides.

In the presence of Pyridine in aprotic solvents, the carboxyl function of a carboxylic acid or a N-Boc-amino acid is activated with the Boc2O reagent. The resulting mixed anhydride can react further with one molecule of the starting acid to give a symmetrical anhydride. At an equimolar ratio of the acid and the Boc2O reagent a mixture of the mixed and the symmetrical anhydrides is formed. If 2 equiv of acid are used, the symmetrical anhydride becomes the main reaction product. Addition of certain nucleophilic agents to the Boc2O/carboxylic acid/pyridine mixture leads to the acylation of the nucleophile (eq 28).58

From a preparative point of view, it is essential that Boc2O reacts much more rapidly with the carboxylate function than with the nucleophile. The reaction has been applied to the synthesis of aryl and alkyl esters and anilides such as o-nitrophenyl, benzyl, or trifluoroethyl esters and p-nitroanilides of N-protected amino acids. The formation of esters derived from secondary alcohols (benzhydryl, menthyl, or cholesteryl esters) is accelerated by addition of DMAP. Depsipeptides are obtained in good yields. DMAP is a necessary catalyst for the synthesis of t-butyl esters and the esterification of N-protected amino acids occurs without epimerization.58

t-Butoxycarbonylation of Carbanions.

Preferential C-t-butoxycarbonylation of diethyl acetamidomalonate occurs by treatment with Boc2O/DMAPcat in acetonitrile (eq 29).60 From the reaction of the potassium salt of diphenylphosphinyl isocyanide and Boc2O in CH2Cl2 at -70 °C, the corresponding Wittig-Horner reagent, t-butyl (diphenylphosphinyl)isocyanoacetate, is formed in near quantitative yield.95 Similarly, treatment of a-lithioalkylphosphonates with Boc2O gives C-t-butoxycarbonylated enolates which react with aldehydes to give substituted t-butyl acrylates.96 The lithium salt of the Schiff base derived from the aminomethyldiphenylphosphine oxide reacts with Boc2O at low temperature to give the imine of t-butyl a-(diphenylphosphinoyl)glycinate.97

t-Butoxycarbonylation of Imines.

In previous examples, the acylation occurred either at the amino function30 or at the carbanionic center97 and not at the imine function. However, the reaction of a nucleophilic imine possessing an electron-releasing substituent (Ar = p-MeOC6H4) with Boc2O in ethanol proceeds through the intermediacy of an N-alkoxycarbonyl iminium ion to give an a-ethoxy carbamate (eq 30). As the trapping of the iminium ion by the alcohol is a reversible process, the a-ethoxy t-butyl carbamate is a precursor of the electrophilic N-Boc iminium ion in an intermolecular condensation with propargyltrimethylsilane.98

Related Reagents.

1-(t-Butoxycarbonyl)imidazole; 1-N-(t-Butoxycarbonyl)-1H-benzotriazole 3-N-Oxide; 2-(t-Butoxycarbonyloxyimino)-2-phenylacetonitrile; N-(t-Butoxycarbonyloxy)phthalimide; N-(t-Butoxycarbonyloxy)succinimide; 1-t-Butoxycarbonyl-1,2,4-triazole; t-Butyl Azidoformate; t-Butyl Chloroformate.

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Michel Wakselman

CNRS-CERCOA, Thiais, France

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