Azidoformates

The use of azidoformates as protecting groups deserves special comment. Increased importance has been attached to the -butoxy-carbonyl (BOG) function as a protecting group for amines due to the ease with which it may be introduced and removed ° . Acylation may be carried out under mild conditions with -butoxy-carbonyl azide and subsequent removal of the BOG group may be 

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The /-butoxycarbonyl group (Boc, "t-box ) has been eMens vely used in peptide synthesis, and Boc derivatives of many amino acids are commercially available. The customary reagent for the preparation from the amine is t-butyl azidoformate in water, dioxane/water, DMSO, or DMF. The cleavage by acids of medium strength proceeds with concomitant loss of isobutene and carbon dioxide (L.A. Carpino, 1957, 1973 see section 4.1.2.2). 

Metallic Pd is a good catalyst for the conversion of the primary azide 34 into the nitrile 35 in the presence of a hydrogen acceptor such as diphenylacety-lene[33]. By this method, organic halides can be converted into nitriles without increasing the carbon number. Reaction of the azidoformate 36 with an allylic... 

Aluminum chloride [7446-70-0] is a useful catalyst in the reaction of aromatic amines with ethyleneknine (76). SoHd catalysts promote the reaction of ethyleneknine with ammonia in the gas phase to give ethylenediamine (77). Not only ammonia and amines, but also hydrazine [302-01-2] (78), hydrazoic acid [7782-79-8] (79—82), alkyl azidoformates (83), and acid amides, eg, sulfonamides (84) or 2,4-dioxopyrimidines (85), have been used as ring-opening reagents for ethyleneknine with nitrogen being the nucleophilic center (1). The 2-oxopiperazine skeleton has been synthesized from a-amino acid esters and ethyleneknine (86—89). 

Among the less widely exploited interconversion processes are those involving thermal reactions with ethyl azidoformate, which convert furan into A-ethoxycarbonyl-A -pyrrolin-2-one, and thiophenes into A-ethoxycarbonylpyrroles (Scheme 96a) (64TL2185). The boron trifluoride catalyzed reaction of l,3-diphenylbenzo[c]furan with A-sulfinylaniline results in the replacement of the oxygen by an iV-phenyl group (Scheme 96b) 63JOC2464). 

The diphenylmethyl carbamate, prepared from the azidoformate, is readily cleaved by mild acid hydrolysis (1.7 N HCl, THF, 65°, 10 min, 100% yield). ... 

Tests conducted by the Eastman Kodak Company have shown that tert-butyl azidoformate [Formic acid, azido, -butyl ester], also known as iert-butoxy carbonyl azide and 1-BOC azide, is a thermally unstable, shock-sensitive compound (TNT equivalence 45%). 

A number of less-hazardous reagents that can be substituted for tert-hutyl azidoformate in tert-butoxycarbonylation reactions are available including 2-(te/t-butoxycarbonyloxyimino)-2-phenylacetonitrile (Aldrich Chemical Company), 0-teri-hutyl N-phenyl thiocarbonate (Eastman Organic Chemicals), di-butyl dicarbonate and tert-butyl phenyl carbonate. ... 

The functionalized allene, DIMETHYL 2,3-PENTADIENEDIOATE, the first in the series, is an intriguing substrate for various addition and cycloaddition reactions. Finally, a new reagent, DI-ferf-BUTYL DICARBONATE, for he formation of A-f-BOC derivatives which eliminates the use o the hazardous fert-BUTYL AZIDOFORMATE (WARNING) is intrqduced. 

The photolytic and thermolytic decomposition of azides in the presence of olefins has been applied to aziridine synthesis. However, only a limited number of steroid aziridines have been prepared in this manner. The patent literature reports the use of cyanogen azide at ca. 50° for 24 hours in ethyl acetate for the preparation of an A-nor- and a B-norsteroidal aziridine. The addition is believed to proceed via a triazoline. The reaction of cholest-2-ene with ethyl azidoformate takes place in a nonselective manner to produce a mixture of substances, including C—H insertion products. 

These base-sensitive protective groups were introduced from the chloroformate or azidoformate. They are more sensitive to base than is the Fmoc group. Cleavage times with 0.2 mL of piperidine to 0.1 mmole of urethane in 5 mL of CHCL at It occur as follows Climoc, <10 min Bimoc, <14 h Fmoc, 18 h. °... 

Analogously to ynamines and o, /3-acetylenic ketones, 4-aminobut-3-yn-2-ones react with 1,3-dipoles (68HCA443 73HCA2427 92KGS867). The reaction of 4-dimethylaminobut-3-yn-2-one with diphenylketene follows a route of [2-1-21-cycloaddition (30°C, THF, 1 h) to give 2-acetyl-3-dimethylamino-4,4-diphenyl-cyclobut-2-en-l-one (377) in 15% yield. With ethyl azidoformate (30°C, THF, 3 h), the tiiazole 378 is formed in 82% yield, whereas with phenyl isocyanate, the quinoline 379 is the product (by a [2- -4] scheme) in 70% yield (68HCA443). 

On the other hand, poly(ethoxycarbonylimino-4-vi-nylpyridinium ylide) (Scheme 13) was prepared essentially by the same method from 1-ethoxycarbonylimino-pyridinium ylide, as described by Hafner [15] from the reaction of poly (4-vinylpyridine) with nitrene, generated from the pyrolysis of ethyl azidoformate. 

The nitrene can be generated by a variety of methods, the most popular being the thermal or photolytic decomposition of azidoformates. Other methods, particularly the base-catalyzed a-elimination of arylsulfonate ion from 7V-[(arylsulfonyl)oxy]urethanes, are useful as they avoid the use of the potentially explosive azido esters. 

A solution of ethyl azidoformate (10 g, 87 mmol) in anhyd benzene (250 mL) was photolyzed at 60-70 C for 60 h, using a high-pressure Hg ultraviolet lamp, whereupon N2 was evolved and the solution became yellow. The benzene and remaining azido ester were removed under reduced pressure, and the yellow-brown oily residue distilled under high vacuum to give a yellow oil yield 8.35 g (67%) bp 46-47 C/5 x 10"3 Torr bp 130 C/0.2 Torr. 

Careful chromatographic and detailed HNMR spectroscopic analysis of the products from the thermolyses of ethyl azidoformate in o-, m- and p-xylene revealed in all cases a mixture of 1 //-azepines.80 In o-xylene, only two of the four possible isomers were separated and characterized, namely, ethyl 4,5-dimethy 1-1 //-azepine-1 -carboxylate (9 %) and ethyl 3,4-dimethyl-l H-azepine-1-carboxylate (7 %). w-Xylene yielded a 2 3 mixture of ethyl 3,5-dimethyl-l//-azepine-1-carboxylate and ethyl 2,4-dimethyl-l//-azepine-l-carboxylate. The 2,4-dimethyl isomer (20 %) can be isolated from the mixture by removal of the 3,5-dimethyl isomer as its Diels-Alder cycloadduct with ethenetetracarbonitrile. p-Xylene gave a mixture of the two possible isomeric azepines which were partially separated by column chromatography. A pure sample of ethyl 2,5-dimethyl-1//-azepine-1-carboxylate (26%) was obtained from the mixture by selective decomposition of the 3,6-dimethyl isomer with refluxing alcoholic potassium hydroxide. 

Some degree of regioselectivity can be imposed on l//-azepine formation if the arene has substituents of high steric demand.63 For example, the thermolysis of ethyl azidoformate in a tenfold molar excess of 1,4-di-fert-butylbenzene yields a 95 5 mixture of the di-zerr-butyl-l//-azcpincs 3 and 4, crystallization of which yields the pure 3,6-di-/er/-butyl isomer 3. 

The products from the thermolyses of other alkyl and aryl azidoformates in 1,4-di-tm-butylbenzene are unpredictable. In some cases, e.g. with cyclopropylmethyl, tert-butyl and 4-methoxyphenyl azidoformates, only the corresponding 3,6-di-/< rt-butyl-l//-azepines are... 

The concentration of alkyl azidoformate used in these decompositions is important since with an excess (0.5 molar equiv) of azide, thermolysis at 130°C results in the formation of 1 2 1 //-azepine (methoxycarbonyl)nitrene adducts as the major products.145,146... 

Thermolysis of ethyl azidoformate in a mixture of ethylbenzene and dichloromethane, a known singlet nitrene stabilizer, failed to improve the yield of the 1//-azepine.148... 

Surprisingly, in view of the use of hexafluorobenzene as an inert solvent for (ethoxycar-bonyljnitrene insertions into alicyclic C —H bonds,149 the thermolysis, or photolysis, of ethyl azidoformate in an excess of hexafluorobenzene yields hexafluoro-1//-azepine 7.150... 

The metalloporphyrin-catalyzed decomposition of ethyl azidoformate in the presence of an arene has been investigated but with little success in improving the yields of the 1 //-azepines.151 The nickel and copper complexes had no effect, whereas the cobalt-tetraphenylporphyrin complex accelerated the decomposition rate of the azido ester but produced more A-arylurethane rather than 1//-azepine. 

Intramolecular acylnitrene-induced ring expansions of arenes are of great interest for the synthesis of novel 1//-azepines. Benzyl azidoformates, when subjected to spray-vacuum pyrolysis (SVP),152 yield l//,3//-oxazolo[3,4-a]azepin-3-ones which dimerize spontaneously 153,154 however, 2,6-dichlorobenzyl azidoformate yields the thermally stable (< 100 C) 5,9-dichloro-1 //,3//-oxazolo[3,4-a]azepin-3-one (8).154... 

In contrast, flash-vacuum pyrolysis (FVP)155 or spray-vacuum pyrolysis (SVP)154 of the homologous phenethyl azidoformates yield, in every instance except for the 4-cyano and 4-nitro-derivatives, the thermally stable [1,3]oxazino[3,4-a]azepines 9 accompanied by lesser amounts of the oxazolidinones 10, formed by nitrene insertion at the benzylic carbon center. 

Biphen-2-yl azidoformate (11) on SVP yields a mixture of 12 and 13, the products of nitrene insertion at the 1,2-position of the adjacent phenyl ring, and at the vacant ort/to-position, respectively.156... 

An elegant extension of these intramolecular acylnitrene-induced ring expansions has been used for the synthesis of cyclopent[h]azepines.2 2-Haloindan-l-yl azidoformates 14 (X = Cl, Br), when subjected to pyrolysis at 300 °C in a hot tube packed with calcium oxide and copper turnings, produce cyclopent[6]azepine (15), as a dark turquoise oil, in excellent yield. Lesser yields (30 and 50%, respectively) of the 4-bromo and 3-methoxy derivatives can be similarly obtained. 

Methyl 3,6-di-fert-butyl-1 //-azepine-1 -carboxylate (8), on heating with one equivalent of methyl azidoformate, yields a separable mixture of 2,6-and 2,8-diazabicyclooctadienes 10 and 11.145 Initial addition of the nitrene to C4-C5 of the azepine ring, followed by a [1,3]-C or [1,3]-N shift in the resulting azahomoazepine 9, accounts for the products. 

In the formation of tert-butyl azidoformate by the addition of phosgene to alcohols followed by the addition of Na nitride or hydrazoic acid in the presence of pyridine, reaction of phosgene with the azide can cause the formation of expl carbazide (Ref 9)... 

The triazoles previously obtained from jS-keto-ylides and acyl azides or ethyl azidoformate are the 2-acyltriazoles (80) formed by isomerization under the basic conditions of the initially formed 1-substituted triazoles (79). The latter can be isolated in some cases if the reactions are interrupted. Aryl mono- and bis-azides have also been used in the preparation of the triazolcs (81). 

The nitrenes that most consistently give addition and insertion reactions are carboalkoxynitrenes generated from alkyl azidoformates. 

Reacts with vapors of sodium with luminescence at about 260°C. Reacts explosively with thionyl chloride or potassium reacts violently with hexafluoro isopropylidene, amino lithium, ammonia, and strong acids reacts with tert-butyl azidoformate to form explosive carbide reacts with 24-hexadiyn-l, 6-diol to form 2, 4-hexadiyn-l, 6-bischloro-formate, a shock-sensitive compound reacts with isopropyl alcohol to form isopropyl chloroformate and hydrogen chloride thermal decomposition may occur in the presents of iron salts and result in explosion. 

The preparation of N-carbethoxy-8-azabicyclo [5.1.0] oct-3-ene (158) from ethyl azidoformate (157) and 1,4-cycloheptadiene through a photolytic reaction, and its palladium(II)-catalyzed multistep rearrangement to N-carbethoxynortropidine (159), has been presented by Wiger and Retting as a new route to the 8-azabicyclo[3.2.1]octene skeleton (87) (Scheme 8). 

In this connection it may be of interest to mention that a wide variety of reagents such as the fatty acid salts of Cu11, Mn, Co, Ni, and Al, and magnesium acetylacetonate were reported to have no effect upon the rate of decomposition of w-octadecyl azidoformate in diphenyl ether solution 58>. 

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