Nitrogen diethyl azodicarboxylate

Attack on Nitrogen. A variety of cyclic derivatives of phosphorous acid have been converted into spirophosphoranes (51), using diethyl azodicarboxylate as the condensing agent,42 probably by initial addition to nitrogen to give (50). Several... 

Oxidation of hydrazines to diazines. Propargylic hydrazines are oxidized rapidly and efficiently in CH3OH at 0° by 4-methyl-l,2,4-triazoline-3,5-dione (MTAD) or diethyl azodicarboxylate (DEAD) with evolution of nitrogen to provide the corresponding allenes in 50-70% yield. The reaction occurs with high stereospecificity, and can be used to obtain optically active allenes (equation I).1... 

A related synthesis of 3-substituted fervenulins (394) uses an azo group at the 5-position of the pyrimidine precursor (393) instead of a nitroso group <81H(16)559>. Finally, yet another type of nitrogen functionality at the pyrimidine 5-position is that shown in (396), introduced by treatment of a pyrimidine (395) with diethyl azodicarboxylate. Cyclization of (396) using nitrobenzene or lead tetraacetate affords fervenulin (394) or toxoflavin (397) derivatives <76JCS(Pl)2398>. All these reactions are shown in Scheme 31. 

Relatively acidic indoles such as 44 can be alkylated on nitrogen using an alcohol and diethyl azodicarboxylate (DEAD), i.e. Mitsunobu reaction conditions (Scheme 11). 

S,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexyl 4-nitrobenzoate. A 250-mL, three-necked, round-bottomed flask is equipped with a stirring bar, nitrogen inlet, rubber septum, and thermometer. The flask is charged with 3.00 g of (lR,2S,5R)-(-)-menthol (19.2 mmol), 12.9 g of 4-nitrobenzoic acid (77.2 mmol), 20.1 g of triphenylphosphine (PPh3> (76.6 mmol) (Note 1), and 150 mL of tetrahydrofuran (Note 2). The flask is immersed in an ice bath, and 12.1 mL of diethyl azodicarboxylate (77 mmol) is added dropwise at a rate such that the temperature of the reaction mixture is maintained below 10°C (Note 3). Upon completion of the addition (Note 4), the flask is removed from the ice bath and the solution is allowed to stir at room temperature overnight (14 hr) and subsequently at 40°C for 3 hr (Note 5). The reaction mixture is... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

The synthetic potential of a simple method for the direct introduction of nitrogen into the 5-position of the pyrimidine ring is illustrated by the synthesis of 1,3-dimethyluric acid (15) from 1,3-dimethyluracil-6-amine by reaction with diethyl azodicarboxylate, reduction to 5-[(ethoxycarbonyl)amino]-l,3-dimethyluracil-6-amine, and thermal ring closure. "... 

Annulation of aminomethyl and ring-nitrogen functions with ethyl acetimi-date hydrochloride gives a good yield of a dihydroimidazo compound [3736]. Glyddylaldehyde reacts with guanine derivatives to give the linear tricyclic pr uct [3066]. 6-Aminopyrimidine-2,4-diones are converted into purines by reaction with diethyl azodicarboxylate [2914]. The chemistry of a-halo-aldehydes and -ketones has been reviewed [B-4S, 2348]. 

Diethyl azodicarboxylate can join two ring-carbon atoms through a nitrogen atom. An alternative is to treat the compound with nitrous acid so as to connect the two rings through an iV-oxide function. Both methods can give good yields. 

Purines Fusion of the 6-benzylaminouracil (1) with 3 eq. of diethyl azodicarboxylate (DAD) (2) at 170-180° for 2 hr. gives the purine 8-phenyl-theophylline (4) in 71% yield. Use of 1 eq. of DAD gives a Michael-type adduct (3), which is not converted by thermolysis into (4). However, when it is heated with DAD, (4) is obtained, but in lower yield. It is suggested that DAD acts as a dehydrogenation reagent to form (a), which cyclizes immediately to the purine. The reagent also supplies the new nitrogen atom in (4). Yields of purines... 

Tetrazoles are usually prepared by the reaction of an azide with a nitrile, or an activated amide tri-n-butyltin azide and trimethylsilyl azide are more convenient and safer reagents than azide anion is some cases. The second example shown illustrates the use of a cyanoethyl group as a removable protecting group for amide nitrogen. Other variations on this method from nitriles include the use of triethylammonium chloride (instead of ammonium chloride) to avoid the possible sublimation of potentially explosive azides, and the use of micelles as reaction media. Amides can be activated with trifluoromethanesulfonic anhydride, or via formation of the thioamide, or by the use of triphenylphosphine with diethyl azodicarboxylate the equivalent imidochloride will react under phase transfer conditions. ... 

Oxepan and other oxygen- or nitrogen-containing saturated heterocycles can be prepared in high yield by the dehydrative coupling of aamino-alcohols, using diethyl azodicarboxylate and triphenylphosphine. The synthetically useful oxepin-2,7-diones (muconic acid anhydrides) can be conveniently prepared by the oxidation of ortho-henzoquinones with w-chloroperoxybenzoic acid. °... 

Additional examples of oxidations at a nitrogen center inciude the foiiowing the PhI(OAc)2-induced oxidation of aromatic amines to imines appiied for deprotection of protected amino diois [512], N-acylation of 1,3-disubstituted thioureas using PhI(OAc)2 [513], PhI(OAc)2-promoted oxidation of 1,2-dicarbethoxyhydrazine to diethyl azodicarboxylate as a key step in an organocatalytic Mitsunobu... 

The acetate of this alcohol is used in a Diels-Alder reaction with the interesting dienophile DEAD (diethyl azodicarboxylate—in orange). The product is formed in excellent yield and has the trans stereochemistry that was predicted. The amide nitrogen atoms are planar, so there is no question of stereochemistry there. DEAD itself can equilibrate rapidly between E and Z isomers, but the E predominates. 

A review containing 123 references on recent mechanistic and theoretical studies of hetero-Diels-Alder reactions has been presented. The hetero-Diels-Alder reactions of homochiral 1,2-diazabuta-1,3-dienes with diethyl azodicarboxylate are accelerated by microwave irradiation to produce the corresponding functionalized 1,2,3,6-tetrahydro-l,2,3,4-tetrazines. " The transition structures for hetero-Diels-Alder reactions involving the heteroatoms O, S, and N in dienes and also in dienophiles were determined at the MP2 and the hybrid DPT levels of theory. The activation volume of the Diels-Alder reaction between dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate and hex-l-ene indicates the conservation of all four nitrogen atoms in the transition state. " 4-n-Propyl-l,2,4-triazoline-3,5-dione reacts with cyclopentadienes, cyclohexadienes, and cycloheptadienes to yield 4 + 2-cycloadducts. ... 

Almost simultaneously, two groups reported for the first time the direct organocata-lyzed a-amination of aldehydes using (5)-proline (20) and different azodicarboxy-late derivatives as the electrophilic nitrogen source (Schane 4.4). In the work of J0rgensen s group [13], the reaction was carried out in methylene chloride at room temperature using diethyl azodicarboxylate (DEAD, 18a, R =Et) as electrophile. 

Diazo Compounds. Diazomethane reacts immediately with 1 dissolved in diethyl ether in a regioselective manner to give 2,5-dihydro- 1,3,4-thiadiazole (17) as a relatively stable sohd. This confound is a superior precursor of the reactive thiocarhony 1 5-methylide (8, eq 9) as it smoothly eliminates nitrogen at 45 °C. In the absence of an appropriate interceptor, thiirane 9 is formed. In the presence of electron-deficient dipolarophiles, diverse five-membered spiro-heterocycles (18) are formed via 1,3-dipolar cycloaddition (eq 9).22.23 Representative examples of dipolarophiles leading to 18 in high yield are DMAD, TV phenyl maleinimide, chloral, dimethyl azodicarboxylate, adamantanethione, as well as 1.21... 

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