Electrophilic with azodicarboxylates

An oxidative cyclization, (151) -> (152), with azodicarboxylate (78CC764) is balanced by the synthesis of 5-deazaalloxazines from aryl bis(6-aminouracilyl)methanes, which involves azodicarboxylate in an intermediate electrophilic capacity (153 -> 154) (79CPB2507). Other methods involve reductive cyclizations (72AP751). 

Enamines derived from ketones undergo some of the same reactions described for enol ethers, for example with arenesulfonyloxy carbamates as in Eq. 96120 121 3" and with ethyl azidoformate as in Eq. 98.302 303 The reaction with activated azo compounds occurs readily at room temperature or below and diamination often cannot be avoided with the more electrophilic reagents (Eq. lOl).400,401 The proline-catalyzed reaction of ketones with azodicarboxylic esters, which proceeds by way of the enamines, has been mentioned above (Eq. 91). 

Such phosphazenes could play a role in enantioselective Lewis base-catalyzed transformations (13JA15306, 14CC4319). The catalytic performances of the phosphazene hase 129-HI have been evaluated in the electrophilic amination of2-alkyltetralones 130 with azodicarboxylate. The best conditions employed the use of 10mol% of phosphazene 129-HI and 20 mol% of NaHMDS. The reaction afforded excellent yields and ee, up to 99% and 97%, respectively. However, the position of methoxy groups on the tetralones 130 has a deep influence on enantioselectivity and yield. The 6- and 8-methoxy substituted tetralones 130 require higher temperatures for sufficient conversion 8-MeO-130 gave only 78% conversion and 10% ee at 25 °C (Scheme 34). 

FIGURE 11.1. Chiral secondary amine catalysts used for the enamine mediated electrophilic a-amination of carhonyl compounds with azodicarboxylate esters. 

In another context, excellent enantioselective nickel-catalysed a-ami-nations of N-Boc-oxindoles with azodicarboxylates have been achieved by using chiral Schiff base nickel catalysts. BINAP ligands have also encountered success in asymmetric nickel-catalysed electrophilic a-aminations and also in combination with other metals such as palladium. On the other hand, the use of other sources of electrophilic nitrogen, such as nitroso compounds and iodinanes, in reactions catalysed by nickel has so far not been described. 

Only few procedures for enantioselective animation of enoiates have been developed [256]. The stoichiometric use of several chiral electrophilic animation reagents was plagued by low enantioselectivity [257]. Evans and Johnson developed a first efficient catalytic approach that is based on the reaction of sihcon enoiates with azodicarboxylate derivatives [258]. Thus, silyl enol ethers 526 were reacted with azoimide 527 under catalysis of the copper f-butyl-PHOX complex 216a. The presence of 1 equiv. of trifluoroethanol was crucial for high conversion. 

In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionahzed P-amino alcohols 35 [29, 30], The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30], The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophilic substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-armnation reaction, which selectively forms 36. 

The chemistry of chiral 1,3-dithiane 1-oxides, in particular their use as chiral auxiliaries, has been reviewed <19980PP145>. Some further developments in this field are the stereoselective a-alkylation with alkyl halides <1997T13149> or a-hydrazination with di-fert-butyl azodicarboxylate (DBAD) <2000T9683>. The carbonyl group of 2-acyl-l,3-dithiane 1-oxides was also used as an electrophile (Scheme 82). Interestingly, acyclic enolates react with these substrates to give a 95 5 mixture of anti- and ry -adduct, whereas cyclic enolates produce a mixture of anti- and ry -adduct in 8 92 ratio <2000JOC6027>. 

Some unexpected results were obtained when deprotonation with LDA was followed by reaction with diethyl azodicarboxylate (Scheme 44). The ester 147 was isolated suggesting that this reagent could be considered as a C-electrophile rather than a N-electrophile. However, when this reaction was performed with a 4-monosubstituted /3-sultam, the expected N-addition products 148 were isolated. N-Addition occurs also with 4-phenyl-3/7-l,2,4-triazole-3,5(4/7)dione leading to compound 149 <2004HCA1574>. 

The direct a-amination of aldehydes by azodicarboxylates as the electrophilic nitrogen source can be catalyzed by, for example i-proline 3a, to give the a-hydrazino aldehydes 4 having (R -configuration in moderate to good yields and with excellent enantioselectivities (89-97% ee) (Scheme 2.27) [4]. The optically active a-hydrazino aldehydes 4 are prone to racemization, and it was found beneficial to reduce them directly with NaBFU to stereochemical stable compounds which, by treatment with NaOH, can cyclize to form the N-amino oxazolidinones 5 in a one-pot process. The N-amino group in 5 could be cleaved with Zn/acetone to give the oxazolidinone 6 (Scheme 2.27). 

Stereoselective Electrophilic Amination with Sulfonyloxycarbamates and Azodicarboxylates... 

Azodicarboxylates 4 have been used in the electrophilic reaction with diethyl malonate since 1924 [3] however only recently were these reagents recognized as particularly useful for the introduction of an amino moiety after hydrogenolysis of the hydrazide adduct [3], More recently, chloro nitroso reagents of type 5 have been introduced by Oppolzer [4]. These reagents are particularly reactive, giving... 

The preparation of chiral dialkylazodicarboxylates and their use as electrophilic enolate animation reagents, were first reported in 1995 by Vederas and co-workers [51]. A series of chiral dialkyl (menthyl 97a, bomyl 97b, isobomyl 97c) azodicarboxylates were prepared by conversion of the corresponding alcohols into chloro-formates, condensation with hydrazine and oxidation with IV-bromosuccinimide and pyridine. Compounds 97 were obtained in 35-50% yield (Scheme 45). 

Diethyl azodicarboxylate (DAD) behaves like a reactive electrophilic alkene and attack on a substituted cyclohexanone enamine can occur from an axial or equatorial direction depending on the steric effects in the transition state. For example, DAD reacts with 159 to give 160 by equatorial attack, together with 161 (ratio 1 9), whereas the... 

The electrophilic, aromatic substitution of electron-rich arenes with the electron-deficient azodicarboxylate BTCEAD is a powerful method for the introduction, in a single operation, of a masked hydrazine or amino group.3 4 Several activators can be used for this amination reaction ZnCl2,4 BF3-Et20,4 LiCIO.4,3 and here, trifluoromethanesulfonic acid.5 Trifluoromethanesulfonic acid dramatically increases the rate of the amination reaction and makes possible the use of this methodology with poorly reactive substrates. 

The chemistry of nitrogen electrophiles R R2NX (I) was excellently summarized in 1989Ia. Recent studies in the field of stereoselective electrophilic amination, however, have shown that azidation with sulfonyl azides III, reactions with di-tert-butyl azodicarboxylate (II) and reactions with 1-chloro-l-nitroso reagents IV, are superior to the previously mentioned nitrogen electrophiles. 

Electrophilic Amination of Chiral Enolates with Di-ferf-butyl Azodicarboxylate... 

The procedure outlined here160,11 closely resembles the methodology detailed in Section 7.1.1.1., except for the choice of nitrogen electrophile used, which in this case is the commercially available di-tert-butyl azodicarboxylate (DBAD). The reaction of the lithium derivatives of N-acyloxazolidinones 1 with DBAD affords diastereomerically pure (>300 1) hydrazines 2 in yields exceeding 90%1 a. 

In summary, the electrophilic amination of lithium enolates derived from 1 with di-toT-buty] azodicarboxylate (DBAD) provides an excellent approach to the stereoselective synthesis of a-hydrazino and a-amino acids. 

The diastereoselective electrophilic amination of ketone enolates in 2-substituted 2-acyl-1,3-dithiane 1-oxides 19 with di-/m-butyl azodicarboxylate (DBAD) was reported recently21. The un/i-isomcr, anti-19, led to the major isomer anti-20, while. vyn-19 gave predominantly. 9171-20. 

Thus, benzenediazonium tetrafluoroborate is not the electrophilic aminating reagent of choice, although the diastereoselection in the formation of the new C-N bond is very good. The yields, however, cannot compete with the results obtainable by the use of trisyl azide and di-Ze/7-butyl azodicarboxylate aminations, as shown in the preceding sections. It is possible that some other modified aryldiazonium tetrafluoroborates will prove to be more successful in electrophilic amination reactions. 

Azodicarboxylate esters are the reagents of choice for electrophilic N-amino amination leading to hydrazine derivatives. Besides Grignard reagents and alkyl or aryl lithium compounds,enolates and silyl enol ethersderived from ketones have been aminated by this method. In particular, di-r-butyl azodicarboxylate has been reacted with a variety of chiral enolates (Scheme I9)i03->o and chiral silyl ketene acetds (Schemes 20 and to afford a-hydrazino acid derivatives with high dia-... 

In the Mitsunobu reaction, a chiral 2° alcohol and a carboxylic acid are converted to an ester with clean inversion at the electrophilic C. The reaction requires PI13P and Et02CN=NC02Et (diethyl azodicarboxylate, DEAD). It is usually carried out by adding DEAD slowly to a mixture of the alcohol, PI13P, and the nucleophile in its protonated form. 

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