Diamidates, symmetrical

Ketone syntheses. Acyl derivatives that favor the arrestment of Grignard reactions beyond the first round include A-acylpyrazoles, acyl hemiacetals, and acyl tributylphosphonium chlorides (generated in situ from RCOCl and Bu,P). The protocol involving Al-methoxy-Al-methyl carboxamides has been extended to the preparation of a-chloro ketones, a-keto amides, and a-diketones (the last two from the oxalyl diamides). Symmetrical diketones are obtained by the Grignard reaction of bis(benzimidazole) methiodides. Note that an analogous reaction of 1,3-disubstituted benzimidazolium salts furnishes aldehydes. ... 

The NMR spectra (300 MHz) of the model diamides 1 and 2, and the polyamide 3, were recorded in trifluroacetic acid-d (TFA-d). Since the xylaramide component of 1-3 is symmetrical, one observes a single average coupling for H2-H2 and Experimental... 

The alkyl substituent meta to the methoxy substituent was easily introduced into the symmetrical diamide 72 by yet another ortholithiation. Allyl electrophiles react poorly with aryllithiums, so the ortholithiated amide 73 was first transmetallated to the Grignard reagent before allylation with allyl bromide to give 74. 

In aromatic compounds bearing two rotationally restricted amide groups, diastereoiso-meric atropisomers can arise because of the relative orientation of the amides. Ortholithi-ation can therefore lead to diastereoselectivity if the ortholithiation forms one of the two diastereoisomers selectively. A simple case is 169, whose double lithiation-ethylation leads only to the C2-symmetric diamide 170, indicating the probable preferred conformation of the starting material (Scheme 85) . 

The biphenyl diamide 171 also displays diastereoselectivity in its ortholithiation-electrophilic quench, giving the C2-symmetric, chiral diastereoisomer of the diamide 172 . 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

Churchill MEA, Tullius TD, Kallenbach NR, Seeman NC (1988) A Holliday recombination intermediate is twofold symmetric. Proc Natl Acad Sci USA 85 4653-4656 Clark EP, Michaels HB, Peterson EC, Epp ER (1983) Irradiation of mammalian cells in the presence of diamide and low concentrations of oxygen at conventional and at ultrahigh dose rates. Radiat Res 93 479-491... 

Conformations of primary, secondary, and tertiary amides of (R,R)-tartaric acid, both symmetrically and asymmetrically substituted, have been studied ciys-tallographically [22, 24, 29, 30-40] Moreover, ab initio studies up to MP2 / 6-31G //RHF/6-31G level [41] for both the diamide and N,N,N ,N -tctramcthyl-diamide of (/ ,/ [-tartaric acid have been carried out [20, 22]. X-ray results have shown that primary and secondary amides of (R,R [-tartaric acid tend to adopt a conformation with the extended carbon chain - the Taa structure. In this Taa conformation both the a-hydroxy-amide moieties form planes and the structure gains stabilization from hydrogen bonding between donors, the NH, and acceptors, the proximal OH groups. Moreover, the Taa structure is favorably stabilized by the attraction of antiparallel local dipoles formed along distal C H and Csp2=0 bonds [18, 21, 22],... 

This chemistry can be very powerful, since the amide product itself offers further possibilities for functionalisation by lithiation. The synthesis of the natural product ochratoxin A (section 9.1) illustrates this point. Two successive ortholithiations of carbamate 210 are used first to introduce one amide group and then a second, by anionic ortho-Fries rearrangement. The symmetrical diamide 211 can be allylated and then cyclised in acid, with concomitant hydrolysis of the second amide and deprotection of the phenol to yield a known intermediate... 

Ring-opening of cyclic anhydride 4 by aminolysis and subsequent formation of the second amide function led to the diamides, 5b. Either the mero-isomer or the ( -symmetrical chiral derivative is thus available in a controlled way.19... 

In 2003, O Shaughnessy and Scott reported the first example of rare-earth metal complexes supported by biaryl diamide ligands as the catalysts for the hydroamination reactions [159]. A series of C2 symmetric secondary diamine proligands L37-L40 were prepared by arylations of (7 )-2,2 -diamino-6,6 -dimethybiphenyl under palladium catalysis. L37 reacted with complexes [Ln N(SiHMe2)2 3(THF)2] to form the biaryl diamide complexes [Ln(L37) N(SiHMe2)2 (THF)2] (Ln = Y (190), La (191), Sm (192)). Deprotonation... 

Disconnection of hydrazine 30a from allopurinol leaves a diamide with an extra aldehyde group 33. Disconnection of that aldehyde leaves a simple and available symmetrical heterocycle that exists in the dihydroxy tautomer 34 and will require a one-carbon electrophile corresponding to the synthon 35. We shall meet reagents for this synthon soon. 

The antiviral antibiotic limocrocin (61) is the pigment produced by Streptomyces limosus [123a] an enzyme inhibitor agams reverse transcriptase [123b]. This is a symmetrical diamide derived from... 

Fig. 12 Phosphate and phosphonate prodrugs based on symmetrical diamidates...

When the amide is derived from an amino acid, achieving a neutral species requires esterificatiOTi of the carboxyl group as well (e.g., 60). After examination of a series of 25 diamidates for activity against HCV [120] and HIV replication, and anti-proliferative effects in several cell lines, it was found that this strategy is sufficient to afford good cellular activity with several different nucleoside analogues [119]. Preparation of symmetrical bisamidates from the symmetrical diesters also has been reported (Fig. 12) [121]. 

Jansa P, Baszczynski O, Dracinsky M, Votruba I, Zidek Z, Bahador G, Stepan G, Cihlar T, Mackman R, Holy A et al (2011) A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate) prodrags of acyclic nucleoside phosphonates and evaluation of their biological activities. Eur J Med Chem 46 3748-3754... 

Oxanilide UV stabilisers of the general form ArNH(C=0)(C=0) NHAr have been known for some time in symmetric [89] and asymmetric [90] forms. Both are available commercially from Clariant as Sanduvor EPU and VSU respectively. Also patented were bis-oxalic acid diamides [91] of basic structure ArNH(C=0)(C=0) NH-R-NH(C=0)(C=0)NHAr. 

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