1- Hydroxybenzotriazoles

With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

This derivative is prepared from an A-protected amino acid and the anthrylmethyl alcohol in the presence of DCC/hydroxybenzotriazole. It can also be prepared from 2-(bromomethyl)-9,10-anthraquinone (Cs2C03). It is stable to moderately acidic conditions (e.g., CF3COOH, 20°, 1 h HBr/HOAc, / 2 = 65 h HCl/ CH2CI2, 20°, 1 h). Cleavage is effected by reduction of the quinone to the hy-droquinone i in the latter, electron release from the —OH group of the hydroqui-none results in facile cleavage of the methylene-carboxylate bond. The related 2-phenyl-2-(9,10-dioxo)anthrylmethyl ester has also been prepared, but is cleaved by electrolysis (—0.9 V, DMF, 0.1 M LiC104, 80% yield). ... 

A-Hydroxybenzotriazole, trifluoroethanol, it. Trityl and Nps (2-nitrophen-ylsulfenyl) groups are also cleaved under these conditions. 

Hydroxybenzotriazole hydrate (HOBt) [2592-95-2] M 135.1, m 159-160 . Crystd from aqueous EtOH or water. [Dryland and Sheppard J Chem Soc Perkin Trans 1 125 1986.]... 

HOAt, 7-aza-l-hydroxybenzotriazole HATU (CAS Registry No. 148893-10-1), A-[(dimethylamino) (3//-1,2,3-triazolo(4,5- )pyridin-3-yloxy)methylene]-A-methyl-methanaminium hexafluorophosphate, previously known as G-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate. [Note Assignment of structure to HATU as a guanidinium species rather than as a uronium species, i.e., attachment of the (Mc2NC=NMe2) unit to N3 of 7-azabenzotriazole 1-A-oxide instead of to the O, is based on X-ray analysis (ref. 33b)]. 

There was never any doubt that the major tautomer in the case of in-dazole 27 is the IH-one 27a (Scheme 16), and C chemical shifts compared with those of the two V-methyl derivatives confirmed that this is the case in DMSO-dg (770MR716). NMR has been used to determine the equilibrium isomeric composition of N-CHROH, N-C(CH3)20H, N-COCH3 and N-Si(CH3)3 derivatives for azoles and benzazoles, the conclu-sipn being that this composition parallels the annular tautomeric composition [78JCS(P2)99]. The tautomerism of 1-hydroxybenzotriazole was also studied... 

A side chain carboxyl group in perhydropyrido[l,2-a]pyrazines was obtained from an ester group by acidic or alkalic hydrolysis. A side chain carboxyl group was converted into a carboxamide group by the treatment with an amine in the presence of 1-hydroxybenzotriazole (OOJAP(K)OO/ 86659). 

Saponification next frees the carboxy group for condensation with -butyl 7-aminocephalosporinate mediated by dicyclohexyl-carbodiimide and 1-hydroxybenzotriazole. The synthesis is... 

Photosensitive functions are in many cases also heat sensitive, so the preparation of photosensitive polyimides needs smooth conditions for the condensations and imidization reactions. Some chemical reactants, which can be used for polyamide preparation, have been patented for the synthesis of polyimides and polyimide precursors. For example, chemical imidization takes place at room temperature by using phosphonic derivative of a thiabenzothiazoline.102 A mixture of N -hydroxybenzotriazole and dicyclohexylcarbodiimide allows the room temperature condensation of diacid di(photosensitive) ester with a diamine.103 Dimethyl-2-chloro-imidazolinium chloride (Fig. 5.25) has been patented for the cyclization of a maleamic acid in toluene at 90°C.104 The chemistry of imidazolide has been recently investigated for the synthesis of polyimide precursor.105 As shown in Fig. 5.26, a secondary amine reacts with a dianhydride giving meta- and para-diamide diacid. The carbonyldiimidazole... 

Dimethoxy-6-quinoxalinamine (125, R = H) gave 6-lauramido-2,3-dimethoxy-quinoxaline [6-dodecanoylamino-2,3-dimethoxyquinoxalme 125, R = Me-(CH2)ioCO] [Me(CH2)ioC02H, (C6HnN=)2C, 1-hydroxybenzotriazole hydrate, no further details 87%]. ... 

Fig. 6 Commonly used additives and coupling reagents. DCC dicyclohexylcarbodiimide, HOSu A-hydroxysuccinimide, HOBt 1 -hydroxybenzotriazole, HOAt 1 -hydroxy-7-azabenzotriazole...

---