Coupling with triphosgene

A cyclic process for producing triphosgene, in which dimethyl carbonate chlorination is coupled with triphosgene methanolysis (i.e. a manufacturing process essentially based on methanol and chlorine as raw materials), has been claimed in the past [78, 79]. The cost of manufacturing the product in this way is considerably lower than that using the traditional liquid-phase photochlorination of DMC. 

The method is particularly well-suited for coupling N-alkyl amino acids. Tcboc-Phe-OH 1355 and FemLeu-OtBu 1357 (Fem = ferrocenylmethyl [1025, 1026]) can be coupled with triphosgene/DMF/TEA to afford moderate to excellent yields (50-97%) of Tcboc-Phe-FemLeu-OtBu 1358, depending on the excess of the activated component 1356 [1023, 1024]. 

Typical procedure. Coupling with triphosgene [1029] Fmoc peptidyl resin was de-protected with 20% piperidine/DMF (2 min + 8 min). After washing, the resin was treated with dry THF (1 mL) for 15 min. Meanwhile, the requisite Fmoc amino acid (483 pmol, 3.5 equiv.) was added to a 68 mM solution of triphosgene in dry THF (2.4 mL 1.15 equiv. triphosgene). sym-Collidine (180 pL, 10 equiv.) was added... 

Carbamoyl chlorides. A direct preparation of carbamoyl chlorides from tertiary benzylamines (debenzylation) is by reaction with triphosgene. A-Methoxy-N-methyl-carbamoyl chloride, which is useful for coupling with various unsaturated organostannanes, is obtained from chloroformylation of the methoxylamine in the presence of pyridine. ... 

Limal et al. [33] reported the synthesis of the carbaza-peptide (56) (in 40% overall yield after HPLC purification) by coupling A -Boc or A -Fmoc iV -alkyl-propylenediamine derivatives (57) on solid-supported amines activated with triphosgene or GDI (Fig. 8). Reaction with triphosgene was found to be faster than with GDI and hydantoin formation was kept at a low level (<3%) when no tertiary base (DIEA) was added during the coupling procedure. 

The synthesis was initiated from 45 by displacement of the primary tosyl group with either functionalised or nonfunctionalised primary or secondary amines in NMP at 80°C to give 46. After coupling of the primary amines, the resulting secondary amines 46 were converted into ureas 47 by reaction with isocyanates or by stepwise treatment with triphosgene followed by amine addition. In addition, acyl chlorides can be employed to provide amides as exemplified for 4 9 (Scheme 4.1.10). 

Another important reagent, particularly used for the coupling of functional groups, such as carboxylic groups, is N,N -disuccinimidyl carbonate (DSC) 904, which has been prepared from N-hydroxysuccinimide with triphosgene in 94% yield [653]. 

The use of triphosgene as an acid activator has been reported in several recent applications. Eckert and Seidel activated the N-protected amino acid Tcboc-valine 1351 (Tcboc = 2,2,2-trichloro-fert-butyloxycarbonyl [1022] for a preparation, see also Section 4.3.2.1) with triphosgene/DMF/TEA for racemization-free coupling with valine benzyl ester to afford Tcboc-Val-Val-OBn in 85% yield [1023, 1024]. 

Triphosgene reacts with hydrazine ester 194 to give an activated intermediate 195, probably the carbamoyl chloride, which was not isolated but rapidly coupled to the amino terminus of a peptide to give the desired aza-peptide motif. Coupling of HCI, H-Pro-NH-iPr resulted in the aza-dipeptide 196, which was transformed into the AzAsn derivatives by the action of ammonia or methylamine. A similar transformation has been observed for Boc-Me hydrazine. 

Ureas from DL-a-methyltryptophan were obtained by coupling the amino group with 4naphthyl isocyanate 273, or triphenylmethyl isocyanate 275, the latter two intermediates being prepared from the corresponding amines and triphosgene [182]. 

Phosphorylated furanose derivatives, such as compounds 36, were obtained in hi yields by exposure of alcohol 35 to dialkyl phosphorochloridates in the presence of 1-methylimidazole. Triphosgene-mediated coupling of phos-phonic acid with suitably protected nucleosides produced nucleoside-3 -H-phos-phonate monoesters, e.g. compound 37, in good to excellent yields. 6-Chloro-6-deoxy-l,2-0-isopropylidene-a-D-glucofuranose 3,5-cyclophosphorochloridate (38) has been converted to the novel cyclophosphates 39. ... 

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