Carbamate deprotection

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of /ert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX-2LiCl (X = -Cl, -CN) to afford a-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to a,(3-alkynyl ketones affording a,(3-enones 37, which upon treatment with PhOH/TMSCl undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 . 

Two approaches to the 2-benzazepine system, in particular the 2-benzazepinone 142, have been reported by Le Diguarher et al. The first started from (acid-catalyzed cyclization to 141 N-alkylation and carbamate deprotection then afforded 142. The second route was based on A-HOC aminomalonate 144 and 2,2 -dibromo-o-xylene, and then steps via 145 and... 

Figure 5 Preparation procedures used to create imprinted silica comprising (a) sol-gel hydrolysis and condensation catalyzed by HCl and (b) carbamate deprotection with trimethyl-silyliodide in acetonitrile.

Figure 6 Illustration of carbamate deprotection of 1 with trimethylsilyliodide. The first step is a transesterification reaction to convert the benzylcarbamate in (a) to the trimethylsilyl-carbamate shown in (b). Treatment with a suitable OH such as water yields the free carbamic acid in (c), which spontaneously loses carbon dioxide to provide (d) an imprinted site comprising a pair of free amines in 2.

One gram of TMS-capped silica was treated with 15 mL of 0.25 M TMSI in dry acetonitrile at 70° C for a period of at least 12 h. Temperatures of less than40°C (which were sufficient to deprotect systems based on one benzyl carbamate per imprint molecule) did not show appreciable deprotection of material 1. Given the treatment necessary to achieve carbamate deprotection, it is important to emphasize that the TMSI procedure does not change the connectivity of the silica framework, as ascertained by studies on model crystalline materials such as a high-silica zeolite faujasite [42]. Following TMSI treatment, the silica was filtered and washed with acetonitrile, methanol, saturated aqueous sodium bicarbonate, methanol, and acetonitrile. The purpose of the aqueous treatment was hydrolysis of the silyl carbamate intermediate as shown in Fig. 6b-c. 

The deprotection process illustrated in Figs. 5 and 6 was followed by solid-state CP/MAS NMR spectroscopy. As illustrated in Fig. 7, the carbonyl (158.2 ppm), aromatic (128.2 and 137.4 ppm), and benzylic (67.4 ppm) resonances decreased due to cleavage of those functional groups by the carbamate deprotection. However, the propyl tether resonances at 10.5, 23.1, and 43.2 ppm remained intact (Fig. 7b). Incomplete hydrolysis left a small amount of residual ethoxy moieties at 54.1 and 17.5 ppm. The degree of deprotection achieved in the material resulted in an amine number density of approximately 0.25mmol/g, as ascertained by nonaqueous titration of the amines with benzoic acid [42]. 

Since the initial studies of Tsuji and Trost, it has been known that Tr-allylpalladium complexes react irreversibly with active methylene compounds to form new carbon-carbon bonds. Applying this information, Kunz introduced dimedone and A,A-dimethylbarbi-turic acid (NDMBA) as nucleophiles in the Pd-catalyzed deprotection of allyl carbamates and carbonates. The presumed catalytic cycle for this process is shown in Scheme 4. Dimedone and NDMBA have also been employed as nucleophiles in the deprotection of aUyl esters. Dimethyl malonate has also been used occasionally in allyl carbamate deprotection, although it appears to be less reactive than the other carbon nucleophiles.f ... 

The last class of nucleophiles used to scavenge the n-allylpalladium intermediate is that of sulfur nucleophiles. 2-Thiobenzoic acid has been used as a water-soluble scavenger of 7r-allylpalladium complexes in allyl carbamate deprotections. More recently, aryl sulfinic acids have been demonstrated to very effectively serve as nucleophiles in the Pd-mediated deprotection of allyl esters, carbamates, amines, and ethers. This reagent appears to afford substantially bettCT reactivity than most other classes of nucleophiles. 

Tab. 4.22. Cleavage of alkyl carbamates deprotection methods for the most common...

In each step of the usual C-to-N peptide synthesis the N-protecting group of the newly coupled amino acid must be selectively removed under conditions that leave all side-chain pro-teaing groups of the peptide intact. The most common protecting groups of side-chains (p. 229) are all stable towards 50% trifluoroacetic acid in dichloromethane, and this reagent is most commonly used for N -deprotection. Only /ert-butyl esters and carbamates ( = Boc) are solvolyzed in this mixture. 

Benzyl carbamates are readily cleaved under strongly acidic conditions HBr, AcOH 50% CF3COOH (25°, 14 days, partially cleaved) - 70% HF, pyridine CF3S03H FSOaH, or CHjSO.H.- In cleaving benzyl carbamates from peptides, 0.5 M 4-(methylmercapto)phenol in CF3CO2H has been recommended to suppress Bn additions to aromatic amino acids. To achieve deprotection via an Sn2 mechanism that also reduces the problem of Bn addition, HF-Me2S-p-cresol (25 65 10, v/v) has been recommended for peptide deprotection. 

Protective group chemistry for these amines has been separated from the simple amines because chemically they behave quite differently with respect to protective group cleavage. The increased acidity of these aromatic amines makes it easier to cleave the various amide, carbamate, and sulfonamide groups that are used to protect this class. A similar situation arises in the deprotection of nucleoside bases (e.g., the isobutanamide is cleaved with methanolic ammonia ), again, because of the increased acidity of the NH group. 

Pd(OAc)2, TPPTS, CH3CN, H2O, Et2NH, 30 min, 89-99% yield. Deprotection can be achieved in the presence of a prenyl or cinnamyl ester, but as the reaction times increase, these esters are also cleaved.Prenyl carbamates and allyl carbonates are cleaved similarly. 

In 2004, Alterman et al. apphed their cyanation protocol to the synthesis of N-(t-butyl)-3-(4-cyanobenzyl)-5-isobutylthiophene-2-sulfonamide [61]. Deprotection of the sulfonamide followed by carbamate formation via reaction with butyl chloroformate finally gave the target compoimd for biological evaluation as a selective angiotensin 11 AT2 receptor agonist (Scheme 65). The cyano derivative, however, showed only a low affinity for the AT2 receptor (Ki value >10 p,M). 

The choice of the acyl substituent X for Diels-Alder reactions of l-N-acylamino-l,3-butadicnes depends on the particular synthetic problem. The acyl substituent has a moderate effect on the cycloaddition reactivity of these dienes, and also determines what amine unmasking procedures are required. As a result of their stability and the variety of amine deprotection procedures available, " the diene carbamates are the components of choice in most cases. A particularly attractive aspect of the diene synthesis detailed here is the ability to tailor the amino-protecting group... 

These amino acids were initially synthesized by asymmetric aminomethylation of optically pure (R)- and (S)-N-Acyl-4-phenyhnethyl)oxazolidin-2-ones 52 through TiCVenolates (Evans methodology [135]) with (benzoylamino)methylchloride or benzyl N-(methoxymethyl)carbamate [66, 97-99, 104]. Hydrolytic removal of the auxiliary yielded the N-protected (benzoyl or Z) amino acid 54. Deprotection afforded the free amino acid which was converted to the required Boc- or Fmoc-pro-tected derivatives (Scheme 2.7). 

The deprotection of the Cbz protected amino acid proceeds via a two step mechanism (Figure 1). The first step comprises the catalytic hydrogenolysis of the benzyloxy group of the Cbz-protected amino acid (1). Toluene (3) is formed from the O-benzyl group as well as an unstable carbamic acid intermediate (2). This intermediate decomposes to form the unprotected amino acid (4) and carbon dioxide (5). 

The removal of a carbobenzyloxy group can be separated into two steps (Figure 1). The first step comprises the hydrogenolysis of the benzyl oxygen bond of the Cbz-protected amino acid 1 to form a carbamic acid intermediate 2 and toluene 3. The carbamic acid intermediate decaiboxylates to give the deprotected amino acid 4 and one equivalent of carbon dioxide 5. 

Removal of the carbamate group of thiadiazolidine 65 was achieved with conventional procedures and the resulting deprotected thiadiazolidine 66 can be iV-alkylated (Scheme 6) <2004CEJ5581>. 

Gronowitz and associates coupled 2-(2-trimethylstannyl-3-thienyl)-l,3-dioxolane (75) with tert-butyl N- (o/t/io-bromo tbienyl)carbamate (127) to give the Stille adduct, which underwent acid-catalyzed deprotection and cyclization to deliver dithienopyridine 128 [112]. The... 

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