Amines silyl derivatives

Succinimide is readily silylated by HMDS 2 to the N-silylated product 201, which seems, however, to be in equilibrium with the O-silylated derivative 202 a (cf the closely related reactive center in persilylated uridine 3) and reacts after 6-10 days at 24 °C with one equivalent of primary or secondary amines such as morpholine to give the crystalline colorless cyclic acylamidine 203 and HMDSO 7, even in the absence of any protective gas [33] (Scheme 4.12). The reaction is much faster on heating to 120 °C under argon. At these temperatures 201 and 202 a, and possibly also the acylamidine 203, are apparently partially O-silylated by HMDS 2 to the very sensitive 2,5-bis(trimethylsilyloxy)pyrrole 202b or to 2-tri-... 

According to these concepts, the reaction shown in Scheme 3.243 could be characterized by the presence of an induction period. Silyl derivatives of amines (> N-Si) are not involved in this reaction. The sterically hindered triorganosilyl substituents in BENAs (434) also should inhibit the process. 

The GC analysis of silylated derivatives of ethoxylated amines and fatty acid diethanolamides, among other non-ionic surfactants, has been described for many years and reviewed recently [43]. However, most of the determinations deal with the use of old packed columns for the characterisation of commercial blends and there are no applications of GC to their study in the environment. 

Verdini and co-workers 71,81 107 were able to silylate the amine with Af,0-bis(trimethylsilyl)-acetamide 108 (BTMSA) and to ring-open Meldrum s acid in a one-pot procedure without isolating the labile Af-silyl derivative. Additional, less frequently employed methods for the synthesis of C2-substituted malonic acids are summarized in a review. 73 ... 

Silyl derivatives to protect alcohols, 68-87 to protect amines, 377 to protect carbonyl groups, 208 to protect carboxylic acids, 261-263 to protect 1,2- and 1,3-diols, 137-139 to protect phenols, 160-162 to protect thiols, 297... 

Examples of amination of oxopurines to aminopurines via silyl derivatives include conversion of inosine into adenosine with catalysis by mercury ions (76LA745), and hypoxan-thines have been converted directly into adenines with phosphoramides at 225-230 °C (69IZV655). 

In the case of silylation-amination (Section IV,D), usually no solvents are employed since silylation transforms the polar and often high-melting hydroxy-nitrogen heterocycles, as well as polar hydroxy amines, into nonpolar lipophilic silylated derivatives that mix readily without solvents (84CBI523). 

A stirred solution of l,2-di(acetylamino)benzene (38) (19.2 g, 0.1 mol), triethyl-amine (30.1 g, 0.298 mol), and toluene (300 ml) is heated under reflux while trimethylchlorosilane (37.9 ml, 0.298 mol) in toluene (50 ml) is added. After heating (4h), the triethylamine hydrochloride is filtered off, and the solvent is removed under reduced pressure. Distillation in vacuo gives the silyl derivative (40) as a fraction, bi 107°C (92%). Addition of triflic acid (0.033 g) to (40) (2.026 g, 0.006 mol) induces instant cyclization at room temperature. The l-acetyl-2-methylbenzimidazole separates as a solid, and is recry stallized from diethyl ether in 100% yield, m.p. 80 C. 

Treatment of cycloserine with Fmoc-Cl or Fmoc-OSu in the presence of pyridine afforded a mixture of endo- and exocyclic N-acylated products (Fmoc = 9-fluorenylmethyloxycarbonyl). Selective protection of the primary amine was achieved on multigram scale and in high yield by in situ formation of the bis-silylated derivative with T,0-bis(trimethylsilyl)acetamide (BSA) followed by acylation (Scheme 76) <1998T15879>. 

The most recent source of these iminium ion precursors is the amide derived from 3-chloropropionyl chloride. Using the procedure reported by Ruhlmann for the preparation of 1-methoxy-l-trimethylsilyloxycyclopropane, Wasserman and Dion " converted the piperidide (58) to the 1-piperidino-l-trimethylsilyloxycyclopropane (59) by treatment with sodium metal in dry ether at 0°C. This reaction, which takes place smoothly and in high yield, serves as a short, inexpensive way to form the stable cyclopropanone equivalent. Further reaction of the silyl derivative (59) with tetrabutylam-monium fluoride in THF yields the corresponding carbinol amine (60). 

Both the silyl derivative (59) and the alcohol (60) may be used as sources of the iminium salt (61) in reactions with a wide variety of nucleophiles. In practice, it was found feasible to use Grignard reagents for reaction with the silyl derivative, while TiC was effective in promoting attack on the carbinol amine by weaker nucleophiles. The process is shown in Scheme 24 using the addition of indole as an example. 

Alkyldithio carbamates are prepared from the acid chloride (EtsN, EtOAc, 0°C) and amino acid, either free or as the O-silyl derivatives (70-88% yield). They may also be prepared by the addition of carbon disulfide to the amine which can then be alkylated with an alkyl halide using CS2CO2 as the base. The A-(i-propyldithio) carbamate has been used in the protection of proline during peptide synthesis. Alkyldithio carbamates can be cleaved with thiols, NaOH, PhsP/TsOH. They are stable to acid. Cleavage rates are a function of the size of the alkyl group as illustrated in the table below. 

The great breakthrough for silylation methods was its great analytical applicability. It could be shown that silyl derivatives of alcohols, phenols, carboxylic acids (incl. fatty acids), amino acids, amines and carbohydrates are useful tools for analyzing mixtures of several unknown compounds via GLC by means of their retention time ). 

With ketone enolates, issues of site selectivity arise. Generation of enolates under conditions of kinetic control results in preferential amination at the less substituted a-carbon (product 49, Eq. 87 388 Eq. 88217) unless one of the a-positions is benzylic (Eq. 89).134 Trialkylsilyl groups may also be used to direct animations (Eq. 90).156 On the other hand, in reactions involving ketone enamine intermediates under thermodynamic control, amination at the more highly substituted a-carbon predominates, but as the bulk at that position increases, reaction times increase and selectivity decreases (products 51 and 52, Eq. 91).228 A potential solution to this problem that apparently has not been explored extensively is to selectively generate silyl enol ethers and treat them with one of the reagents that are known to aminate these derivatives. The lone example of this approach is shown in Eq. 92.173... 

Conversions of the amino acids to methyl-a-hydroxy esters (L8, Wl) and methyl a-chloro esters (M5) have been described, and Bier and Teitelbaum (B13) have chromatographed the volatile amines produced by decarboxylation of amino acids. More recently, attention has been focused on the use of the AT-acylated esters of amino acids, e.g., n-amyl JV-aoetyl (J7), n-butyl iV-trifluoroacetyl (Z3), w-propyl iV-acetyl (G6), n-amyl A -trifluoroacetyl (B14), and methyl AT-trifluoroacetyl (C13, HI). Silyl derivatives have also been prepared (R5). 

Dehydrogenative silylation. I-Alkynes and amines are converted to silyl derivatives by hydrosilanes with iridium carbonyl" and ytterbium-imine complexes as catalyst, respectively. 

Iminium salts. N-Silyl derivatives of secondary amines react with carbonyl compounds afford a-siloxyamines. On further treatment with Me,SiCl, iminium chlorides are obtained. Trimethylsilyl triflate is superior to Me SiCl since it can induce the transformation in the cases of enolizable aldehydes. a-Chloro ethers are more reactive than carbonyl compounds, enabling the preparation of vinylogous Viehe salts. 

In an interesting application of enolate chemistry associated with silyl derivative 79, electrophilic amination allows convenient access to the synthetic equivalent of 2-deoxy-2-aminotetroses. This methodology has been applied to the stereoselective synthesis of D-ribo- Ci8-phytosphingosine (96) (Scheme 11) [41]. 

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