Silyl amine

Thionyl imide, HNSO, is a thermally unstable gas, which polymerizes readily. It can be prepared by the reaction of thionyl chloride with ammonia in the gas phase. Organic derivatives RNSO have higher thermal stability, especially when R = Ar. The typical synthesis involves the reaction of a primary amine or, preferably, a silylated amine with thionyl chloride. A recent example is the preparation of FcNSO (Fc = ferrocenyl) shown in Eq. 9.8. In common with other thionylimines, FcNSO readily undergoes SO2 elimination in the presence of a base, e.g., KO Bu, to give the corresponding sulfur diimide FcNSNFc. 

It is also possible to prepare them from amino acids by the self-condensation reaction (3.12). The PAs (AABB) can be prepared from diamines and diacids by hydrolytic polymerization [see (3.12)]. The polyamides can also be prepared from other starting materials, such as esters, acid chlorides, isocyanates, silylated amines, and nitrils. The reactive acid chlorides are employed in the synthesis of wholly aromatic polyamides, such as poly(p-phenyleneterephthalamide) in (3.4). The molecular weight distribution (Mw/Mn) of these polymers follows the classical theory of molecular weight distribution and is nearly always in the region of 2. In some cases, such as PA-6,6, chain branching can take place and then the Mw/Mn ratio is higher. 

After silylation-amination in situ transsilylation (cf Section 2.3) of the intermediate persilylated cytidines 5 with excess boiling methanol for 3-5 h gives the desired free cytidines 6 and methoxytrimethylsilane 13a (b.p. 57°C) [13]. Thus protection of the alcohohc hydroxyl groups of the ribose moiety and silylation-activation of the 4-position in the pyrimidine moiety in persilylated uridine 3, and the concomitant amination of 3, aU in one reaction step, to 5 is followed finally by in situ transsilylation (cf. Section 2.3) with excess boihng methanol in one reaction vessel. 

All these steps proceed to afford free or N -substituted crystalline cytidines 6 in high yields [11] (cf. the preparation of N (tetramethylene)cytidine 6b in 95.4% yield in Section 1.1.). This simple one-pot reaction is also very easy to perform on a technical scale, as are the subsequently discussed analogous silylation-aminations of purine nucleosides and other hydroxy-N-heterocycles (cf. Sections 4.2.4 and 4.2.5). The concept of silylation-activation while simultaneously protecting hydroxyl groups in alcohols, phenols, or phosphoric acids by silylation was subsequently rediscovered and appropriately termed transient protection [16-18]. 

Polar functional groups such as alcohols or phenols 11 or trimethylsilanol 4 are transformed by monofunctional silylating reagents Me3SiX 12 into their hpophilic and often volatile trimethylsilyl ethers 13 whereas water is converted into persilyl-ated water (=Me3SiOSiMe3, hexamethyldisiloxane, HMDSO, 7, b.p. 100 °C). The persilylation of phenols and, in particular, catechol (or hydroquinone) systems (Scheme 2.1) protects them efficiently against air oxidation even at temperatures of up to 180 °C. (cf, e.g., the silylation-amination of purine nucleosides with dopamine hydrochloride in Section 4.2.4)... 

Thus removal of water from classical rather inactive fluoride reagents such as tetrabutylammonium fluoride di- or trihydrate by silylation, e.g. in THF, is a prerequisite to the generation of such reactive benzyl, allyl, or trimethylsilyl anions. The complete or partial dehydration of tetrabutylammonium fluoride di- or trihydrate is especially simple in silylation-amination, silylation-cyanation, or analogous reactions in the presence of HMDS 2 or trimethylsilyl cyanide 18, which effect the simultaneous dehydration and activation of the employed hydrated fluoride reagent (cf, also, discussion of the dehydration of such fluoride salts in Section 13.1). For discussion and preparative applications of these and other anhydrous fluoride reagents, for example tetrabutylammonium triphenyldifluorosilicate or Zn(Bp4)2, see Section 12.4. Finally, the volatile trimethylsilyl fluoride 71 (b.p. 17 °C) will react with nucleophiles such as aqueous alkali to give trimethylsilanol 4, HMDSO 7, and alkali fluoride or with alkaline methanol to afford methoxytri-methylsilane 13 a and alkali fluoride. 

As yet, a number of experiments have failed to convert ureas 205 such as N-phenylurea or imidazolin-2-one by silylation amination with excess amines R3NHR4 such as benzylamine or morpholine and excess HMDS 2 as well as equivalent amounts of NH4X (for X=C1, I) via the silylated intermediates 206 and 207 in one reaction step at 110-150°C into their corresponding guanidines 208 with formation of NH3 and HMDSO 7 [35] (Scheme 4.13). This failure is possibly due to the steric repulsion of the two neighbouring bulky trimethylsilyl groups in the assumed activated intermediate 207, which prevents the formation of 207 in the equilibrium with 206. Thus the two step Rathke-method, which demands the prior S-alkylation of 2-thioureas followed by amination with liberation of alkyl-mercaptans, will remain one of the standard syntheses of guanidines [21, 35a,b,c]. 

For further related silylation-amination-cyclizations, see also Chapter 10. 

Finally, silylation-amination of 5,6-diliydro-6-oxauracil 231 with excess diphenyl-methylamine 232/HMDS 2 and (NH4)2S04 for 17 h in boiling dioxane affords, via protonation of or of the persilylated intermediate 233 and subsequent addition of the amine to the 4-position, the cytosine analogue 234 in 74% yield [60] (Scheme 4.21). 

On silylation-amination of the disodium salts of inosine-5 -phosphate 238a or of guanosine-5 -phosphate 238 b with benzylamine, the phosphate moieties are also transiently protected during amination by silylation (cf also the silylation of uridine-5 -phosphate 224) to give, after transsilylation with methanol and addition of NaOH, the desired sodium salt of N -benzyladenosine-5 -phosphate 239a in 80% yield and the sodium salt of the 2-amino derivative 239 b in 78% yield [64] (Scheme 4.23). 

As might be expected, the add-catalyzed silylation-amination of the free purine-bases such as hypoxanthine 242 (R=H) and guanine 242 (R=NH2) proceeds, via 243, to the corresponding substituted adenines 244 in high yields [64] (Scheme 4.24). 

Unfortunately, the two fuU papers on the silylation-amination of pyrimidine [49] and purine nucleosides [64] as discussed in Sections 4.2.3 and 4.2.4, were pubhshed in German and are thus not readily accessible, although a few detailed procedures from Sections 4.2.3 and 4.2.4 were subsequently published in English [65]. The third paper on the silylation-amination of aromatic hydroxy-N-hetero-cycles, however, as discussed in Section 4.2.5 was, fortunately, pubhshed in English [27]. 

Because aromatic purines and purine nucleosides and free purines such as hypo-xanthine and guanine 242 are readily silylated-aminated [64] (cf Scheme 4.24), it is obvious that 6-membered hydroxy-N-heterocycles are analogously silylated-aminated, with reactivity in the order given in Scheme 4.25 [73] X=OTf is the best leaving group and X=NHSiMe3 (cf the transamination as discussed in Section 4.2.4) is the weakest. 

In the reactivity scale of Scheme 4.25 the reactivity of any of these heterocycles is substantially increased by annellation with a conjugated aromatic ring. Thus 2-quinolone is much more reactive than pyridine-2-one 245, which is the least reactive hydroxyheterocycle and requires reaction temperatures higher than 190-200 °C for silylation-amination [27]. To achieve these temperatures at normal pres-... 

Silylation-amination of 4(lH)-quinohnone 255 with a twofold excess of dopamine hydrochloride 256 as amine and an acidic catalyst affords, on heating with excess HMDS 2 for 21 h at 145 °C and subsequent transsilylation in excess boihng methanol, 75% of the crystalline hydrate of 257 (Scheme 4.28). The silylation-amination of 2-thio-6-azauracil 258 with homoveratrylamine 259, HMDS 2, and SnCLj as catalyst for 48 h at 145 °C furnishes 63% of the diamine 260, and MesSiOSiMes 7 and Me3SiSH or Me3SiSSiMe3 601 as leaving groups. 

Silylation-aminations of a variety of other hydroxy-N-heterocycles, for example 4(lH)-pyridinone, 2(lH)-pyrimidone, uracil, 2(lH)-quinoline, and 9(10H)-acridone are described in the full paper, which was published in English [27]. 

The advantages of the one-step silylation-amination of hydroxy-N-heterocycles are demonstrated by the amination of 2-methylpyrido[3,4-d]pyrimidin-4-one 261. Whereas silylation-amination of 261 with three equivalents of benzylamine-... 

Silylation-amination of 6-acetoxymethyl-5-deazapterine 265 with NH3, HMDS 2, and TsOH for 120 h at 155-160°C in an autoclave affords, after subsequent trans-silylation with boiling methanol, the diamino compound 266 in 74% yield [76]. Silylation-amination-cychzation of the substituted 4-quinolone 267 gives the alkaloid isoaptamine hydrochloride 268 in 51% yield [77, 78] (Scheme 4.30). 

Whereas silylation-amination of 2-amino-5,8-dihydroxypyrimido[4,5-d]pyridazine 269 with 3-amino-l-propanol, HMDS 2, and TsOH affords, after 24 h at 120-140 °C, the mono-8-hydroxypropylamino derivative 270 in 50% yield [79], reaction of 269 with a shght excess of ethanolamine and HMDS 2 provides, after 30 h at 120-150°C, only 20% of the bis(amino) product 271 [79]. (Scheme 4.31) A larger excess of ethanolamine and longer reaction times wiU certainly increase the yield of 271. 

The silylation-amination of l-benzyl-4,7-dihydroxy-l,2,3-triazolo[4,5-d]pyridazine 272 with N-methylpiperazine, HMDS 2, and (NH4)2S04 gives, after 24 h at... 

The silylation-amination of 5,10-dihydroxy-l,4-dioxo-l,2,3,4-tetrahydroben-zo[g]phthalazine 281 for 27 h at 170 °C with excess N(2-aminoethyl)piperidine 282 and HMDS 2 proceeds with catalytic amounts of Ts0H-H20 to afford, via the activated persilylated intermediate in which the sensitive phenolic hydroxy groups are protected, the 1,4-bis-amine 283 in 67% yield. All conventional efforts with POCI3, PCI5, or SOCI2 to convert 281 into the corresponding 1,4-dichloro compound, to be followed by amination, resulted in failure [86] (Scheme 4.35). 

In contrast with the hitherto described silylation-aminations of six-membered heterocycles, silylation-amination of five-membered hydroxy-N-heterocycles such as benzoxazol-2-one 289 with excess benzylamine and HMDS 2, to give 2-benzyla-minobenzoxazole, fails, because of the equilibrium between 2-trimethylsilyloxy-... 

The silylation-amination of the condensed tropone derivative 293 to 295 by use of N-trimethylsilylmorpholine 294 (cf also Section 5.2) is somehow related [90]. 

N-Acetals such as 429 react with silylated amines such as 294 at ambient temperature or on gentle heating in the presence of trimethylsilyl iodide 17 in diethyl ether to afford, e.g., the N,N-acetal 453 in 88% yield and HMDSO 7 [53]. The silylated tetrazole 454 reacts on heating to 160 °C with the 0,N-acetal 422 to... 

Adding butyllithium to N-silylated amines such as N-trimethylsilylaniline 1309 to form the salt 1310 and then introducing SO2 induces elimination of Me3SiOLi... 

A mechanistic proposal, which is based on the mthenium-catalyzed dehydration reaction reported by Nagashima and coworkers [146], is shown in Scheme 44. Reaction of a primary amine with hydrosilane in the presence of the iron catalyst affords the bis(silyl)amine a and 2 equiv. of H2. Subsequently, the isomerization of a gives the A,0-bis(silyl)imidate b and then elimination of the disiloxane from b produces the corresponding nitrile. Although the disiloxane and its monohydrolysis product were observed by and Si NMR spectroscopy and by GC-Mass-analysis, intermediates a and b were not detected. 

Ti-F bond and generate a Ti-H species when 99 was treated with phenylsilane. The chirality transfer may take place through imine insertion into the Ti-H bond, similar to that in the catalytic hydrogenation process.1000 The reaction can be carried out by the subsequent addition of imines. The corresponding silylated amines can be obtained and further converted to enantiomerically enriched amines upon acid treatment. For example, in the presence of 99, N-methylimine 100 undergoes complete hydrosilylation within 12 hours at room temperature, with 97% ee and up to 5000 turnovers.103... 

The added primary amine may facilitate the cleavage of the Ti-N bond of the key intermediate 107 through the coordination to the titanium center followed by u-bond metathesis. Such an intramolecular exchange process is expected to be facile. The amine exchange product is 106, which can then be rapidly converted to 105 and the corresponding silylated amine to complete the catalytic cycle. 

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