[88211-44-3]  · C8H23NOSi2  · (Methoxymethyl)bis(trimethylsilyl)amine  · (MW 205.50)

(electrophilic N,N-bis(trimethylsilyl)aminomethylating agent for a variety of molecules; after desilylation, the overall transformation achieves primary aminomethylation1,2)

Physical Data: bp 94-95 °C/83 mmHg; d 0.873 g cm-3; n20D 1.431-1.434.

Solubility: sol organic solvents such as hexane, dichloromethane, ether, alcohol; stable in neutral or basic solvents; unstable in protic solvents.

Form Supplied in: colorless liquid.

Analysis of Reagent Purity: 1H NMR d (CDCl3): 0.14 (18H, s, 2 × (CH3)3Si), 3.17 (3H, s CH3O), 4.82 (2H, s, CH2); 13C NMR d (CDCl3): 1.90 (q), 53.4 (q), 80.9 (t).

Handling, Storage, and Precautions: fairly stable at rt; for long storage, keep at 0-10 °C in the absence of moisture.

General Considerations.

This reagent, conveniently prepared3,4b by the reaction of Lithium Hexamethyldisilazide or Sodium Hexamethyldisilazide with Chloromethyl Methyl Ether in THF, is utilized for introduction of a primary aminomethyl unit into a variety of molecules by a two-step procedure involving N,N-bis(trimethylsilyl)aminomethylation followed by solvolytic removal of the trimethylsilyl groups. The reagent can be regarded as a synthetic equivalent for +CH2NH2, and it functions as a reagent for achieving Mannich-type transformations5 which are rarely possible to afford primary amines. The reagent reacts successfully with Grignard and organolithium compounds,3 ketene silyl (or bissilyl) acetals,4 silyl sulfides, and silyl phosphites.6 While the N,N-bis(trimethylsilyl)aminomethylated products themselves are useful as N-protected primary amines,7 they are easily desilylated to the corresponding primary aminomethyl compounds in protic media.

Primary Aminomethylation of Organometallic Compounds.3

Grignard compounds react with the reagent in equimolar proportions to produce aminomethylated products in the N-silyl-protected form. Alkyl, allyl, and aryl Grignard reagents react smoothly in Et2O at rt usually in high yield, whereas alkynyl Grignard reagents react under reflux in THF. Alkyllithium compounds and aryllithium compounds (prepared in situ by lithiation of arenes with n-BuLi) do not react with the reagent unless an equimolar amount of anhydrous Magnesium Bromide (best prepared from 1,2-dibromoethane and Mg in Et2O) or MgCl2 is present. Organoaluminum compounds derived from allyl and propargyl bromides have also been shown to undergo N,N-bis(trimethylsilyl)aminomethylation with this reagent (eqs 1-6).8

Solvolytic removal of the N-trimethylsilyl groups in the products leads to the corresponding primary amines and is easily accomplished in refluxing MeOH or EtOH in the presence of a catalytic amount of acid such as TsOH or HCl. Silica gel is also capable of catalyzing the solvolysis.

Primary Aminomethylation of Carboxylic Acids and Esters.4

The reaction of ketene silyl acetals with the reagent followed by desilylation provides a general method for a-aminomethylation of carboxylic acids and esters. Ketene silyl acetals and bissilyl acetals, prepared from carboxylic esters and acids, respectively, by treatment with Lithium Diisopropylamide (LDA) and Chlorotrimethylsilane, react smoothly with the reagent in CH2Cl2 at rt in the presence of a catalytic amount (0.01 mol equiv) of Trimethylsilyl Trifluoromethanesulfonate to afford N,N-bis(trimethylsilyl)-b-aminocarboxylic esters, generally in high yields. The triflate-catalyzed reaction involves electrophilic attack of [(Me3Si)2N=CH2]+TfO- with release of Me3SiOMe (eqs 7-9).

The alkyl and trimethylsilyl esters of N,N-bis(trimethylsilyl)-b-aminocarboxylic acids are desilylated to the corresponding b-amino acids by treatment with catalytic amounts of acid in aqueous solvents. Selective removal of the N-trimethylsilyl groups of the alkyl esters can be performed with AcOH-aq. THF to give the corresponding b-amino acid esters.

N,N-Bis(trimethylsilyl)aminomethylation of Heteroatoms.6

Electrophilic introduction of a N,N-bis(trimethylsilyl)aminomethyl group with this reagent is possible at sulfur and phosphorus atoms by using silyl sulfides and silyl phosphites. The reaction of the reagent with phenyl- or alkylthiotrimethylsilanes and trimethylsilyl dithiocarbamates smoothly proceeds on heating at 60 °C in the presence of Zinc Bromide (0.05 mol equiv) to give N,N-bis(trimethylsilyl)aminomethylated sulfur compounds. PhSCH2N(SiMe3)2 behaves similarly to the title reagent and is especially effective for N,N-bis(trimethylsilyl)aminomethylation of cuprate complexes.2

The reaction of the reagent with trimethylsilyl phosphite proceeds well at 60 °C in the presence of Tin(II) Chloride (0.05 mol equiv) to give N,N-bis(trimethylsilyl)aminomethylphosphonates in good yields (eqs 10-12).

N,N-Bis(trimethylsilyl)aminomethylphosphonates are desilylated to give aminomethylphosphonates, whereas N,N-bis(trimethylsilyl)aminomethylated sulfur compounds are not convertible to primary aminomethyl sulfides because of their instability.

1. Fieser, M. FF 1986, 12, 62.
2. Morimoto, T. Advances in Pharmaceutical Sciences; The Research Foundation for Pharmaceutical Sciences: Japan, 1987; Vol. 3, pp 153-166.
3. (a) Morimoto, T.; Takahashi, T.; Sekiya, M. CC 1984, 794. (b) Bestmann, H. J.; Wölfel, G. AG(E) 1984, 23, 53. (c) Bestmann, H. J.; Wölfel, G.; Mederer, K. S 1987, 848. (d) McCarthy, J. R.; Charlotte, L. B.; Matthews, D. P.; Bargar T. M. TL 1987, 28, 2207.
4. (a) Okano, K.; Morimoto, T.; Sekiya, M. CC 1984, 883. (b) Okano, K.; Morimoto, T.; Sekiya, M. CPB 1985, 33, 2228.
5. (a) Blicke, F. F. OR 1942, 1, 303. (b) Tramontini, M. S 1973, 703.
6. Morimoto, T.; Aono, M.; Sekiya, M. CC 1984, 1055.
7. Morimoto, T.; Sekiya, M. CL 1985, 1371.
8. Courtois, G.; Mesnard, D.; Dugue, B.; Miginiac, L. BSF(2) 1987, 93.

Toshiaki Morimoto & Minoru Sekiya

University of Shizuoka, Japan

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