N-Benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine1

[93102-05-7]  · C13H23NOSi  · N-Benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine  · (MW 237.42)

(nonstabilized azomethine ylide precursor;1 reacts with alkenes to give pyrrolidines;2 alkynes give 3-pyrrolines;2 carbonyl and thiocarbonyl groups afford 1,3-oxazolidines and 1,3-thiazolidines, respectively3)

Physical Data: bp 77-80 °C/0.5 mmHg.

Preparative Methods: most conveniently prepared by treatment of benzylamine with chloromethyltrimethylsilane followed by formaldehyde and methanol.4 Access to higher ether homologs is achieved by replacing methanol with the appropriate alcohol.5 An alternate procedure involves alkylation of lithium N-benzyltrimethylsilymethylamide with methoxymethyl chloride.2

Purification: distillation under reduced pressure, although good yields can be obtained with undistilled reagent.

Handling, Storage, and Precautions: the reagent should be handled in a well ventilated fume hood.

1,3-Dipolar Cycloadditions.

N-Benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (1) is a valuable reagent for in situ generation of the N-benzyl azomethine ylide (2). It is generally preferred over alternative silylmethylamine precursors6-8 because of ease of handling and use. The ylide (2) is most conveniently generated from (1) using a catalytic amount of Trifluoroacetic Acid as described by Achiwa.2 Alternative catalysts include LiF,3,4 TBAF,7 Me3SiOTf-CsF,5 or Me3SiI-CsF.5 Mechanistic studies provide evidence that the reactive intermediate generated from (1) with either CF3CO2H or F- is a 1,3-dipolar species.7,8 Reaction of (2) with alkenes provides an efficient convergent route to pyrrolidine derivatives. Alkynes afford 3-pyrrolines2 which can be converted into pyrroles.6a The ylide (2) reacts most readily with electron deficient alkenes and alkynes since this pairing results in a narrow dipole HOMO-dipolarophile LUMO energy gap.9 Examples of suitable dipolarophiles include unsaturated esters,2-5 ketones,2 imides,2,4 nitriles,4 and sulfones.3,4 Cycloaddition occurs with complete cis stereospecificity2-4 (eq 1) which is consistent with a concerted mechanism. Dipolarophiles containing an endocyclic double bond afford fused bicyclic pyrrolidines,10 whereas substrates with an exocyclic double bond provide access to spirocyclic systems.11

Styrenes bearing electron withdrawing aromatic substituents such as CN and NO2 give high yields of 3-arylpyrrolidines (eq 2).12 When electron withdrawing groups are absent yields tend to be poor. Vinylpyridines afford 3-pyridylpyrrolidines.12 The reactivity of alkenes can be enhanced by the introduction of a CF3 substituent. For example, a-trifluoromethylstyrene gives a high yield of cycloadduct whereas a-methylstyrene is unreactive.13

Cycloaddition reactions with aldehydes and ketones afford 1,3-oxazolidines while thioketones give 1,3-thiazolidines (eq 3).3 Adducts derived from reaction at both the carbonyl and alkenic double bond have been observed with an a,b-unsaturated aldehyde.3

Diastereoselective 1,3-Dipolar Cycloadditions.

Several examples of high diastereofacial selectivity with homochiral dipolarophiles have been reported. Cycloaddition of (1) with the cyclic dipolarophile (3) occurs with complete p-facial selectivity as a result of addition from the side opposite the bulky silyloxymethyl group (eq 4).14 The key step in an asymmetric synthesis of (S)-(-)-cucurbitine involves cycloaddition of (1) with the a,b-dehydrolactone (4) to give the pyrrolidine (5) as a single diastereomer (eq 5).15

Double asymmetric induction employing a chiral N-a-methylbenzyl analog of (1) has been described.16


1. (a) Terao, Y.; Aono, M.; Achiwa, K. H 1988, 27, 981. (b) Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231.
2. Terao, Y.; Kotaki, H,; Imai, N.; Achiwa, K. CPB 1985, 33, 2762.
3. Padwa, A.; Dent, W. JOC 1987, 52, 235.
4. Padwa, A.; Dent, W. OSC 1992, 8, 231.
5. Hosomi, A.; Sakata, Y.; Sakurai, H. CL 1984, 1117.
6. (a) Padwa, A.; Chen, Y. Y.; Dent, W.; Nimmesgern, H. JOC 1985, 50, 4006. (b) Pandey, G.; Lakshmaiah, G.; Kumaraswamy, G. CC 1992, 1313.
7. Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. CPB 1985, 33, 896.
8. Terao, Y.; Imai, N.; Achiwa, K. CPB 1987, 35, 1596.
9. Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. JACS 1973, 95, 7301.
10. Orlek, B. S.; Wadsworth, H.; Wyman, P.; Hadley, M. S. TL 1991, 32, 1241.
11. Orlek, B. S.; Wadsworth, H.; Wyman, P.; King, F. D. TL 1991, 32, 1245.
12. Laborde, E. TL 1992, 33, 6607.
13. Begue, J. P.; Bonnet-Delpon, D.; Lequeux, T. TL 1993, 34, 3279.
14. Wee, A. G. H. JCS(P1) 1989, 1363.
15. Williams, R. M.; Fegley, G. J. TL 1992, 33, 6755.
16. Fray, A. H.; Meyers, A. I. TL 1992, 33, 3575.

Barry S. Orlek

SmithKline Beecham Pharmaceuticals, Harlow, UK



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.