SODIUM HEXAMETHYLDISILAZIDE 1

Sodium Hexamethyldisilazide1

NaN(SiMe3)2

[1070-89-9] C6H18NNaSi2 (MW 183.42)InChI = 1/C6H18NSi2.Na/c1-8(2,3)7-9(4,5)6;/h1-6H3;/q-1;+1/

rC6H18NNaSi2/c1-9(2,3)7(8)10(4,5)6/h1-6H3InChIKey = WRIKHQLVHPKCJU-JSJAVMDOAQ

(useful as a sterically hindered base and as a nucleophile)

Alternate Names: NaHMDS; sodium bis(trimethylsilyl)amide.Physical Data: mp 171–175 ◦C; bp 170 ◦C/2 mmHg.Solubility: soluble in THF, ether, benzene, toluene.1

Form Supplied in: (a) off-white powder (95%); (b) solution inTHF (1.0 M); (c) solution in toluene (0.6 M).

Analysis of Reagent Purity: THF solutions of the reagentmay be titrated using 4-phenylbenzylidenebenzylamine as anindicator.2

Handling, Storage, and Precautions: the dry solid and solutionsare flammable and must be stored in the absence of moisture.These should be handled and stored under a nitrogen atmo-sphere. Use in a fume hood.

Introduction. Sodium bis(trimethylsilyl)amide is a synthet-ically useful reagent in that it combines both high basicity3

and nucleophilicity,4 each of which may be exploited foruseful organic transformations such as selective formation ofenolates,5 preparation of Wittig reagents,6 formation of acyl anionequivalents,7 and the generation of carbenoid species.8 As a nu-cleophile, it has been used as a nitrogen source for the preparationof primary amines.9,10

Sterically Hindered Base for Enolate Formation. Like othermetal dialkylamide bases, sodium bis(trimethylsilyl)amide is suf-ficiently basic to deprotonate carbonyl-activated carbon acids5

and is sterically hindered, allowing good initial kinetic vs. ther-modynamic deprotonation ratios.11 The presence of the sodiumcounterion also allows for subsequent equilibration to the ther-modynamically more stable enolate.5f More recently, this basehas been used in the stereoselective generation of enolates forsubsequent alkylation or oxidation in asymmetric syntheses.12 Asshown in eq 1, NaHMDS was used to selectively generate a (Z)-enolate; alkylation with Iodomethane proceeded with excellentdiastereoselectivity.12a In this case, use of the sodium enolate waspreferred as it was more reactive than the corresponding lithiumenolate at lower temperatures.

NO

O

Et

O

i-Pr

NO

O

Et

O

i-Pr

Na

NO

O

Et

O

i-Pr

(1)

79%99:1 diastereoselectivity

NaHMDS MeI

The reagent has been used for the enolization of carbonyl com-pounds in a number of syntheses.13 For ketones and aldehydeswhich do not have enolizable protons, NaHMDS may be used toprepare the corresponding TMS-imine.14

Generation of Ylides for Wittig Reactions. In the Wittig re-action, salt-free conditions have been shown to improve (Z):(E)ratios of the alkenes which are prepared.15 NaHMDS has beenshown to be a good base for generating ylides under lithium-salt-free conditions.6 It has been used in a number of synthe-ses to selectively prepare (Z)-alkenes.16 Ylides generated underthese conditions have been shown to undergo other ylide reactionssuch as C-acylations of thiolesters and inter- and intramolecularcyclization.6 Although Wittig-based syntheses of vinyl halidesexist,17 NaHMDS has been shown to be the base of choice for thegeneration of iodomethylenetriphenylphosphorane for the stere-oselective synthesis of (Z)-1-iodoalkenes from aldehydes and ke-tones (eq 2).18

(2)

I

O

I

96%(Z):(E) = 62:1

61%

[Ph3PCH2I]+ I– [Ph3PCHI]NaHMDS

PhCHO

THF

NaHMDS has been shown to be the necessary base for thegeneration of the ylide anion of sodium cyanotriphenylphospho-ranylidenemethanide, which may be alkylated with various elec-trophiles and in turn used as an ylide to react with carbonylcompounds.19 NaHMDS was used as the base of choice in aHorner–Emmons–Wadsworth-based synthesis of terminal conju-gated enynes.20

Intramolecular Alkylation via Protected Cyanohydrins(Acyl Anion Equivalents). Although NaHMDS was not the baseof choice for the generation of protected cyanohydrin acyl carban-ion equivalents in the original references,21 it has been shown to bean important reagent for intramolecular alkylation using this strat-egy (eqs 3 and 4).7,22 The advantages of this reagent are (a) thatit allows high yields of intramolecularly cyclized products withlittle intermolecular alkylation and (b) the carbanion produced inthis manner acts only as a nucleophile without isomerization ofdouble bonds α,β to the anion or other existing double bonds inthe molecule. Small and medium rings as well as macrocycles22a

have been reported using this methodology (eqs 3 and 4).

(3)

ClCN

OEtO

CN

OEtO1. H2SO42. NaOHNaHMDS

O

61% 85%

2 SODIUM HEXAMETHYLDISILAZIDE

(4)

OTs

NC

OOEt O

1. NaHMDS 78%

2. NaOH 81%

Generation of Carbenoid Species. Metal bis(trimethylsilyl)amides may be used to effect α-eliminations.23 It is proposed thatthese nucleophilic agents undergo a hydrogen–metal exchange re-action with polyhalomethanes to give stable carbenoid species.23b

NaHMDS has been used to generate carbenoid species which havebeen used in a one-step synthesis of monobromocyclopropanes(eqs 5 and 6).23c,d NaHMDS has been shown to give betteryields than the corresponding lithium or potassium amides in thisreaction.

(5)

CH2Br2NaHMDS

Br

cis:trans = 1.5:1

40%

(6)

CH2Br2NaHMDS

Br50%

A similar study which evaluated the use of NaHMDS ver-sus Butyllithium for the generation of the active carbenoidspecies from 1,1-dichloroethane and subsequent reaction withalkenes, forming 1-chloro-1-methylcyclopropanes, suggested thatthe amide gave very similar results to those with n-butyllithium.24

In an initial report, the carbenoid species formed by the treat-ment of diiodomethane with NaHMDS was shown to react as anucleophile, displacing primary halides and leading to a synthe-sis of 1,1-diiodoalkanes; this is formally a 1,1-diiodomethylenehomologation (eq 7).25 This methodology is limited in that elec-trophiles which contain functionality that allows facile E2 elim-ination (i.e. allyl) form a mixture of the desired 1,1-diiodo com-pound and the iododiene. In the case of Allyl Bromide, additionof 2 equiv of the sodium reagent allows isolation of the iododieneas the major product.

(7)Br

I

R I

RX, THF

NaHMDSTHF

I

1/2

(E):(Z) = 40:60

61–66%

R = Et, Bu, heptyl

83%

CH2I2 [NaCHI2]–90 °C

Synthesis of Primary Amines. The nucleophilic propertiesof this reagent may be utilized in the SN2 displacement of primaryalkyl bromides, iodides, and tosylates to form bis(trimethylsilyl)amines (1) (eq 8).9a HCl hydrolysis of (1) allows isolation ofthe corresponding hydrochloride salt of the amine, which maybe readily separated from the byproduct, bis(trimethylsilyl) ether.In one example a secondary allylic bromide also underwent theconversion with good yield.

(8)R N(TMS)2RX + NaHMDS

(1) (2)

75%77%73%66%

99% 98%100% 97%

RNH3Cl + (TMS)2O

RMeEtBr

XIOTsBrBr

Aminomethylation. NaHMDS may be used as the nitrogensource in a general method for the addition of an aminomethylgroup (eq 9).10 The reagent is allowed to react with chloromethylmethyl ether, forming the intermediate aminoether. Addition ofGrignard reagents to this compound allows the displacement of themethoxy group, leaving the bis(trimethylsilyl)-protected amines.Acidic hydrolysis of these allows isolation of the hydrochloridesalt of the corresponding amine in good yields.

(9)

MeO Cl MeO N(TMS)2

R NH3 Cl–

1. RMgX, Et2O

+

R = Me, 89%; allyl, 76%; Cy, 75%; Ph, 78%; propargyl, 66%

NaHMDS

THF 2. HCl, H2O

Related Reagents. Lithium Hexamethyldisilazide; PotassiumHexamethyldisilazide.

1. Wannagat, U.; Niederpruem, H., Chem. Ber. 1961, 94, 1540.

2. Duhamel, L.; Plaquevent, J. C., J. Organomet. Chem. 1993, 448, 1.

3. Barletta, G.; Chung, A. C.; Rios, C. B.; Jordan, F.; Schlegel, J. M.,J. Am. Chem. Soc. 1990, 112, 8144.

4. (a) Capozzi, G.; Gori, L.; Menichetti, S., Tetrahedron Lett. 1990, 31,6213. (b) Capozzi, G.; Gori, L.; Menichetti, S.; Nativi, C., J. Chem.Soc., Perkin Trans. 1 1992, 1923.

5. (a) Evans, D. A., In Asymmetric Synthesis; Morrison, J. D., Ed.;Academic: New York, 1984; Vol 3, p 1. (b) Tanabe, M.; Crowe,D. F., Chem. Common. 1969, 1498. (c) Barton, D. H. R.; Hesse, R. H.;Pechet, M. M.; Wiltshire, C., Chem. Common. 1972, 1017. (d) Krüger,C. R.; Rochow, E., J. Organomet. Chem. 1964, 1, 476. (e) Krüger, C. R.;Rochow, E. G., Angew. Chem., Int. Ed. Engl. 1963, 2, 617. (f) Gaudemar,M.; Bellassoued, M., Tetrahedron Lett. 1989, 30, 2779.

6. Bestmann, H. J.; Stransky, W.; Vostrowsky, O., Ber. Dtsch. Chem. Ges.1976, 109, 1694.

7. Stork, G.; Depezay, J. C.; d’Angelo, J., Tetrahedron Lett. 1975, 389.

8. Martel, B.; Hiriart, J. M., Synthesis 1972, 201.

9. (a) Bestmann, H. J.; Woelfel, G., Ber. Dtsch. Chem. Ges. 1984, 117,1250. (b) Anteunis, M. J. O.; Callens, R. De Witte, M.; Reyniers, M. F.;Spiessens, L., Bull. Soc. Chim. Belg. 1987, 96, 545.

10. Bestmann, H. J.; Woelfel, G.; Mederer, K., Synthesis 1987, 848.

11. Barton, D. H. R.; Hesse, R. H.; Tarzia, G.; Pechet, M. M., Chem.Commun. 1969, 1497.

12. (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J., J. Am. Chem. Soc. 1982,104, 1737. (b) Evans, D. A.; Morrissey, M. M.; Dorow, R. L., J. Am.Chem. Soc. 1985, 107, 4346. (c) Davis, F. A.; Haque, M. S. Przeslawski,R. M., J. Org. Chem. 1989, 54, 2021.

13. (a) Schmidt, U.; Riedl, B., Chem. Commun. 1992, 1186. (b) Glazer,E. A.; Koss, D. A.; Olson, J. A.; Ricketts, A. P.; Schaaf, T. K.; Wiscount,R. J., Jr., J. Med. Chem. 1992, 35, 1839.

SODIUM HEXAMETHYLDISILAZIDE 3

14. Krueger, C.; Rochow, E. G.; Wannagat, U., Ber. Dtsch. Chem. Ges. 1963,96, 2132.

15. (a) Schlosser, M.; Christmann, K. F., Justus Liebigs Ann. Chem. 1967,708, 1. (b) Schlosser, M., Top. Stereochem. 1970, 5, 1. (c) Schlosser, M.;Schaub, B.; de Oliveira-Neto, J.; Jeganathan, S., Chimia 1986, 40, 244.(d) Schaub, B.; Jeganathan, S.; Schlosser, M., Chimia 1986, 40, 246.

16. (a) Corey, E. J.; Su, W., Tetrahedron Lett. 1990, 31, 3833. (b) Niwa,H.; Inagaki, H.; Yamada, K., Tetrahedron Lett. 1991, 32, 5127. (c)Chattopadhyay, A.; Mamdapur, V. R., Synth. Commun. 1990, 20, 2225.(d) Mueller, S.; Schmidt, R. R., Helv. Chim. Acta 1993, 76, 616.

17. (a) Miyano, S.; Izumi, Y.; Fuji, K.; Ohno, Y.; Hashimoto, H., Bull. Chem.Soc. Jpn. 1979, 52, 1197. (b) Smithers, R. H., J. Org. Chem. 1978, 43,2833.

18. Stork, G.; Zhao, K., Tetrahedron Lett. 1989, 30, 2173.

19. Bestmann, H. J.; Schmidt, M., Angew. Chem., Int. Ed. Engl. 1987, 26,79.

20. Gibson, A. W.; Humphrey, G. R.; Kennedy, D. J.; Wright, S. H. B.,Synthesis 1991, 414.

21. (a) Stork, G.; Maldonado, L., J. Am. Chem. Soc. 1971, 93, 5286.(b) Stork, G.; Maldonado, L., J. Am. Chem. Soc. 1974, 96, 5272.

22. (a) Takahashi, T.; Nagashima, T. Tsuji, J., Tetrahedron Lett. 1981, 1359.(b) Takahashi, T.; Nemoto, H.; Tsuji, J., Tetrahedron Lett. 1983, 2005.

23. (a) Martel, B.; Aly, E., J. Organomet. Chem. 1971, 29, 61. (b) Martel,B.; Hiriart, J. M., Tetrahedron Lett. 1971, 2737. (c) Martel, B.; Hiriart,J. M., Synthesis 1972, 201. (d) Martel, B.; Hiriart, J. M., Angew. Chem.,Int. Ed. Engl. 1972, 11, 326.

24. Arora, S.; Binger, P., Synthesis 1974, 801.

25. Charreau, P.; Julia, M.; Verpeaux, J. N., Bull. Soc., Chem. Fr. Part 2 1990,127, 275.

Brett T. WatsonBristol-Myers Squibb Pharmaceutical Research Institute,

Wallingford, CT, USA