Alkali Metal Amides

Strong Base Chemistry for Chemical Synthesis

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Alkali Metal Hexamethyldisilazane

Potassium hexamethyldisilazane (KHMDS), sodium hexamethyldisilazane (NaHMDS), and lithium hexamethyldisilazane (LiHMDS) are strong non-nucleophilic base reagents useful in a wide variety of chemical reactions and transformations. Applications include alkylation, arylation, acylation, ring formation, isomerization, rearrangements, aldol condensations, Wittig and Horner-Emmons reactions and polymerization. Chemists strive for selectivity and speci city in a reaction to increase the yield of the desired product and minimize by-product formation. High selectivity and speci city can lead to simpler, less expensive puri cation routes to the desired product. Alkali metal hexamethyldisilazane (MHMDS) bases can help achieve these goals. They are selective base reagents because of the following characteristics:
      

non-nucleophilic, hindered amine base, higher base strength than alkali metal alkoxides, kinetic deprotonation achieved, hydrocarbon soluble base, reduction of substrate rarely occurs, not prone to one-electron-transfer side-reactions, and safer than alkali metal hydrides and lithium alkyls.

pKa of hexamethyldisilazane is 26 in THF, Fraser, R.R.; Mansour, T.S.; Savard, S. J. Org. Chem. 1985, 50, 3232. pKa of hexamethyldisilazane is 26 in DMSO, Grimm, D.T.; Bartmess, J.E. J. Am. Chem. Soc. 1992, 114, 1227.

Deprotonation and Alkylations

The bulky nature and absence of protons on the atom adjacent to the nitrogen give the MHMDS bases considerable advantages for deprotonation. Due to the intermediate base strength of the MHMDS bases coupled with the non-nucleophilic nature by-product formation is minimized. During the investigation of the alkylation of cyanohydrin acetonides with allyl chloride several bases were tested. However, an excellent yield was obtained using KHMDS base for the deprotonation followed by alkylation instead of LDA. Rycknovsky,
S.D.; Swenson, S.S. J. Org. Chem. 1997, 62, 1333.

The counterion of the base also plays a role in determining the selectivity of the reaction. For example, in the synthesis of E-hydroxy-D-amino phosphonates, which are structural analogs of D-amino acids, MHMDS bases were examined for the deprotonation of dimethyl phosphonate. Davis, F.A.; Prasad, K.R. J. Org. Chem. 2003, 68, 7249. Reaction of metalated phosphonates with protected D-hydroxy sul nimine gave a higher diastereomer ratio using KHMDS than NaHMDS or LiHMDS.

Wang took advantage of the umpolung nature of aryl acetonitrile derivatives as aryl carbonyl synthons in the synthesis of drug intermediates. Wang, T. et al. J. Org. Chem. 2004, 69, 1364. For example, the aryl acetonitrile was deprotonated with NaHMDS, then reacted with an aryl chloride and oxidized in a one-pot process to the desired ketone in 74% isolated yield.

Enolate Reactions
Alkali metal amide bases are often the reagent of choice for the formation of enolates due to rapid complete enolization of the carbonyl substrate. Because of the higher base strength of the alkali metal hexamethyldisilazanes (relative to alkoxide bases), the kinetic enolate ef ciently forms from a carbonyl compound with D-hydrogens. a) Evans, D.A. In Asymmetric Synthesis: Morrison, J.D., Ed.; Academic: NY, 1984; Vol. 3. p1. b) Brown, C.A. J. Org. Chem. 1974, 39, 3913. Deprotonation of esters and amides with the MHMDS bases occurs more slowly than ketone deprotonation due to the lower acidity of ester and amide protons. The cation can have an effect on the subsequent selectivity of the alkylation of the enolate anion. The sodium and lithium enolates yield primarily carbon-alkylation products while potassium enolates favor oxygen-alkylation. For example, in the multi-kilogram synthesis of intermediates for production of LFA-1 inhibitors, a bislactam was deprotonated with KHMDS and O-alkylated with (EtO)2POCl. Frutos, R.P.
et al. Org. Process Res. Dev. 2005, 9, 137.

Because lithium is closely associated with the oxygen of the enolate, the sodium Evans, D.A.; Ennis, M.D.; Mathre, D.J. J. Am. Chem. Soc. 1982, 104, 1737 and potassium enolates
Potassium enolate of oxindol reacted 10 times faster than lithium enolate. Overman, L.E. et al. J. Am. Chem.

often react at a much faster rate than the corresponding lithium enolate. The potassium and sodium enolates also equilibrate to the thermodynamic enolate faster than lithium enolates. Equilibration to the thermodynamic potassium enolate by warming to ambient temperature allowed for the O-alkylation of an enolate to prepare a Claisen precursor as shown below. Boeckman, R.K., Jr. et al. J. Am.
Soc. 2004, 126, 14043. Chem. Soc. 2002, 124, 190.

Condensations and Ring Formation

Many pharmaceutical intermediates are in cyclic forms, therefore reaction schemes to prepare such structures are exceedingly useful. The intramolecular ring opening of an epoxide by the nitrogen on an amide required extensive experimentation to nd the optimal base for the amide deprotonation. NaH and KTB lead to mixtures of products while Lewis acid catalysts lead to decomposition of starting materials. NaHMDS proved the best choice and gave the desired oxazolidinone in 88% yield. Riera, A. et al. J. Org. Chem. 2005, 70, 2325.

Directed Ortho-Metalation of Aromatic Systems

Directed ortho-metalation (DoM) has found utility for the preparation of substrates for Suzuki C-C bond formation. Nitro-substituted aromatics were made very successfully with NaHMDS or KHMDS as the base for the directed deprotonation. Lithium alkyls and amides for DoM reactions of nitro compounds are prone to electron transfer and reduction of the nitro group. An in situ electrophile was necessary to capture the aryl anion and obtain high yields. Black, W.C.; Guay, B.;
Scheuermeyer, F. J. Org. Chem. 1997, 62, 758.

Wittig Reaction
The Wittig reaction is an effective way to replace a carbonyl group with an ole nic residue. a.) Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989, 89, 863, b.) Vedejs, E.; Peterson, M.J. Top. Stereochem. 1994, 21, c.) Schroeder, U.; Berger, S. Eur. J. Org. Chem. 2000, 2601. The reaction typically involves formation of an ylid by deprotonation of an alkyltriphenylphosphonium salt with a strong base. The alkali metal counterion plays a role in determining the (Z):(E) ratio of alkene products. An example of the complimentary nature of the alkali metal counter ion in the Wittig reaction was demonstrated by Jacobsen. A 30:1 E/Z ratio using LiHMDS in DMF/HMPA was observed versus a 1:8 ratio with NaHMDS in THF without complexing additives. Liu, P.; Jacobsen, E.N. J. Am. Chem. Soc. 2001, 123, 10772. Both NaHMDS and KHMDS have been used effectively to generate ylid under lithium-free conditions to attain high (Z) selectivity. a) Storck, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. b) Tago, K. Arai, M.; Kogen, H. Perkin 1 2000, 13, 2073. A recent example to make a glaucoma drug used KHMDS in the Wittig reaction to deliver 97.8% cis product along with only 2.2% trans product, compared to KTB giving 3.5% trans. Fox, M.E. et al.
J. Org. Chem. 2005, 70, 1227.

Base Induced Rearangements and Isomerization

The Cope rearrangement is a useful tool of organic chemists for carbon-carbon bond and ring formation. The anionic version of this rearrangement proceeds more rapidly and is called the oxyanionic Cope rearrangement. KHMDS used with 18crown-6 to complex the potassium cation was a convenient alternative to potassium hydride for the generation of anions in oxyanionic Cope rearrangements. Paquette, L.A.; et al. J. Am. Chem. Soc. 1990, 112, 277. In the synthesis of taxol derivatives, Paquette used KHMDS in the oxyanionic Cope rearrangement to give optically pure tricyclic compounds. Paquette, L.A.; Huber, S.K.; Thompson, R.C. J. Org. Chem. 1993, 58, 6874.

Use of MHMDS as a Nucleophile

Although the HMDS amide anion is primarily used as a base, its utility as an ammonia synthon has increased the awareness that it can act as a nucleophile in speci c cases. When used as a nucleophile, the substrate must have a reasonably good leaving group and no protons of low acidity. NaHMDS will displace the phthalimide group to give high yields of silylated sulfenamides, a new class of compounds. Capozzi, G.; Gori, L.; Menichetti, S.; Nativi, C. J. Chem.
Soc. Perkin Trans. 1 1992, 1923.

Potassium Hexamethyldisilazane

Sodium Hexamethyldisilazane

Lithium Hexamethyldisilazane

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