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lkali 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 ????-hydroxy-????-amino phosphonates, which
are structural analogs of ????-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 ????-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 ????-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.
Soc. 2004, 126, 14043. 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.
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 18-
crown-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.