J . Org. Chem. 1998, 63, 3677-3679
3677
Use of th e Non ion ic Su p er ba se P (MeNCH2CH2)3N in th e Selective
Mon oa lk yla tion of Active-Meth ylen e Com p ou n d s
Subramaniam Arumugam, Dale McLeod, and J ohn G. Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received December 31, 1997
The symmetric active-methylene compounds CH2(CO2Et)2 and CH2[C(O)Me]2 are selectively
monoalkylated in the presence of 1.1 equiv of a variety of alkyl halides and 1 equiv of the nonionic
superbase P(MeNCH2CH2)3N in 85-98% yields in 30 min at room temperature. The unsymmetrical
active-methylene compound EtO2CCH2C(O)Me is selectively monoalkylated under the same
conditions, except for the temperature, which is 0 °C, in 59-88% yields. The observation of selective
C- rather than O-alkylation is rationalized in terms of the formation of an enolate whose negatively
charged oxygen is sterically protected by a nearby HP(MeNCH2CH2)3N+ counterion in a tight ion
pair.
In tr od u ction
Resu lts a n d Discu ssion
Here, we report monoalkylation reactions of 1-3 in the
presence of the commercially available nonionic super-
base 4. Substrates 1 and 2 are converted to their
monoalkylated products 5a -g and 6a -g, respectively
(Scheme 1) in very high yields (Table 1) with 100%
conversion of starting material and no formation of
corresponding dialkylated product (8a -g and 9a -g,
respectively) according to 1H NMR spectroscopy.7 Al-
though in the case of 3 unreacted starting material as
well as dialkylated side products 10a -g were detectable
by 1H NMR spectroscopy, respectable yields of mono-
alkylated product 7a -g were obtained (Table 1) under
the mild conditions employed in these reactions (Scheme
1).7
We suggest that the ease of alkylation of 1-3 encoun-
tered with 4 as a base is attributable to a basicity of 4
that exceeds that of DBU by 17 orders of magnitude,8
thus providing relatively high concentrations of enolate
ion for electrophilic attack by RX. We speculate that the
selective C-alkylation over O-alkylation we observe is due
Alkylations and acylations of active-methylene com-
pounds, such as malonic esters, â-diketones, and â-keto
esters, are important transformations in organic chem-
istry that have been explored extensively.1 Monoalky-
lated products of such substrates are highly useful
because of their ready conversion to the corresponding
ketenes or esters, and they also function as starting
materials for the preparation of R,â-unsaturated ketones2
and esters.3
A frequent difficulty encountered in attempts to
monoalkylate the aforementioned substrates is concur-
rent formation of a second C-alkylated side product,
O-alkylated systems and, in some cases, condensation
products. Significant O-alkylation is especially favored
when the equilibrium concentration of the enol tautomer
is relatively high, as with â-keto esters and â-diketones.
Numerous attempts to improve the efficiency of C-
alkylation have met with limited success. It has been
observed that O-alkylation can be inhibited by suppress-
ing the concentration of enolate ion using carefully
controlled reaction conditions,1a by coordinating the eno-
late oxygen to a metal cation,1a or by employing a
hydrogen-bonding solvent.4 A particularly efficacious
procedure for favoring C-alkylation with short-chain alkyl
iodides employs crystalline Tl(I) enolates that apparently
maintain ion pairing via partially covalent Tl+--O
binding in solution.5 However, such salts are not very
reactive as nucleophiles, and their reactions require
several hours in a refluxing solvent. Although active-
methylene compounds can be monoalkylated using DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene) as a base, yields are
moderate, reaction times are relatively long, and dialkyl-
ation as well as O-alkylation are observed.6
(6) Ono, N.; Yoshimura, T.; Saito, T.; Tamura, R.; Tanikaga, R.; Kaji,
A. Bull. Chem. Soc. J pn. 1979, 52, 1716.
(7) All reagents were used as received from chemical suppliers.
Base 4 was prepared as reported previously (Tang, J .-S.; Verkade,
J . G. Tetrahedron Lett. 1993, 34, 2903). Alkylations of 1 and 2
were carried out under N2 at 25 °C. Acetonitrile was dried by refluxing
over CaH2, and then it was distilled from CaH2 under nitrogen. The
general procedure for alkylating 1 and 2 was to dissolve 1 mmol each
of 4 and active methylene compound in 10 mL of dry CH3CN with
stirring. After the mixture was stirred for 10 min, a solution of 1.1
mmol of alkyl halide in 5 mL of CH3CN was added under nitrogen
and stirring was continued for 30 min. After all volatiles were removed
under vacuum, 20 mL of hexanes was added to the residue and the
solids were filtered off. The filtered material was subjected once
more to the same extraction/filtration cycle. Both filtrates were
combined, and the solvent was evaporated to give the alkylated product
in >98% purity as determined by 1H NMR spectroscopy. The general
procedure for alkylating 3 was to dissolve 1 mmol each of 4 and active
methylene compound in 10 mL of dry CH3CN with stirring. After the
mixture was stirred for 30 min at 0 °C, 1.1 mmol of alkyl halide was
added under nitrogen, and stirring was continued for 5 min at 0 °C.
After all volatiles were removed under vacuum, 20 mL of hexanes was
added, and then the solids were filtered off. The filtered material was
subjected once more to the same extraction/filtration cycle. Both
filtrates were combined, and the solvent was evaporated to give the
crude alkylated product. The monoalkylated product was isolated by
silica gel column chromatography using gradient elution with hexanes/
Et2O.
(1) (a) House, H. O. Modern Synthetic Research, 2nd ed.; Benjamin,
Inc.: Menlo Park, CA, 1972; p 492. (b) Cope, A. C.; Holmes, H. L.;
House, H. O. Org. React. 1957, 9, 108.
(2) Ono, N.; Tamura, R.; Hayami, J .; Kaji, A. Chem. Lett. 1977, 189.
(3) Ono, N.; Tamura, R.; Hayami, J .; Kaji, A. Tetrahedron Lett. 1978,
763.
(4) Kornblum, N.; Berrigan, P. J .; Lenoble, W. J . J . Am. Chem. Soc.
1963, 85, 1141.
(5) Taylor, E. C.; Hawkes, G. H.; McKillop, A. J . Am. Chem. Soc.
1968, 90, 2421.
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Published on Web 05/12/1998