2266
J . Org. Chem. 1996, 61, 2266-2267
Sch em e 1a
Allyl a s P r otective Gr ou p for th e Acid ic
Hyd r ogen of Ma lon ic Ester
Takanori Yamazaki, Aleksandr Kasatkin,†
Yasufumi Kawanaka, and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of
Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226, J apan
Received J anuary 12, 1996
The malonic ester synthesis is one of the most funda-
mental methodologies in organic synthesis.1 The reaction
has been widely used for the preparation of mono- and
disubstituted acetic acids via mono- and dialkylation,
respectively, and subsequent hydrolysis and decarboxy-
lation. The presence of two acidic hydrogens in the
starting compound, however, sometimes causes difficulty
in applying this methodology in organic synthesis. Thus,
dialkylation becomes a significant side reaction in
monoalkylations of malonic ester with reactive alkyl
halides or R,ω-dihaloalkanes.1a,2 Another problematic
point is the fact that chemical transformations of func-
tional groups which can be introduced through monoalky-
lation are somewhat limited because of the presence of
an acidic hydrogen. It is, therefore, surprising that no
protective group for the acidic hydrogen of malonic ester
has been developed.3
a
Reagents and conditions: (a) NaH (1.05 equiv), THF, 20 °C,
1 h; (b) allyl bromide (1.2 equiv), 20 °C, overnight; (c) I(CH2)nI
(2.0 equiv), 20 °C, overnight; (d) Bu2CuLi (1.2 equiv), THF, 0 °C,
4 h; (e) Ti(O-i-Pr)4 (2.0 equiv), i-PrMgCl (4.0 equiv), Et2O, -45 to
-40 °C, 1 h; (f) 1 N HCl.
at -45 °C, the reaction mixture was stirred for 1 h at
-45 °C and then treated with benzaldehyde (-45 to 0
°C for 1 h) to provide, after hydrolysis, diethyl benzyl-
malonate and 1-phenyl-3-buten-1-ol in 97 and 89% yield,
respectively. This finding strongly indicated that the
reaction proceeded according to eq 1 as expected.
Recently, we found that allyl compounds CH2dCHCH2X
such as halides (X ) Cl, Br, or I) or alcohol derivatives
(X ) OCOCH3, OCOOC2H5, OTs) react with the titanium-
(II) compound (η2-propene)Ti(O-i-Pr)2 (1), readily gener-
ated in situ by the reaction of Ti(O-i-Pr)4 with 2 equiv of
i-PrMgX (X ) Cl, Br), to afford the corresponding
allyltitanium compounds.4 The reaction can be rational-
ized by a mechanism which involves ligand exchange of
the coordinated propene in 1 with the olefinic moiety of
the substrate and subsequent â-elimination. With these
findings we anticipated that allyl compounds where X )
RC(COOEt)2 might also furnish allyltitaniums on treat-
ment with 1, since the RC(COOEt)2 anion is stable and
thus might be a sufficiently good leaving group.5 If the
reaction proceeds in excellent yield, as expected, the allyl
group can be regarded as a protective group for the acidic
hydrogen of malonic ester. We pursued this possibility.
First, we examined the expected elimination reaction.
After addition of 4 equiv of i-PrMgCl to a mixture of
diethyl allyl(benzyl)malonate and 2 equiv of Ti(O-i-Pr)4
With this result in hand, we examined the potential
applicability of the reaction in organic synthesis. The
results described below show that the allyl group can
indeed be conveniently used as a protective group for the
acidic hydrogen of malonic ester.
Treatment of readily preparable and also commercially
available diethyl allylmalonate (2) with NaH and then
1,5-diiodopentane in THF provided the monoiodide 3 in
good yield. The reaction of 3 with Bu2CuLi in ether gave
the expected cross-coupling product 4 which upon reac-
tion with 1 provided the deallylated poduct 5 quantita-
tively as shown in Scheme 1. In contrast, the reaction
of diethyl 5-iodopentylmalonate (obtained similarly from
sodium diethyl malonate and 1,5-diiodopentane in 57%
yield) with Bu2CuLi furnished 5 in only 10% yield but
afforded diethyl cyclohexane-1,1-dicarboxylate in 90%
yield presumably via deprotonation and cyclization of the
resulting ester enolate. Although sodium diethyl mal-
onate mainly underwent monoalkylation by treatment
with 1,5-diiodopentane, it did not provide the correspond-
ing monoalkylated product 6 by reaction with 1,4-
diiodobutane in more than 5% yield, but afforded diethyl
cyclopentane-1,1-dicarboxylate in 62% yield via intramo-
lecular dialkylation.6 Compound 6, however, was readily
† On leave from the Institute of Organic Chemistry, Ufa Research
Center, Russian Academy of Sciences.
(1) (a) Cope, A. C.; Holmes, H. L.; House, H. O. In Organic Reactions;
Adams, R., Ed.; J ohn Wiley & Sons: New York, 1957; Vol. 9, p 107.
(b) House, H. O. Modern Synthetic Reactions; Benjamin: New York,
1972; p 492. (c) Mathieu, J .; Weill-Raynal, J . Formation of C-C Bonds;
Georg Thieme Publishers: Stuttgart, 1975; Vol. 2, p 12.
(2) For some improvements to avoid dialkylation, see: Brandstrom,
A.; J unggren, U. Tetrahedron Lett. 1972, 473. Bram, G.; Fillebeen-
Khan, T. J . Chem. Soc., Chem. Commun. 1979, 522.
(3) Protective Groups in Organic Chemistry; McOmie, J . F. W., Ed.;
Plenum Press: New York, 1973. Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis; J ohn Wiley & Sons: New York,
1991. Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: Oxford, 1991; Vol. 6, p 631.
(4) Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F. J . Am. Chem.
Soc. 1995, 117, 3881.
(5) Reactions in which the malonate carbanion can be regarded as
a leaving group have been reported as, for example, reactions of
cyclopropane-1,1-dicarboxylates with nucleophiles; see: Danishefsky,
S. Acc. Chem. Res. 1979, 12, 66. Hiyama, T.; Morizawa, Y.; Yamamoto,
H.; Nozaki, H. Bull. Chem. Soc. J pn. 1981, 54, 2151. Burgess, K. J .
Org. Chem. 1987, 52, 2946. However, there is no precedent to use this
type of reactions for protection of malonates.
(6) It is known that cyclization of carbanions derived from (ω-
haloalkyl)malonates to five-membered carbocycles is much faster than
to six-membered ones, see: Knipe, A. C.; Stirling, C. J . M. J . Chem.
Soc. B 1968, 67. Casadei, M. A.; Galli, C.; Mandolini, L. J . Am. Chem.
Soc. 1984, 106, 1051.
0022-3263/96/1961-2266$12.00/0 © 1996 American Chemical Society
Yamazaki, Takanori
