Zinc-mediated alkylation and acylation of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1246/cl.2010.280

1,3-Dicarbonyl compounds undergo smooth allylation, benzylation, propargylation, and acylation with halides using metallic zinc in DMF at 60 °C to afford the corresponding allyl, benzyl, 2-propynyl, and acylated 1,3-diesters in good yields. In the case of cyclic 1,3-diketones, the corresponding enol ethers are obtained as sole products instead of C-alkylation.

Full text of DOI:10.1246/cl.2010.280

doi:10.1246/cl.2010.280
280
Published on the web February 16, 2010
Zinc-mediated Alkylation and Acylation of 1,3-Dicarbonyl Compounds
J. S. Yadav,* B. V. Subba Reddy, and Anand Kumar Mishra
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received December 9, 2009; CL-091091; E-mail: yadavpub@iict.res.in)
1,3-Dicarbonyl compounds undergo smooth allylation,
addition to malonate, ¢-ketoester, for instance, ethyl benzoyl-
benzylation, propargylation, and acylation with halides using
metallic zinc in DMF at 60 °C to afford the corresponding allyl,
benzyl, 2-propynyl, and acylated 1,3-diesters in good yields. In
the case of cyclic 1,3-diketones, the corresponding enol ethers
are obtained as sole products instead of C-alkylation.
acetate also participated well in C-benzoylation (Entry h,
Table 1). In the case of cyclic 1,3-diketones, the corresponding
¢-ketoenol ethers9 were obtained as sole products (Scheme 2,
Entries i-n, Table 1).
Table 1. Zinc-mediated alkylation and acylation of 1,3-dicar-
bonyl compounds
The development of new methods for efficient C-C bond
formation via alkylations and acylations of active methylene
compounds are important chemical transformations in organic
synthesis.1 Earlier approaches for monoalkylation and acylation
require the use of catalyst and the stoichiometric amount
of bases such as non-ionic super base P(MeNCH2CH2)3N,2a
Producta
Yield/%b
Entry
Time/h
Substrate
Alkyl halide
O
O
O
O
O
O
O
O
O
O
O
O
75
a
O
O
5.0
Br
Br
O
O
O
O
O
O
10.0
6.0
b
c
82
80
PdCl2/K2CO3,2b
(3S,4S)-1-benzyl-3,4-dihydroxy-1-methyl-
pyrrolidinium iodide,2c n-BuLi,2d BaH2,2e Et3N, and SmCl3.2f
In recent years, there have been some interesting reports for this
transformation which involve silicon-controlled alkylation of
1,3-dioxocompounds using allyltrimethylsilane and ceric ammo-
nium nitrate3 and C-alkylation by Mitsunobu reagents.4
The ¢-ketoenol ethers are also widely adaptable intermedi-
ates in organic synthesis.5 During recent years, activated zinc has
been used as a versatile promoter in organic synthesis and has
attracted great interest.6 Previously, we have reported some zinc-
catalyzed organic transformations.7
O
O
Br
O
O
O
Ph
O
O
O
O
O
O
O
d
e
O
O
O
O
O
O
Br
9.0
6.0
70
68
O
O
O
O
Cl
O
O
O
O
O
O
O
Cl
O
O
f
5.0
4.0
O
O
75
77
O
O
O
O
Ph
O
In continuation of our work on zinc-mediated reactions for
various transformations,8 we report herein a novel and simple
method for the monoalkylation and acylation of 1,3-dicarbox-
ylates and ¢-ketoesters using activated zinc metal. Initially, we
have attempted the coupling of diethyl malonate (1) with allyl
bromide (2) using zinc metal. The reaction proceeds smoothly in
DMF at 60 °C and the corresponding monoallyl derivative 3a
was obtained in 75% yield (Scheme 1).
Similarly, 2-propynyl bromide, benzyl bromide, and
prenyl bromide reacted effectively with diethyl malonate to
give the corresponding 2-propynyl, benzyl, and prenyl deriv-
atives of malonates respectively, in good yields (Entries b-d,
Table 1). Besides alkylation, we have attempted the acylation
of diesters as well. Interestingly, 1,3-dicarbonyl compounds
such as 1,3-diesters and ¢-ketoesters underwent smooth
acylation with acid chlorides. For instance, diethyl malonate
reacted smoothly with acetyl chloride, benzoyl chloride, and 2-
chlorobenzoyl chloride to furnish C-acyl or C-benzoyl deriv-
atives of malonates respectively (Entries e-g, Table 1). In
O
O
g
Cl
Cl
O
O
O
Cl
Cl
O
O
O
O
O
O
h
i
Ph
Ph
6.0
7.0
76
68
66
O
Ph
O
O
O
Br
Br
Br
O
O
O
O
j
9.0
O
O
O
O
k
l
10.0
5.0
76
86
O
O
O
O
Br
O
Ph
O
O
O
m
n
7.0
63
68
Br
O
O
O
O
Br
O
O
O
O
12.0
2
Br
O
O
O
O
O
Zn, DMF, 60 °C
1
3a
aThe products were characterized by NMR, IR, and mass
b
spectrometry. Yield refers to pure products after chromatog-
Scheme 1. C-Allylation of diethyl malonate with allyl bromide.
raphy.
Chem. Lett. 2010, 39, 280-281
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

281
O
O
References and Notes
1
O
Br
a) H. O. House, Modern Synthetic Research, 2nd ed.,
Benjamin, Inc., Menlo Park, CA, 1972, p. 492. b) A. C.
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Wang, X. Zhou, Org. Lett. 2007, 9, 4491.
Zn, DMF, 60 °C
O
OH
O
2
Scheme 2. O-Allylation of 1,3-cyclohexadione.
ZnBr
O
O
O
O
+
BrZn
EtO
OEt
EtO
OEt
Br
3
4
5
J. R. Hwu, C. N. Chen, S.-S. Shiao, J. Org. Chem. 1995, 60,
856.
O
O
EtO
OEt
T. Tsunoda, M. Nagaku, C. Nagino, Y. Kawamura, F. Ozaki,
H. Hioki, S. Itô, Tetrahedron Lett. 1995, 36, 2531.
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Venkanna, Tetrahedron Lett. 2007, 48, 7332.
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Krishna, J. S. Yadav, Tetrahedron Lett. 2005, 46, 7205. b) P.
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Scheme 3. A plausible reaction mechanism.
No C-alkylation was observed with cyclic 1,3-diketones
6
7
under these conditions. In the absence of zinc metal, no
alkylation or acylation was achieved in DMF alone. Further-
more, alkyl bromides such as propyl and butyl bromides were
ineffective for this reaction. Similarly, aryl bromides also failed
to give the desired product. Among various solvents such as
CH3CN, THF, and toluene studied for alkylation, DMF was
found to give high conversions. No bis-alkylation was observed
under the present reaction conditions whereas bis-alkylation
was common under base-promoted alkylations. The effects of
various metals such as zinc, indium, yttrium, and samarium were
studied for the alkylation. Of these, zinc was found to be the best
in terms of conversion. The present method may be useful for
alkylation and acylation especially for base sensitive substrates.
The results are presented in Table 1.10
8
9
Mechanistically, one equivalent of activated zinc and two
equivalents of allyl bromide would be enough for this reaction
(Scheme 3). But good yields were obtained when two equiv-
alents of both zinc and allyl bromide were used. Therefore,
further studies are in progress to explore the reaction mecha-
nism.
In conclusion, we have developed a simple, convenient, and
base-free protocol for the monoalkylation and acylation of active
methylene compounds such as 1,3-diesters and ¢-ketoesters.
This method is also effective for the preparation of enol ethers
from cyclic 1,3-diketones. The use of readily available zinc
metal makes this method simple, convenient, and practical.
10 Experimental procedure: To a stirred suspension of activated
zinc (86 mg, 1.24 mmol) in DMF (5 mL) under N2 at-
mosphere at 60 °C was added diethyl malonate (100 mg,
0.624 mmol) and stirred for 5 min and then allyl bromide
(149.8 mg, 1.24 mmol) was added. The resulting mixture
was allowed to stir at 60 °C for specified time (Table 1). The
progress of the reaction was monitored by TLC. After
completion as monitored by TLC, the reaction mixture was
quenched by saturated ammonium chloride solution and
extracted with ether (2 © 5 mL). The combined organic
layers were dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the resulting residue
was further purified by column chromatography on silica gel
(ethyl acetate/hexane, 1.5:98.5) to afford monoallyl deriv-
ative.
A. K. M. thanks CSIR, New Delhi, India for the award of a
fellowship.
Chem. Lett. 2010, 39, 280-281
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/