Intramolecular Michael addition reaction for the synthesis of benzylbutyrolactones

Article abstract of DOI:10.1039/b924770j

A convenient synthesis of benzyl-γ-butyrolactone derivatives via intramolecular Michael addition reaction of nitro-substituted aryl allyl β-ketocarboxylates is reported. The method features simple operation, mild reaction conditions and high efficiency. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b924770j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Intramolecular Michael addition reaction for the synthesis of
benzylbutyrolactones†
Hu He, Li-Xin Dai and Shu-Li You*
Received 25th November 2009, Accepted 28th April 2010
First published as an Advance Article on the web 20th May 2010
DOI: 10.1039/b924770j
A convenient synthesis of benzyl-g-butyrolactone derivatives via intramolecular Michael addition
reaction of nitro-substituted aryl allyl b-ketocarboxylates is reported. The method features simple
operation, mild reaction conditions and high efficiency.
The structure of the Michael addition product was further
Introduction
confirmed by an X-ray crystallographic analysis (Fig. 1).11 Al-
though various a,b-unsaturated compounds have been used in the
Michael addition reaction, to our knowledge, this represents a rare
example of the application of an electron-deficient phenyl alkene
as the Michael acceptor. Notably, a similar cyclization reaction
has also been observed by Craig and coworkers during their
study on the decarboxylative Claisen rearrangement reactions
of diallyl 2-sulfonylmalonates; however, only moderate yield was
obtained.12 An elegant study by Tan and Chen demonstrated
that Mn(OAc)3 could promote a similar cyclization efficiently
via a radical process.13 The extensive synthetic efforts towards
g-butyrolactone derivatives14 emboldened us to carry out further
studies into this Michael addition reaction.
The lignan1 lactones have attracted considerable interest over
the years because of their broad biological activities.2,3 Diben-
zylbutyrolactones, such as enterolactone 1 and matairesinol 2,
are such examples of bioactive lignans. Recent investigations
have shown that enterolactone 1 inhibits breast and colon cancer
and suppresses the growth of prostate cancer cells.4 Matairesinol
2 and its analogs have also been demonstrated to be potent
inhibitors of HIV-type 1 integrase.5 In addition to antitumor
and antiviral activities, these compounds display phytoestrogenic,6
immunoregulatory,7 and neuroprotective properties.8 Despite their
enormous biological applications, there have been only a few
synthetic studies documented in the literature.9
Recently, we reported the Ir-catalyzed decarboxylative alkyla-
tion of g-substituted allyl b-ketocarboxylates.10 Highly regio- and
enantioselective allylation of ketone enolates has been achieved
through Ir-catalyzed decarboxylative allylic alkylation of allyl
b-ketocarboxylate (eqn (1)). Surprisingly, when 4-nitrocinnamyl
3-oxo-3-phenylpropanoate (3a) was tested under the same reaction
conditions, no decarboxylative alkylation product was obtained
but an intramolecular Michael reaction proceeded, affording
g-butyrolactone 4a.
(1)
State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai, 200032, P. R. China. E-mail: slyou@mail.sioc.ac.cn; Fax: (+86)
21-54925087
Fig. 1 X-Ray crystal structure of 4a (thermal ellipsoids are set at 30%
probability).
† Electronic supplementary information (ESI) available: Experimental
procedures and analysis data for new compounds. CCDC reference
numbers 747012 (4a) and 747013 (4j). For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b924770j
Further investigation of the reaction disclosed that DBU alone
could catalyze the intramolecular Michael addition to afford
trans-g-butyrolactones (eqn (2)). Herein, we report our detailed
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Table 1 Optimization of the reaction conditions for the Michael addition
of 3aa
Table 2 Substrate scope for the intramolecular Michael addition
reactiona
Entry
R1, R2, 4
t/h
Yield (%)b
Entry Solvent Base
Base (mol%) T/◦C
t/h Yield (%)b
1
2
3
4
5
6
7
4-NO2, Ph, 4a
10
36
3
8
8
8
8
24
30
14
98
90
96
96
93
99
93
75
1
2
3
4
5
6
7
8
CH2Cl2 DBU
CH2Cl2 Et3N
CH2Cl2 Et3N
CH2Cl2 DBN
CH2Cl2 KOAc
CH2Cl2 DABCO 100
CH2Cl2 Cs2CO3 100
CH2Cl2 K2CO3
CH2Cl2 DIEA
CH2Cl2 BSA
CH2Cl2 TMP
CH2Cl2 PS
100
100
100
100
100
Reflux
25
Reflux 36
2
12
79
Trace
82
4-NO2, 4-Me-C6H4, 4b
4-NO2, 4-MeO-C6H4, 4c
4-NO2, 4-Cl-C6H4, 4d
4-NO2, 4-Br-C6H4, 4e
4-NO2, 2-naphthyl, 4f
4-NO2, 2-furyl, 4g
4-NO2, i-Pr, 4h
25
25
25
25
25
25
25
25
25
8
77
12
12
12
12
12
12
12
12
NR
NR
NR
NR
NR
NR
NR
NR
NR
86
94
85
93
89
8
100
100
100
100
100
9c
10c
4-NO2, Me, 4i
71
83 (4 : 1)
9
4j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CH2Cl2 Quinine 100
CH2Cl2 DBU
CH2Cl2 DBU
Reflux 12
25
Reflux 36
Reflux
Reflux 12
Reflux 18
60
60
60
60
25
100
20
20
10
5
10
10
10
10
10
4
11
12
13
14
15
2-NO2, Ph, 4k
3-NO2, Ph, 4l
2-NO2, 4,5-MeO,MeO Ph, 4m
4-NO2, 4-NO2, 4n
12
n.r.
12
6
92
—
72
76
72
THF
THF
THF
DBU
DBU
DBU
2
4o
10
toluene DBU
43
43
8
1.5
10
62
48
99
99
EtOH
DME
DMF
DMF
DBU
DBU
DBU
DBU
98
16
4p
13
78
a Reaction conditions: 0.1 M of 3a. b Isolated yields.
studies on this DBU-catalyzed intramolecular Michael addition
reaction.
a Reaction conditions: 10 mol% of DBU, 0.1 M of 3 in DMF, rt. b Isolated
(2)
yields. c Reaction was run at 60 ◦C.
were all tolerated, and the reaction at 60 ◦C in DMF gave 4a
in almost quantitative yield (99%) in 1.5 h (entry 22, Table 1).
Notably, the reaction in DMF with 10 mol% DBU at room
temperature could also give 4a in 98% yield (entry 23, Table 1).
Given the mildness of these reaction conditions, they were chosen
as the optimal reaction conditions.
Results and Discussion
Initially, 4-nitrocinnamyl-3-oxo-3-phenylpropanoate (3a) was
chosen as a model substrate to optimize the reaction conditions.
The results are summarized in Table 1.
In the presence of 1 equiv. of DBU, refluxing 3a in CH2Cl2 for
2 h afforded the cyclized product 4a in 79% yield (entry 1, Table 1).
We first examined different bases, as no reaction occurred without
DBU. Most of the bases, such as KOAc, DABCO, Cs2CO3, K2CO3,
DIEA, BSA, Proton Sponge and quinine were not suitable for this
transformation (entries 5–13, Table 1), only DBN, Et3N and DBU
could promote this reaction (entries 1–4, Table 1). With Et3N, the
desired product 4a was obtained only in trace amounts at 25 C
but in 82% yield in boiling dichloromethane (entries 2–3, Table 1).
In the presence of 1 equiv. of DBN at 25 C, 4a was isolated in
77% yield (entry 4, Table 1). In general, a relatively strong base is
needed for the Michael addition reaction.
In the presence of 10 mol% DBU in DMF at 25 ◦C, various
substrates were tested and the results are summarized in Table 2.
Substrates bearing either electron-donating groups (Me, MeO,
entries 2–3, Table 2) or electron-withdrawing groups (Cl, Br,
NO2, entries 4, 5, and 14, Table 2) on the b-aryl keto esters
were well tolerated and led to their corresponding products in
excellent yields (76–96%). The reaction of 2-furyl and 2-naphthyl-
substituted substrates 3f and 3g occurred also in excellent yields
(93 and 99%, entries 6–7, Table 2). Under the same conditions,
substrates 3h and 3i, derived from b-alkyl keto esters, could also be
tolerated to afford the addition products in 71–75% yields (entries
8–9, Table 2). When substrate 3j was used, a spiro product 4j was
obtained in 83% yield. The structure of the major diastereoisomer
was confirmed by X-ray crystallographic analysis.15
◦
◦
After examining the loading of DBU, an excellent yield (93%)
was obtained with 10 mol% of DBU (entries 14–18, Table 1).
Different solvents such as toluene, THF, EtOH, DME and DMF,
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Moreover, 2-nitro- and 3-nitro-substituted substrates 3k and
3l were tested in this reaction (entries 11–12, Table 2). Substrate
3k bearing a 2-nitro group underwent cyclization smoothly to
give the corresponding product 4k in 92% yield. However, the
reaction with 3-nitro-substituted substrate 3l failed to give the
desired Michael addition product. Only starting material was
of the nitro group in the products makes the current methodology
particularly attractive in organic synthesis.
Experimental
General procedure for the synthesis of benzylbutyrolactone
derivatives 4
◦
recovered, even at elevated reaction temperature (60 C). To our
delight, substrates 3m and 3p proceeded the Michael addition
reaction smoothly to give butyrolactones 4m and 4p in 72 and
78% yield respectively (entries 13 and 16, Table 2). The toleration
of various substituents in the substrates highly broadens the utility
of the current methodology. In addition to the Michael reaction
for C nucleophiles, the aza-Michael reaction was explored. When
substrate 3o was used, the corresponding aza-Michael product 4o
was isolated in 72% yield (entry 15, Table 2).
A straightforward catalytic cycle was proposed as depicted in
Scheme 1. Upon treatment with DBU, substrate 3a will lead to the
formation of the carbanion intermediate I. The strong electron-
withdrawing nature of nitro group facilitates the intramolecular
Michael addition generating intermediate II, which leads to the
formation of product 4a after the protonation and generates DBU
to complete the catalytic cycle.
A flame dried Schlenk tube was cooled to room temperature and
filled with argon. To this flask, b-ketoesters 3 (0.2 mmol), DBU
(0.02 mmol, 3 mg) and DMF (2 mL) were added. The reaction
mixture was stirred at room temperature or 60 ◦C. After the
reaction was complete (monitored by TLC), the reaction mixture
was diluted with Et2O and saturated NH4Cl. The organic layer
was separated, and the aqueous layer was extracted three times
with Et2O. The combined organic layers were dried over Na2SO4,
and concentrated to afford the crude product. The residue was
purified by silica gel column chromatography to afford the desired
product 4.
Full experimental details and characterization data are given in
the ESI.†
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (20821002, 20872159, 20932008), National Basic
Research Program of China (973 Program 2009CB825300), and
the Chinese Academy of Sciences for generous financial support.
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Scheme 1 DBU-catalyzed intramolecular Michael addition reaction.
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15 CCDC 747013 contains the supplementary crystallographic data
for major diastereomer of 4j. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk /data request/cif, and are in the ESI.† Crystal
data for compound 4j: C15H15NO5, M = 289.28, Monoclinic, a =
6.8274(9) A, a = 90◦, b = 8.8266(11) A, b = 96.661(2)◦, c = 23.345(3)
A, g = 90◦, V = 1397.3(3) A3, T = 293(2) K, space group = P21/c,
Z = 4, Number of Reflections = 7130, Independent reflections = 2597
[R(int) = 0.0997], Final R indices [I > 2d(I)] R1 = 0.0632, wR2 = 0.1538,
R indices (all data) R1 = 0.0808, wR2 = 0.1656.
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These data can be obtained free of charge from the Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk /data request/cif,
and are in the ESI.† Crystal data for compound 4a: C18H15NO5, M =
325.31, Monoclinic, a = 5.8692(11) A, a ◦= 90◦, b = 7.6984(14) A,
b = 94.634(3)◦, c = 34.643(7) A, g = 90 , V = 1560.2(5) A3, T =
293(2) K, space group = P21/c, Z = 4, Number of Reflections = 8662,
Independent reflections = 3360 [R(int) = 0.1004], Final R indices [I >
3210 | Org. Biomol. Chem., 2010, 8, 3207–3210
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The Royal Society of Chemistry 2010
©