Copper-mediated reaction of oxazirconacyclopentenes with but-2-ynedioates: A new pathway for the formation of α-methylene-δ-lactone derivatives

Article abstract of DOI:10.1021/om2006134

Oxazirconacyclopentenes reacted with but-2-ynedioates in the presence of CuCl via tandem Michael addition/nucleophilic substitution to afford α-methylene-δ-lactone derivatives.

Full text of DOI:10.1021/om2006134

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Copper-Mediated Reaction of Oxazirconacyclopentenes with But-2-
ynedioates: A New Pathway for the Formation of α-Methylene-δ-
lactone Derivatives†
Yiqing Zhou,‡ Yuxing Wang,‡ and Chanjuan Xi*,‡,§
‡Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, People's Republic of China
§State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People's Republic of China
S Supporting Information
b
ABSTRACT: Oxazirconacyclopentenes reacted with but-2-ynedioates in the
presence of CuCl via tandem Michael addition/nucleophilic substitution to
afford α-methylene-δ-lactone derivatives.
he formation of cyclized compounds is an essential process
in organic synthesis, and metallacycles can be important
Scheme 1
T
intermediates for transformation into cyclic compounds.1 In this
regard, five-membered zirconacycles, which can be easily pre-
pared by reductive coupling of two molecules of unsaturated
compounds on a zirconocene(II) species2 and can participate in a
number of organic reactions,3 are especially attractive. Recently,
it has been reported that zirconacyclopentadiene reacted with
but-2-ynedioates in the presence of CuCl, resulting in a 1,2-
cycloaddition, to afford phthalate derivatives.4 The zirconacyclo-
pentadienes reacted with propynoates, resulting in a 1,1-cycload-
dition, to afford cyclopentadienylacetate derivatives.5 Furthermore,
oxazirconacyclopentenes reacted with the propynoates in the pre-
sence of CuCl, resulting in a 1,1-cycloaddition, to afford 2-(2,5-
dihydrofuran-2-yl)acetate derivatives.6 In all the above reactions, the
last intramolecular cyclization occurred at the carbon of the original
triple bond (Scheme 1). However, there has been no report for
the intramolecular cyclization of zirconacycles and acetylenic ester
directly occurring at the carbon of carbonyl, to the best of our
knowledge. Herein we report a novel reaction of oxazirconacyclo-
pentenes with but-2-ynedioates in the presence of CuCl, affording α-
methylene-δ-lactone derivatives, in which the last intramolecular
cyclization occurred at the carbon of the carbonyl via nucleophilic
substitutions.
Scheme 2
instead of hydrolysis of the reaction mixture afforded the
monodeuterated compound 3a in 82% yield with 92% deuterium
incorporation. This result indicates that one metalÀcarbon bond
remained before hydrolysis.
α-Methylene-δ-lactone skeletons are frequently found in
natural products and medicaments.7 Various substituent groups
make α-methylene-δ-lactones as excellent candidates in activity
of medicaments. The reaction described here allowed the effi-
cient synthesis of various substituted α-methylene-δ-lactones.
A typical procedure is as follows. To a solution of oxazirco-
nacylopentene in THF (5 mL), prepared from Cp2ZrCl2 (292
mg, 1 mmol), EtMgBr (1 M THF solution, 2 mL, 2 mmol),
3-hexyne (114 μL, 1 mmol), and pentan-3-one (106 μL, 1
mmol) according to the reported procedure,2e,k was added
diethyl but-2-ynedioate (170 mg, 1 mmol) and CuCl (198 mg,
2 mmol). The reaction mixture was stirred at room temperature
for 3 h and quenched with 3 N HCl solution (Scheme 2). After
separation and purification by column chromatography, α-
methylene-δ-lactone 2a was obtained in 83% yield. Deuteriolysis
Received: July 10, 2011
Published: September 07, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/om2006134 Organometallics 2011, 30, 5077–5079
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COMMUNICATION
Table 1. Reaction of Oxazirconacycles with But-2-ynedioates
in the Presence of CuCl
Figure 1. Perspective view of 2l.
Scheme 3
(entries 6À8) was observed. For PhCtCMe, the ratio of
the two isomers is 1:1. For PhCtCEt, the ratio of the two iso-
mers is 6:1. For TMSCtCBun, the ratio of the two isomers
is 20:1. When unsymmetrical ketone was used, a 1.1:1 mixture of
diastereoisomer was formed (entry 9). To our delight, the
crystals of 2l were suitable for an X-ray diffraction analysis, and
its structure was confirmed as α-methylene-δ-lactone (Figure 1).
It is noteworthy that when diethyl maleate and fumarate were
used instead of but-2-ynedioates, the reaction resulted in the
formation of a complicated reaction mixture.
To elucidate the lactone ring formation before hydrolysis or
after hydrolysis, the following experiments were conducted. The
reaction mixture of the oxazirconacyclopentene 1a and dimethyl
but-2-ynedioate in the presence of CuCl was treated with iodine
at room temperature for 3 h, and the iodinated compound 7 was
obtained without hydrolysis. Moreover, on monitoring of the
reaction by NMR, the 13C NMR (C6D6, Me4Si) spectrum
showed a signal at 90.50 ppm assigned to an sp3 carbon of the
lactone ring, consisting of the sp3 carbon of the lactone ring in the
product 2d. These results show that the lactone ring formed
before hydrolysis.
On the basis of the results obtained here, the following re-
action mechanism can be proposed for the formation of α-
methylene-δ-lactone (Scheme 3). In the first step the ZrÀC
bond of is transmetalated to CuÀC bond to give 4.8,3mÀ3o The
a Isolated yield. b A 1:1 mixture of two regioisomers. c A 6:1 mixture
of two regioisomers; major isomer is shown. d A 20:1 mixture of
two regioisomers; major isomer is shown. e A 1.1:1 mixture of two
diastereoisomers.
Some representative examples of the reaction are summarized
in Table 1. Reaction of both monocyclic (entries 1À9) and
spirocyclic (entries 10À12) oxazirconacyclopentenes with but-2-
ynedioate gave the corresponding α-methylene-δ-lactone deri-
vatives in good to high yields after hydrolysis. When unsymme-
trical alkynes were used, the formation of two regioisomers
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Organometallics
COMMUNICATION
Scheme 4
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intermediate 4 then adds to the triple bond of but-2-ynedioate
via Michael addition to give metallodiene derivative 5, which
undergoes intramolecular nucleophilic substitution on the ester
group with elimination of Cp2ClZrOR to form γ-metallo-α-
methylene-δ-lactone 6. Hydrolysis of 6 affords α-methylene-δ-
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The remaining CuÀC bond of intermediate 6 could be
converted into functionalized α-methylene-δ-lactones by cou-
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products in good yields (Scheme 4).
In summary, an unprecedented reaction of oxazirconacyclo-
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’ ASSOCIATED CONTENT
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: cjxi@tsinghua.edu.cn.
’ ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (Nos. 20872076, 20972085, and 21032004)
and by the Specialized Research Fund for the Doctoral Program of
Higher Education (No. 200800030072).
’ DEDICATION
†Dedicated to Professor Christian Bruneau on the occasion of
his 60th birthday.
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