Synthesis of benzofuran-containing spirolactones from diarylcyclopropenones

Article abstract of DOI:10.1016/j.tetlet.2013.12.115

Several novel benzofuran-containing spirolactones were synthesized and characterized using copper-catalyzed heterodimerization of 1,2- diarylcyclopropenones, and followed by sequential intramolecular cyclopropene ring opening and oxidative cyclization.

Full text of DOI:10.1016/j.tetlet.2013.12.115

Tetrahedron Letters 55 (2014) 1207–1211
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of benzofuran-containing spirolactones
from diarylcyclopropenones
⇑
Jia-Ru Syu, Chi-Hui Lin, Chiao-Wen Kuo, Ding-Yah Yang
Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 40704, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Several novel benzofuran-containing spirolactones were synthesized and characterized using copper-
catalyzed heterodimerization of 1,2-diarylcyclopropenones, and followed by sequential intramolecular
cyclopropene ring opening and oxidative cyclization.
Received 16 November 2013
Revised 25 December 2013
Accepted 31 December 2013
Available online 8 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
1,2-Diarylcyclopropenone
Spirolactone
Dimerization
Benzofuran
Introduction
the synthesis and characterization of three o-hydroxyphenylcyc-
lopropenone-derived, benzofuran-containing spirolactones from
Ever since the synthesis of diphenylcyclopropenone was re-
ported half a century ago,1 the chemistry and properties of cyclop-
ropenone and its related cyclopropenylium derivatives2 have
inspired substantial research on account of the unusual aromatic-
1,2-diarylcyclopropenones.
Results and discussion
ity associated with this two-p-electron motif. Even today, this
Scheme 1 outlines the synthesis of the spirolactone 1. It started
with the coupling of p-methylanisole (2) with perchlorocycloprop-
1-ene (3) in the presence of aluminum chloride at low temperature
to give 2,3-bis(2-methoxy-5-methylphenyl)cycloprop-2-enone
(4).9 Compound 4 was then coupled with commercially available
1,2-diphenylcyclopropenone (5) under the influence of a catalytic
amount of copper bromide in 1,2-dichloroethane at 75 °C to obtain
the spirolactone 6.6 Selective demethylation of one of the two
methoxy groups on 6 with 1.2 equiv of tribromoborane followed
by in situ cyclopropene ring opening afforded the benzofuran 7.
The subsequent demethylation of the second methoxy group of 7
with tribromoborane induced the oxidative cyclization of the lac-
tone and phenol moiety to furnish the target spirolactone 1. The
molecular structures of 7, 1, and 6 were all elucidated by the X-
ray crystallography as shown in Figures 1 and 2.10
smallest Huckel aromatic continues to attract researchers’ atten-
tion for its unique aromatic cation properties. For instances, Peart
and Tovar3 have incorporated the cyclopropenium moiety into
p-conjugated polymers and found that the increased contributions
of cyclopropenium cation aromaticity restrict the quinoidal charge
carriers. Kelly and Lambert have recently reported the use of
diphenylcyclopropenone as a catalyst to catalyze cyclodehydration
of diols4 and to activate the substitution of alcohols with mesylate
ion.5 Our group was attracted by one of the unique properties of
diphenylcyclopropenone, that is, its ease of dimerization to the
corresponding cyclopropene spirolactone under the influence of
transition metal catalysts.6 We envision the resulting spirolactone,
in the presence of an intramolecular nucleophile, is prone to un-
dergo cyclopropene ring opening reaction due to its intrinsic
strained structure. The proposed ring-opened product is presum-
ably susceptible to oxidative cyclization to afford the benzofu-
ran-containing spirolactone. Since spirolactones are well-known
heterocycles that exhibit various biological7 and functional proper-
ties,8 the design and synthesis of spirolactones with novel molecu-
lar skeletons remain desirable. Here, we describe our effort toward
In the coupling reaction between 4 and 5, four possible
regioisomers were expected. To our delight, the desired product
6 was the major isomer with the ratio of the major product to other
combined three regioisomers to be approximately 7 to 1. The X-ray
crystal structure of the major coupling product
6 (Fig. 2)
unambiguously revealed that the two methoxyphenyl groups were
attached to the cyclopropene ring. Scheme 2 depicts the proposed
mechanism for the Cu(I)-catalyzed heterodimerization of 4 and 5
to 6. We envisioned that the first step involves the preferred
⇑
Corresponding author. Tel.: +886 4 2359 7613; fax: +886 4 2359 0426.
E-mail address: yang@thu.edu.tw (D.-Y. Yang).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.115

1208
J.-R. Syu et al. / Tetrahedron Letters 55 (2014) 1207–1211
O
Ph
O
O
OMe
OMe
OMe
1. AlCl3, CH2Cl2
-20 oC, 45 min
Cl
Cl
Ph
cat. CuBr
Ph
Ph
O
5
MeO
+
2. H2O, 86%
Cl
Cl
ClCH2CH2Cl
75 oC, 12 h
70%
MeO
2
3
4
6
1. BBr3
CH2Cl2, 0 oC, 3 h
2. H2O, 54%
O
Ph
Ph
O
O
O
1. BBr3, CH2Cl2
Ph
H
Ph
0
oC, 3 h
O
OMe
2. H2O, 67%
O
O
1
7
Scheme 1. Synthesis of the spirolactone 1.
Figure 1. X-ray crystal structures of 7 and 1.
chelation of copper(I) with 4 rather than 5, since the former con-
tains two potential chelating sites, that is, the o-methoxy and car-
bonyl oxygens; the latter, however, contains only one. The
resulting 8 then undergoes single-electron transfer from copper(I)
to the attached carbonyl oxygen to yield the radical anion 9. The
negatively charged oxygen of 9 selectively attacks the carbonyl
carbon of 5, which is more electrophilic than that of 4, to yield
the radical anion 10. The subsequent back electron transfer from
the cyclopropene radical moiety of 10 to copper(II) affords the
zwitterion 11. Final ring opening of the dioxygen-substituted
cyclopropene ring of 11 and subsequet neutralization of the posi-
tively charge on the other cyclopropene ring furnish the product
6, along with the regenerated copper(I) catalyst. Presumably, the
high chemoselectivity of this heterodimerization can be attributed
to the combination of chelate11 and electronic effects.
In the first demethylation step, the isolation of the benzofu-
ran 7, rather than the corresponding demethylated phenol deriv-
ative, suggests that the cyclopropene spirolactone moiety is
highly susceptible to ring opening via an intramolecular nucleo-
philic attack to release the ring strain.12 Scheme 3 depicts the
proposed mechanism for the formation of 7 from 6. After BBr3-
mediated demethylation of 6, the boron-complexed phenoxide
Figure 2. X-ray crystal structure of the spirolactone 6.

J.-R. Syu et al. / Tetrahedron Letters 55 (2014) 1207–1211
1209
Cu+
Cu2+
O
O
MeO
OMe
MeO
MeO
Cu+
+
4
9
8
5
Ph
Ph
O
O
O
Ph
+Cu
MeO
Ph
Cu2+
O
OMe
MeO
OMe
Cu+
6
+
11
Scheme 2. Possible mechanism for the generation of 6 from 4 and 5 in the presence of copper(I).
10
Br
Br
Br
Br
Br
Br
B
B
O
Ph
Ph
OMe
O
Ph
Ph
BBr3
H2O
O
O
6
7
OMe
O
O
B
Br
Br
12
13
Scheme 3. Proposed mechanism for the formation of 7 from 6.
O2N
O
O
O
4
1. HNO3, H2SO4
0 oC, 2 h
O
NO2
cat. CuBr
MeO
Ph
Ph
ClCH2CH2Cl
75 oC, 12 h
82%
2. H2O, 90%
5
MeO
NO2
NO2
16
17
1. BBr3, CH2Cl2
0 oC, 3 h
2. H2O, 64%
O2N
O2N
O
NO2
NO2
O
O
1. BBr3, CH2Cl2
0 oC, 3 h
O
H
O
OMe
2. H2O, 50%
O
O
14
18
Scheme 4. Synthesis of the nitro substituted spirolactone 14.

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J.-R. Syu et al. / Tetrahedron Letters 55 (2014) 1207–1211
O
OMe
OMe
OMe
1. AlCl3, CH2Cl2
Cl Cl
-20 oC, 45 min
+
2. H2O, 94%
MeO
Ph
OMe
Cl
Cl
MeO
20
19
3
O
cat. CuBr
ClCH2CH2Cl
75 oC, 12 h
71%
Ph
O
5
O
Ph
Ph
Ph
Ph
O
O
O
1. BBr3, CH2Cl2
0 oC, 3 h
Ph
OMe
Ph
1. BBr3, CH2Cl2
0 oC, 3 h
O
O
OMe
H
HO
OMe
MeO
2. H2O, 67%
MeO
2. H2O, 62%
O
O
OMe
OH
21
15
22
OMe
Scheme 5. Synthesis of the spirolactone 15.
the pyran moiety of 1. Schemes 4 and 5 show the syntheses of the
m-nitro-substituted spirolactone 14 and the m-hydroxyl-substi-
tuted spirolactone 15, respectively. For the preparation of 14, it
called for first nitration of diphenylcyclopropenone (5) with nitric
acid in sulfuric acid to give 2,3-bis(3-nitrophenyl)cycloprop-2-en-
one (16).14 Compound 16 was then coupled with 4 under the influ-
ence of a catalytic amount of CuBr in 1,2-dichloroethane to obtain
the spirolactone 17. The subsequent sequential demethylations,
followed by the exact same reaction procedures as that of 1, affor-
ded the benzofuran 18 and the desired spirolactone 14. Figure 3
shows the X-ray crystal structures of 17, clearly revealing that
the two m-nitrophenyl groups were attached to the lactone
moiety.10
For the preparation of the m-hydroxyl-substituted spirolactone
15 (Scheme 5), it was synthesized by the same method as that of
1, except that p-methylanisole (2) was replaced with 1,3-dime-
thoxybenzene (19). The molecular structures of 20–22 and 15 were
all elucidated by 1H and 13C NMR spectroscopy. While various at-
temptsto crystallizethe spirolactone 15proved to be futile, its struc-
ture was indirectly confirmed by dimethylations of 15 via excess of
methyl iodide in the presence of K2CO3 as a base in acetonitrile to af-
ford 23, in which the X-ray crystallography is shown in Figure 4.10
While 1,2-diarylcyclopropenones have long served as precur-
sors for the preparation of various molecular skeletons,15 to the
best of our knowledge, this synthetic strategy, that is, dimerization
of diarylcyclopropenone, intramolecular cyclopropene ring open-
ing, and oxidative cyclization, represents the first example of
utilizing 1,2-diarylcyclopropenone to the preparation of the benzo-
furan-containing spirolactone derivatives.
Figure 3. X-ray crystal structure of the spirolactone 17.
ion 12 attacks the nearby cyclopropenyl carbon to give the ring-
opened vinylogous boronenolate 13. Presumably, this intramo-
lecular nucleophilic attack is facilitated by the coordination of
boron to the lactone carbonyl oxygen atom of 12. The resulting
boronenolate 13 is then trapped by water to afford the product
benzofuran 7. In the second demethylation step, the Lewis acid-
promoted oxidative cyclization of the demethylated benzofuran
7 to the spirolactone 1 is not unprecedented. Similar oxidative
cyclization reactions have been previously reported in the
literature.13
In an effort to investigate the scope and limitation of this syn-
thesis and to tune the potential functional properties of the target
compound by the substituent effect, we incorporated an electron-
withdrawing group onto the two phenyl groups of the lactone moi-
ety and an electron-donating group onto the two phenyl groups of
Conclusions
In summary, we have developed an efficient route for the con-
struction of a novel benzofuran-containing spirolactone skeleton
via copper-catalyzed heterodimerization of 1,2-diarylcycloprope-
nones, and followed by sequential demethylations of highly
strained cyclopropene-derived spirolactones. Three compounds
(1, 14, and 15) were synthesized as examples for illustration and
their molecular structures were all confirmed by the X-ray crystal-
lography. Further investigation of the functional properties of the
prepared spirolactones is currently underway and will be reported
in due course.

J.-R. Syu et al. / Tetrahedron Letters 55 (2014) 1207–1211
1211
Figure 4. X-ray crystal structure of the spirolactone 23.
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Acknowledgment
We thank the National Science Council of the Republic of China,
Taiwan, for financially supporting this research under Contract No.
NSC 100-2113-M-029-005-MY2.
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Supplementary data
10. Crystallographic data (excluding structure factors) for 1, 6, 7, 17, and 23 have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC-814311, -814309, -814310, -826478,
and -962737, respectively. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.
ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
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