Selective formation of spiro dihydrofurans and cyclopropanes through unexpected reaction of aldehydes with 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ol900451d

An efficient methodology for the oxidative addition reaction of various aldehydes with 5,5-dimethylcyclohexane-1,3-dione and 1,3-indandione to selectively afford spiro dihydrofuran and cyclopropane derivatives, promoted by molecular iodine and dimethylami

Full text of DOI:10.1021/ol900451d

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2385-2388
Selective Formation of Spiro
Dihydrofurans and Cyclopropanes
Through Unexpected Reaction of
Aldehydes with 1,3-Dicarbonyl
Compounds
Guan-Wu Wang* and Jie Gao
Hefei National Laboratory for Physical Sciences at Microscale and Department of Chemistry,
UniVersity of Science and Technology of China, Hefei, Anhui 230026, P. R. China
gwang@ustc.edu.cn
Received March 4, 2009
ABSTRACT
An efficient methodology for the oxidative addition reaction of various aldehydes with 5,5-dimethylcyclohexane-1,3-dione and 1,3-indandione
to selectively afford spiro dihydrofuran and cyclopropane derivatives, promoted by molecular iodine and dimethylaminopyridine under mechanical
milling conditions, has been demonstrated. The products were obtained in good to excellent yields. A possible mechanism of this unusual
reaction process is proposed.
Substituted dihydrofurans occur frequently in numerous
natural compounds, showing important biological activities
and wide applications in pharmaceutical use.1 Due to their
important use in organic synthesis, the synthetic methodolo-
gies for dihydrofurans have been studied for many years.
Dimroth and Pasedach presented a methodology to synthesize
2,3-dihydrofurans from the dehydration of 1,4-diols under
high temperature and pressure conditions.2 The intramolecu-
lar cyclization of alkynyl alcohols to generate 2,3-dihydro-
furans was realized by the promotion of a pentacarbonyl-
molybdenum/triethylamine complex.3 The dihydrofuran moiety
could also be constructed by Rh-catalyzed reactions of diazo
compounds or iodonium ylides with alkenes.4 More com-
monly, oxidative cyclization of active methylene compounds
with alkenes by metal salts, such as manganese(III) acetate
and cerium(IV) ammonium nitrate, to generate the requisite
dihydrofuran motif received considerable attention.5
Cyclopropane rings are also ubiquitous in biologically
active compounds.6 The construction of cyclopropane rings
(3) Mcdonald, F. E.; Connolly, C. B.; Gleason, M. M.; Towne, T. B.;
Treiber, K. D. J. Org. Chem. 1993, 58, 6952.
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Lee, Y. R.; Suk, J. Y. Tetrahedron 2002, 58, 2359. (c) Lee, Y. R.; Hwang,
J. C. Eur. J. Org. Chem. 2005, 1568.
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856. (b) Nishino, H.; Nguyen, V.-H.; Yoshinaga, S.; Kurosawa, K. J. Org.
Chem. 1996, 61, 8264. (c) Garzino, F.; Me´ou, A.; Brun, P. Tetrahedron
(1) (a) The Chemistry of Heterocycles: Structure, Reactions, Syntheses,
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¨
Lett. 2000, 41, 9803. (d) Burgaz, E. V.; Yilmaz, M.; Pekel, A. T.; OKtemer,
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Yuan, T.-T.; Shen, Y.-B. J. Org. Chem. 2008, 73, 7088.
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10.1021/ol900451d CCC: $40.75
Published on Web 04/23/2009
 2009 American Chemical Society

is of great importance for their intrinsic utility of key
intermediates for further transformations.7 Among the exist-
ing methods for cyclopropanation reactions, the Simmons-
Smith-type reaction is probably the most widely used.8 The
iodine and Lewis acid-mediated intramolecular cyclopropa-
nation reaction of unsaturated ꢀ-keto esters has been re-
ported.9 Metal-catalyzed cyclopropanation of alkenes with
diazo compounds has also attracted much attention recently.10
However, these reported procedures often required severe
reaction conditions or heavy metal catalysts. A methodology
with smooth reaction conditions and a metal-free reaction
process is rather rare and highly desirable.
As an inexpensive, efficient, and environmentally benign
reagent, molecular iodine has been used extensively in
organic synthesis for a long time. In recent years, more and
more organic transformations mediated by molecular iodine
have been documented.11
On the other hand, solvent-free organic reactions, which
supply environmentally friendly protocols and sometimes
remarkable reaction acceleration and more convenient prod-
uct purification, have drawn the public’s concerns increas-
ingly in recent years. The mechanical milling technique is a
powerful tool to promote solvent-free reactions.12-14 In light
of our successful studies in this field,5e,13 herein we present
the unexpected reaction of aldehydes with 1,3-dicarbonyl
compounds promoted by iodine and DMAP under mechan-
ical ball-milling conditions as a novel and green protocol to
produce dihydrofuran and cyclopropane derivatives in good
yields.
conditions. In an initial experiment, a mixture of 5,5-
dimethylcyclohexane-1,3-dione (dimedone) (1), 3-nitroben-
zaldehyde (2a), dimethylaminopyridine (DMAP), and mo-
lecular iodine in a molar ratio of 2:1:2.5:1.5 was introduced
into a stainless jar (5 mL), together with a stainless ball of
7.0 mm diameter, the same mixture was also introduced into
a second parallel jar. The two reaction vessels were closed
and fixed on the vibration arms of a ball-milling apparatus
(Retsch MM200 mixer mill, Retsch GmbH, Haan, Germany)
and were vibrated vigorously at a rate of 1800 rounds per
minute (30 Hz) at room temperature for 60 min.13
After simple workup, one main product was isolated in a
low yield. However, the NMR spectra of this compound were
not consistent with the pyran structure. Further analysis of
the NMR spectra revealed that this compound might contain
a dihydrofuran framework. Finally, the structure was un-
equivocally established by the X-ray diffraction of its single
crystal (Figure 1). The formation of a spiro dihydrofuran
At the outset of our studies, we attempted to find a feasible
pathway to pyran formation under our mechanical milling
(6) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. ReV. 2003,
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Hudlicky, T. Chem. ReV. 1989, 89, 165. (b) Reissig, H.-U.; Zimmer, R.
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Figure 1. X-ray crystal structure of 3a.
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2003, 125, 13632.
structure is very unusual and may find its application in
related transformations leading to useful products. Encour-
aged by this unexpected result, we further optimized the
reaction conditions by employing various additives. The
results are listed in Table 1. With 1.65 equiv of molecular
iodine and 2.5 equiv of DMAP as the additives, 3-nitroben-
zaldehyde was able to react with 2.4 equiv of dimedone to
afford dihydrofuran product 3a in high yield (91%, entry
1). Other halogen sources such as CBr4, NBS, NCS, and the
combination of Oxone and NaBr were also screened.
However, all of them gave the final product in low to
moderate yields (entries 2-5). The Oxone/ZnCl2 system
failed to give any product (entry 6). Then the effect of various
bases was investigated. Only a trace amount of 3a was
observed when NaHCO3 and Na2CO3 were employed (entries
7 and 8). Other organic and inorganic bases including
Cs2CO3, K2CO3, DABCO, and DBU facilitated the reaction
to some extent, but none exceeded the result of DMAP
(entries 9-12). Therefore, this reaction was most efficient
when using I2 (1.65 equiv) and DMAP (2.5 equiv).
(9) Yang, D.; Gao, Q.; Lee, C.-S.; Cheung, K.-K. Org. Lett. 2002, 4,
3271.
(10) (a) Ni, A.; France, J. E.; Davies, H. M. L. J. Org. Chem. 2006, 71,
5594. (b) Xu, Z.-H.; Zhu, S.-N.; Sun, X.-L.; Tang, Y.; Dai, L.-X. Chem.
Commun. 2007, 1960. (c) Hashimoto, T.; Naganawa, Y.; Kano, T.; Maruoka,
K. Chem. Commun. 2007, 5143. (d) Thompson, J. L.; Davies, H. M. L.
J. Am. Chem. Soc. 2007, 129, 6090.
(11) For a review, see: Togo, H.; Iida, S. Synlett 2006, 14, 2159.
(12) For reviews, see: (a) Wang, G.-W. Fullerene Mechanochemistry.
In Encyclopedia of Nanoscience and Nanotechnology; Nalwa, H. S. Ed.;
American Scientific Publishers: Stevenson Ranch, 2004; Vol. 3, p 557. (b)
Komatsu, K. Top. Curr. Chem. 2005, 254, 185. (c) Rodr´ıguez, B.;
Bruckmann, A.; Rantanen, T.; Bolm, C. AdV. Synth. Catal. 2007, 349, 2213.
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(e) Bruckmann, A.; Krebs, A.; Bolm, C. Green Chem. 2008, 10, 1131. (f)
Kaupp, G. CrystEngComm 2009, 11, 388
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(13) (a) Zhang, Z.; Dong, Y.-W.; Wang, G.-W.; Komatsu, K. Synlett
2004, 61. (b) Zhang, Z.; Wang, G.-W.; Miao, C.-B.; Dong, Y.-W.; Shen,
Y.-B. Chem. Commun. 2004, 1832. (c) Zhang, Z.; Gao, J.; Xia, J.-J.; Wang,
G.-W. Org. Biomol. Chem. 2005, 3, 1617. (d) Wang, G.-W.; Wu, X.-L.
AdV. Synth. Catal. 2007, 349, 1977. (e) Wu, X.-L.; Xia, J.-J.; Wang, G.-W.
Org. Biomol. Chem. 2008, 6, 548. (f) Gao, J.; Wang, G.-W. J. Org. Chem.
2008, 73, 2955
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(14) For selected examples in other groups, see: (a) Balema, V. P.;
Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem. Soc. 2002, 124,
6244. (b) Rodr´ıguez, B.; Tantanen, T.; Bolm, C. Angew. Chem., Int. Ed.
2006, 45, 6924. (c) Schneider, F.; Ondruschka, B. ChemSusChem 2008, 1,
With the optimized conditions in hand, the scope and
generality of the reaction was explored. A variety of
622. (d) Waddell, D. C.; Mack, J. Green Chem. 2009, 11, 79
.
2386
Org. Lett., Vol. 11, No. 11, 2009

corresponding dihydrofuran products in good to excellent
yields. The aldehyde with an electron-withdrawing group
gave a higher yield than that bearing an electron-donating
group (entries 1-8, Table 2). Aliphatic aldehydes, including
paraformaldehyde, propionic aldehyde, and butyraldehyde,
were also investigated. Smooth reactions were observed for
these aldehydes and delivered the final products in good
yields (entries 9-11, Table 2). To our great delight,
heteroaromatic aldehydes, such as 2-pyridinecarboxalde-
hyde, 2-thiophenecarboxaldehyde, and 2-furancarboxalde-
hyde, were also tolerated under the current conditions,
furnishing the dihydrofuran products in good yields (entries
12-14, Table 2).
To further demonstrate the superiority of our methodology
and to extend the utility of this oxidative cycloaddition,
another 1,3-dicarbonyl compound, i.e., 1,3-indandione (4),
was also explored. When 1,3-indandione was treated with
3-nitrobenzaldehyde under similar conditions, a new type
of compound was obtained rather than the expected dihy-
drofuran. On the basis of the spectral analysis, the structure
of this new compound was identified to be a bispiro-
substituted cyclopropane derivative 5a, which was further
confirmed by single-crystal X-ray diffraction analysis (Figure
2).
Table 1. Optimization of Additives for the Reaction of
Dimedone with 3-Nitrobenzaldehyde under Mechanical Milling
Conditionsa
entry
base
promoter
yield (%)
1
2
3
4
5
6
7
8
9
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
Na2CO3
Na2CO3
Cs2CO3
K2CO3
DABCO
DBU
I2
CBr4
NBS
NCS
Oxone/NaBr
Oxone/ZnCl2
I2
I2
I2
I2
I2
I2
91
54
35
26
21
trace
trace
58
67
57
10
11
12
29
a Dimedone (2.4 equiv), 3-nitrobenzaldehyde (1.0 equiv), base (2.5
equiv), and promoter (1.65 equiv) in a ball mill.
aldehydes were investigated to react with dimedone, and the
results are listed in Table 2. Various aromatic aldehydes with
Table 2. Reaction of Dimedone with Aldehydes Mediated by
I2/DMAP under Mechanical Milling Conditionsa
Figure 2. X-ray crystal structure of 5a.
Then a number of substituted aldehydes were investigated
to react with 1,3-indandione to explore the scope and
generality of this cyclopropanation reaction. The results are
summarized in Table 3. As shown in Table 3, all of the
aldehydes bearing electron-withdrawing groups could react
with 1,3-indandione and gave the corresponding cyclopro-
panes 5 as the exclusive products in good yields (entries 1-7,
Table 3). When benzaldehyde was employed, the desired
product was obtained in a relatively low yield (69%, entry
8, Table 3). Surprisingly, the reactions of electron-rich
aromatic aldehydes, aliphatic aldehydes, and heteroaromatic
aldehydes were not very successful. That is, the correspond-
ing cyclopropanes were formed in low yields. For example,
product 5r was obtained in only 60% (entry 9, Table 3).
a Dimedone (2.4 equiv), aldehyde (1.0 equiv), DMAP (2.5 equiv), and
iodine (1.65 equiv) in a ball mill.
substituents of different electronic property reacted smoothly
and efficiently under the present conditions, affording the
It should be pointed out the reactions shown in Tables 2
and 3 could also proceed in traditional liquid phase. For
Org. Lett., Vol. 11, No. 11, 2009
2387

Table 3. Reaction of 1,3-Indandione with Aldehydes Mediated
Scheme 1
.
Proposed Mechanism of the Formation of Spiro
Dihydrofurans and Cyclopropanes
by I2/DMAP under Mechanical Milling Conditionsa
entry
R
product
yield (%)
1
2
3
4
5
6
7
8
9
3-NO2C6H4 (2a)
4-NO2C6H4 (2b)
4-CNC6H4 (2c)
3,4-Cl2C6H3 (2d)
4-CHOC6H4 (2e)
4-BrC6H4 (2o)
4-ClC6H4 (2p)
C6H5 (2q)
5a
5b
5c
5d
5e
5o
5p
5q
5r
88
89
84
80
75
82
83
69
60
4-CH3C6H4 (2r)
a 1,3-Indandione (2.7 equiv), aldehyde (1.0 equiv), DMAP (2.5 equiv),
and iodine (1.65 equiv) in a ball mill.
example, the reaction of 1 with 2a and that of 4 with 2a in
1,4-dioxane at room temperature for 1 h afforded 3a and 5a
in 77% and 59% yields, respectively. However, this proce-
dure required the use of an organic solvent, and the yields
were lower. It is noteworthy that liquid aldehydes could also
be employed in the reactions with both dimedone and 1,3-
indandione (see Tables 2 and 3), and the reaction medium
in the jar was solid alike because all other three components
were excess and solid.
Control experiments showed that only condensation prod-
uct 6 from two molecules of the 1,3-dicarbonyl compound
and one molecule of the aldehyde was obtained if the reaction
was performed without molecular iodine. Accordingly,
compound 6 seemed to be an intermediate of this reaction.
Moreover, when bis-adduct 6 was employed as the starting
material instead of the combination of the 1,3-dicarbonyl
compound and aldehyde, the desired product was also
obtained in similar yield.
two pathways to proceed. An intramolecular nucleophilic
O-attack via 8 (path I) with an elimination of HI afforded
dihydrofurans 3. Alternatively, the nucleophilic C-attack via
9 (path II) with an elimination of HI gave cyclopropanes
5.9
In summary, we have presented a versatile one-pot and
solvent-free reaction of dimedone and 1,3-indandione with
aldehydes to selectively afford spiro dihydrofurans and
cyclopropanes in good yields under mechanical milling
conditions. These iodine-mediated oxidative cycloadditions
provide a rapid and efficient route to the preparation of a
variety of spiro dihydrofuran and cyclopropane derivatives.
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China (Nos. 20621061 and 20772117), National Basic
Research Program of China (2006CB922003), and Knowl-
edge Innovation Project of the Chinese Academy of Sciences
(KJCX2.YW.H16).
Although the exact mechanism of this transformation is
not clear right now, a possible reaction mechanism is
proposed (Scheme 1) based on the above results and the
known literature. It was reported that the reaction of a 1,3-
dicarbonyl compound with iodine gave the R-iodonated
product.9,15 Similarly, the reaction of compound 6 with iodine
gave iodide 7 as the key intermediate. And then there were
Supporting Information Available: Detailed descriptions
of experimental procedures and characterization of com-
pounds; 1H NMR and 13C NMR spectra of 3a-n, 5a-e, and
5o-r; crystal structure data (CIF) of 3a and 5a. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Nierengarten, J.-F.; Gramlich, V.; Cardullo, F.; Diederich, F.
Angew. Chem., Int. Ed. 1996, 35, 2101. (b) Gogoi, S.; Bhuyan, R.; Barua,
N. C. Synth. Commun. 2005, 35, 2811. (c) Tsukano, C.; Siegel, D. R.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 8840
.
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