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,
103, 1625.
(7) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.;
Hudlicky, T. Chem. ReV. 1989, 89, 165. (b) Reissig, H.-U.; Zimmer, R.
Chem. ReV. 2003, 103, 1151.
Figure 1. X-ray crystal structure of 3a.
(8) (a) Cheng, D.; Kreethadumrongdat, T.; Cohen, T. Org. Lett. 2001,
3, 2121. (b) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
ReV. 2003, 103, 977. (c) Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc.
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.
(d) Garay, A. L.; Pichon, A.; James, S. L. Chem. Soc. ReV. 2007, 36, 846.
(e) Bruckmann, A.; Krebs, A.; Bolm, C. Green Chem. 2008, 10, 1131. (f)
Kaupp, G. CrystEngComm 2009, 11, 388
.
(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
.
(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