Unexpected solvent-free cycloadditions of 1,3-cyclohexanediones to 1-(pyridin-2-yl)-enones mediated by manganese(III) acetate in a ball mill

Article abstract of DOI:10.1021/jo800870z

(Chemical Equation Presented) Under solvent-free ball-milling conditions, manganese(III) acetate dihydrate-mediated cycloadditions of 5,5-dimethyl-1,3- cyclohexanedione and 1,3-cyclohexanedione to various 1-(pyridin-2-yl)-enones proceeded efficiently to afford trans-2-acyl-3-aryl/alkyl-2,3,6,7-tetrahydro- 4(5H)-benzofuranone derivatives. The cyclization reactions exhibited good to excellent yields, as well as extremely high diastereoselectivity and unexpected regioselectivity. Manganese(III) acetate behaved both as an oxidant and as a Lewis acid.

Full text of DOI:10.1021/jo800870z

Unexpected Solvent-Free Cycloadditions of 1,3-Cyclohexanediones to
1-(Pyridin-2-yl)-enones Mediated by Manganese(III) Acetate in a
Ball Mill
Guan-Wu Wang,* Ya-Wei Dong, Ping Wu, Ting-Ting Yuan, and Ye-Bing Shen
Hefei National Laboratory for Physical Sciences at Microscale, Joint Laboratory of Green Synthetic
Chemistry, and Department of Chemistry, UniVersity of Science and Technology of China,
Hefei, Anhui 230026, P. R. China
gwang@ustc.edu.cn
ReceiVed April 21, 2008
Under solvent-free ball-milling conditions, manganese(III) acetate dihydrate-mediated cycloadditions of
5,5-dimethyl-1,3-cyclohexanedione and 1,3-cyclohexanedione to various 1-(pyridin-2-yl)-enones proceeded
efficiently to afford trans-2-acyl-3-aryl/alkyl-2,3,6,7-tetrahydro-4(5H)-benzofuranone derivatives. The
cyclization reactions exhibited good to excellent yields, as well as extremely high diastereoselectivity
and unexpected regioselectivity. Manganese(III) acetate behaved both as an oxidant and as a Lewis acid.
Introduction
To circumvent the aforementioned problems, an attractive
alternative is to carry out the reactions under solvent-free
conditions. Solvent-free reactions3 have drawn much attention
recently due to the increasingly stringent requirement of
eliminating/reducing the use of harmful organic solvents.
Solvent-free reactions usually exhibit much higher yield and
selectivity than their liquid-phase counterparts.4 One of our
contributions to solvent-free reactions is focused on those
promoted by the ball-milling technique.5 In continuation of our
interest in this field,6,7 herein we report the novel Mn(OAc)3-
During the past two decades, significant development has
been achieved in manganese(III) acetate [Mn(OAc)3]-mediated
oxidative radical reactions, in which Mn(OAc)3 is most com-
monly used as a single-electron-transfer reagent to generate
carbon-centered radicals from various carbonyl compounds.1
However, with a review of the general radical reactions
promoted by Mn(OAc)3, the obvious drawback arises from the
harsh reaction conditions. Because of the poor solubility of
Mn(OAc)3 in common organic solvents, Mn(OAc)3-mediated
reactions are often carried out in acetic acid, although other
organic solvents (e.g., alcohols, acetonitrile, dichloromethane,
benzene, toluene, chlorobenzene)2 have also been employed in
some cases. Problems are thus encountered for the complete
removal of these organic solvents as well as acetic acid. The
latter generally requires a large quantity of water or aqueous
sodium hydrogen carbonate, resulting in a tedious separation
procedure.
(2) (a) Cossy, J.; Bouzide, A.; Leblanc, C. J. Org. Chem. 2000, 65, 7257–
7265. (b) Yang, D.; Xu, M.; Bian, M.-Y. Org. Lett. 2001, 3, 111–114. (c) Bar,
G.; Parsons, A. F.; Thomas, C. B. Chem. Commun. 2001, 1350–1351. (d) Zhang,
T.-H.; Lu, P.; Wang, F.; Wang, G.-W. Org. Biomol. Chem. 2003, 1, 4403–4407.
(e) Snider, B. B.; Duvall, J. R. Org. Lett. 2004, 6, 1265–1268. (f) Wang, G.-W.;
Zhang, T.-H.; Cheng, X.; Wang, F. Org. Biomol. Chem. 2004, 2, 1160–1163.
¨
(g) Demir, A. S.; Reis, O.; Igdir, A. C. Tetrahedron 2004, 60, 3427–3432. (h)
Wang, G.-W.; Li, F.-B. Org. Biomol. Chem. 2005, 3, 794–797. (i) Mu, X.-J.;
Zou, J.-P.; Qian, Q.-F.; Zhang, W. Tetrahedron Lett. 2006, 47, 2323–2325.
(3) (a) Loupy, A. Top. Curr. Chem. 1999, 206, 153–207. (b) Tanaka, K.;
Toda, F. Chem. ReV. 2000, 100, 1025–1074.
(4) (a) Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975–2978. (b)
Kaupp, G. Top. Curr. Chem. 2005, 254, 95–183. (c) Komatsu, K. Top. Curr.
Chem. 2005, 254, 185–206. (d) Rodr´ıguez, B.; Rantanen, T.; Bolm, C. Angew.
Chem., Int. Ed. 2006, 45, 6924–6926.
(5) (a) Wang, G.-W. Fullerene mechanochemistry. In Encyclopedia of
Nanoscience and Nanotechnology; Nalwa, H. S., Ed.; American Scientific
Publishers: Stevenson Ranch, 2004; Vol. 3, pp 557–565. (b) Rodr´ıguez, B.;
Bruckmann, A.; Rantanen, T.; Bolm, C. AdV. Synth. Catal. 2007, 349, 2213–
2233. (c) Garay, A. L.; Pichon, A.; James, S. L. Chem. Soc. ReV. 2007, 36,
846–855.
(1) For reviews, see: (a) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. ReV.
1994, 94, 519–564. (b) Snider, B. B. Chem. ReV. 1996, 96, 339–363. (c) Demir,
A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 321–351. (d) Wang, G.-W.;
Li, F.-B. J. Nanosci. Nanotechnol. 2007, 7, 1162–1175. For examples, see: (e)
Yang, D.; Ye, X.-Y.; Xu, M.; Pang, K.-W.; Cheung, K.-K. J. Am. Chem. Soc.
2000, 122, 1658–1663. (f) Huang, J.-W.; Shi, M. J. Org. Chem. 2005, 70, 3859–
3863. (g) Lin, C.-Y.; Cheng, Y.-C.; Tsai, A.-I.; Chuang, C.-P. Org. Biomol.
Chem. 2006, 4, 1097–1103. (h) C¸ alıs¸kan, R.; Ali, M. F.; S¸ahin, E.; Watson,
W. H.; Balci, M. J. Org. Chem. 2007, 72, 3353–3359.
7088 J. Org. Chem. 2008, 73, 7088–7095
10.1021/jo800870z CCC: $40.75 2008 American Chemical Society
Published on Web 08/19/2008

SolVent-Free Cycloadditions of 1,3-Cyclohexanediones to 1-(Pyridin-2-yl)-enones
TABLE 1. Oxidative Radical Reaction of Dimedone 1a with
2-Cinnamoylpyridine 4a under Various Conditionsa
SCHEME 1. Mn(OAc)3 ·2H2O-Mediated Reaction of
Dimedone 1a with Chalcone 2
entry
oxidant
base
ratio of reagentsb yield (%)
1
2
3
4
5
6
7
8
Mn(OAc)3 ·2H2O
Cu(OAc)2 ·H2O
FeCl3 ·6H2O
1.2:1:2.4
1.2:1:2.4
1.2:1:2.4
1.2:1:2.4
1:1:2.4
1:1.2:2.4
1:1.2:2.4:2.4
1:1.2:2.4:2.4
1:1.2:2.4:2.4
1:1.2:2.4:2.4
1:1.2:2.4:2.4
1:1.2:2.4:2.4
78
0
promoted cycloadditions of 1,3-cyclohexanediones to 1-(pyridin-
2-yl)-enones affording trans-2-acyl-3-aryl/alkyl-benzofuranone
derivatives as single diastereoisomers with unexpected regiose-
lectivity.
trace
28
73
91
91
83
87
46
8
CAN
Mn(OAc)3 ·2H2O
Mn(OAc)3 ·2H2O
Mn(OAc)3 ·2H2O NaHCO3
Mn(OAc)3 ·2H2O K2CO3
Mn(OAc)3 ·2H2O K3PO4
Mn(OAc)3 ·2H2O DMAP
Mn(OAc)3 ·2H2O DBU
Mn(OAc)3 ·2H2O DABCO
Results and Discussion
9
10
11
12
Recently, we have reported the Mn(OAc)3 ·2H2O-mediated
unusual radical additions of 1,3-cyclohexanediones to in situ
generated imines under ball-milling conditions.6c The intriguing
nonreductive addition mode of 1,3-cyclohexanediones to imines
prompted us to investigate their additions to CdC double bonds
under the same conditions. We first examined the Mn(OAc)3 ·
2H2O-promoted reaction of 5,5-dimethyl-1,3-cyclohexanedione
(1a) with (E)-1,3-diphenylprop-2-en-1-one (2) under our ball-
milling conditions. Product 3 was obtained in only 23% yield
from the reaction of dimedone 1a with chalcone 2 and
Mn(OAc)3 ·2H2O in a molar ratio of 1.2:1:2.4 for 5 h (Scheme
1).
The structure of product 3 was assigned as trans-3-benzoyl-
6,6-dimethyl-2-phenyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-
one on the basis of its 1H NMR, 13C NMR, HRMS, and FT-IR
spectra. This assignment was consistent with the formation of
trans diastereoisomers from the Mn(OAc)3-mediated radical
reactions of ꢀ-ketoesters with cinnamates/cinnamides.8 The trans
stereochemistry was unambiguously established by an X-ray
structure determination.8a The coupling constants between the
two methine protons of dihydrofuran derivatives were reported
to be obviously larger for the cis diastereoisomers (J ) 10-11
26
a All reactions were carried out by ball milling at 30 Hz for 1 h. b For
entries 1-6, the reagent ratio refers to 1a:4a:oxidant; for entries 7-12,
the reagent ratio refers to 1a:4a:oxidant:base.
Hz) than for the trans diastereoisomers (J ) 4-7 Hz).9 The
observed coupling constant of 5.7 Hz for product 3 was pretty
close to the reported data for the trans diastereoisomers,8,9
further supporting its assigned stereochemistry. Deduced from
the above arguments, the previously assigned cis stereochemistry
should likely be the trans stereochemistry for the products from
the Mn(OAc)3-mediated radical reactions of 1,3-dicarbonyl
compounds with chalcones10 and from the ceric ammonium
nitrate (CAN)-promoted radical reactions of 1,3-dicarbonyl
compounds with cinnamtes11a or ꢀ-aryl-R,ꢀ-unsaturated
ketotones,11b as these products had coupling constants of
5.8-7.2 Hz.
Because of the poor yield for the employed chalcone, we
then turned our attention to 2-cinnamoylpyridines. (E)-3-Phenyl-
1-(pyridin-2-yl)prop-2-en-1-one (4a) was chosen as the model
substrate for 2-cinnamoylpyridines to optimize the reaction
conditions. To our gratification, the reaction of dimedone 1a
with 2-cinnamoylpyridine 4a and Mn(OAc)3 ·2H2O in a molar
ratio of 1.2:1:2.4 for only 1 h afforded trans-6,6-dimethyl-3-
phenyl-2-picolinoyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one
(5a) in 78% yield (entry 1, Table 1). Other oxidants such as
Ce(IV), Cu(II), and Fe(III), which have proved to be efficient
for the generation of carbon-centered radicals,1a were also
examined. However, none or only trace amount of the desired
product was obtained in the presence of cupric acetate or ferric
trichloride (entries 2 and 3, Table 1). This situation was hardly
improved when CAN, which has been widely employed in
radical reactions, was used (entry 4, Table 1). Product 5a
constituted a very small portion in the complicated reaction
mixture, and only 28% yield was obtained. We then optimized
the Mn(OAc)3 ·2H2O-promoted reaction by adjusting the reagent
ratio and adding bases. Reducing the amount of dimedone 1a
to 1 equiv (based on the amount of 4a), the yield dropped
slightly to 73% (entry 5, Table 1). Much to our delight, the
reaction of 1a with 4a and Mn(OAc)3 ·2H2O in a molar ratio
(6) For reactions of non-fullerene molecules under ball-milling conditions,
see: (a) Zhang, Z.; Dong, Y.-W.; Wang, G.-W.; Komatsu, K. Synlett 2004, 61–
64. (b) Zhang, Z.; Dong, Y.-W.; Wang, G.-W.; Komatsu, K. Chem. Lett. 2004,
33, 168–169. (c) Zhang, Z.; Wang, G.-W.; Miao, C.-B.; Dong, Y.-W.; Shen,
Y.-B. Chem. Commun. 2004, 1832–1833. (d) Zhang, Z.; Gao, J.; Xia, J.-J.; Wang,
G.-W. Org. Biomol. Chem. 2005, 3, 1617–1619. (e) Wang, G.-W.; Wu, X.-L.
AdV. Synth. Catal. 2007, 349, 1977–1982. (f) Wu, X.-L.; Xia, J.-J.; Wang, G.-
W. Org. Biomol. Chem. 2008, 6, 548–553. (g) Gao, J.; Wang, G.-W. J. Org.
Chem. 2008, 73, 2955–2958.
(7) For reactions of fullerenes under ball-milling conditions, see: (a) Wang,
G.-W.; Murata, Y.; Komatsu, K.; Wan, T. S. M. Chem. Commun. 1996, 2059–
2060. (b) Wang, G.-W.; Komatsu, K.; Murata, Y.; Shiro, M. Nature 1997, 387,
583–586. (c) Komatsu, K.; Wang, G.-W.; Murata, Y.; Tanaka, T.; Fujiwara, K.;
Yamamoto, K.; Saunders, M. J. Org. Chem. 1998, 63, 9358–9366. (d) Wang,
G.-W.; Zhang, T.-H.; Hao, E.-H.; Jiao, L.-J.; Murata, Y.; Komatsu, K.
Tetrahedron 2003, 59, 55–60. (e) Wang, G.-W.; Zhang, T.-H.; Li, Y.-J.; Lu, P.;
Zhan, H.; Liu, Y.-C.; Murata, Y.; Komatsu, K. Tetrahedron Lett. 2003, 44, 4407–
4409. (f) Wang, G.-W.; Li, Y.-J.; Peng, R.-F.; Liang, Z.-H.; Liu, Y.-C.
Tetrahedron 2004, 60, 3921–3925. (g) Peng, R.-F.; Wang, G.-W.; Shen, Y.-B.;
Li, Y.-J.; Zhang, T.-H.; Liu, Y.-C.; Murata, Y.; Komatsu, K. Synth. Commun.
2004, 34, 2117–2126. (h) Zhang, T.-H.; Wang, G.-W.; Lu, P.; Li, Y.-J.; Peng,
R.-F.; Liu, Y.-C.; Murata, Y.; Komatsu, K. Org. Biomol. Chem. 2004, 2, 1698–
1702. (i) Li, Y.-J.; Peng, R.-F.; Liu, Y.-C.; Wang, G.-W. Chin. Chem. Lett. 2004,
15, 1265–1268. (j) Cheng, X.; Wang, G.-W.; Murata, Y.; Komatsu, K. Chin.
Chem. Lett. 2005, 16, 1327–1329. (k) Wang, G.-W.; Chen, Z.-X.; Murata, Y.;
Komatsu, K. Tetrahedron 2005, 61, 4851–4856.
(8) (a) Garzino, F.; Me´ou, A.; Brun, P. Tetrahedron Lett. 2000, 41, 9803–
9807. (b) Garzino, F.; Me´ou, A.; Brun, P. HelV. Chim. Acta 2002, 85, 1989–
1998. (c) Garzino, F.; Me´ou, A.; Brun, P. Tetrahedron Lett. 2002, 43, 5049–
5051. (d) Garzino, F.; Me´ou, A.; Brun, P. Eur. J. Org. Chem. 2003, 1410–1414.
(e) Martinet, S.; Me´ou, A.; Brun, P. Magn. Reson. Chem. 2007, 45, 182–184.
(9) (a) Pohmakotr, M.; Issaree, A.; Sampaongoen, L.; Tuchinda, P.; Reutrakul,
V. Tetrahedron Lett. 2003, 44, 7937–7940. (b) Yang, Z.; Fan, M.; Mu, R.; Liu,
W.; Liang, Y. Tetrahedron 2005, 61, 9140–9146.
(10) Shanmugam, P.; Kumar, K. H.; Perumal, P. T. J. Heterocycl. Chem.
2007, 44, 827–830.
J. Org. Chem. Vol. 73, No. 18, 2008 7089

Wang et al.
TABLE 2. Solvent-Free Radical Reactions of
1,3-Cyclohexanediones 1a,b with 1-(Pyridin-2-yl)-enones 4a-k
Promoted by Mn(OAc)3 ·2H2O
of 1:1.2:2.4 gave product 5a in 91% yield (entry 6, Table 1).
The effect of bases on the reaction was also explored. It was
found that the addition of NaHCO3 had no beneficial effect on
the reaction, and other inorganic bases such as K2CO3 and
K3PO4 were detrimental to the product yield (entries 7-9, Table
1). Organic bases such as 4-dimethylaminopyridine (DMAP),
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and 1,4-diazabicyclo-
[2.2.2]octane (DABCO) afforded product 5a in only 8-46%
yield with poor chemical selectivity (entries 10-12, Table 1).
Traditional Mn(OAc)3-mediated radical reactions carried out in
organic solvents usually require two or more equivalents of
conventional bases.2h,10 In contrast, the presence of a base in
our solvent-free reaction was not profitable to the yield of target
product 5a.
To demonstrate the advantages of our current protocol, we
carried out the reaction in organic solvents. For example, when
the Mn(OAc)3 ·2H2O-promoted reaction of 1a and 4a in the
presence of sodium acetate was carried out in acetic acid at 80
°C under argon atmosphere, a very complicated reaction mixture
was obtained, and the yield of the desired product 5a was 32%.
When the reaction was carried out with the existence of
potassium carbonate in absolute ethanol at refluxing temperature
for 12 h, a mixture of 2,3,6,7-tetrahydrobenzofuran-4(5H)-one
derivative 5a (15%) and 6,7-dihydrobenzofuran-4(5H)-one
derivative 6a (vide infra, 48%) was obtained. Either of these
results turned out to be less efficient compared with the present
mechanical milling procedure.
Under the optimized reaction conditions, we next extended
the Mn(OAc)3 ·2H2O-mediated reaction to other 2-cinnamoylpy-
ridines 4b-h and 1,3-cyclohexanedione 1b. The detailed results
for the reactions of 2-cinnamoylpyridines 4a-h (1.2 equiv) with
1,3-cyclohexanediones 1a,b (1.0 equiv) and Mn(OAc)3 ·2H2O
(2.4 equiv) are summarized in Table 2.
As can be seen from Table 2, 2,3,6,7-tetrahydrobenzofuran-
4(5H)-one derivatives 5a-o were obtained in good to excellent
yields (up to 91% yield) under our solvent-free conditions
(entries 1-15, Table 2). The efficiency of the current solvent-
free protocol could be ascribed to an enhanced reaction rate
resulted from ultimately high concentrations of reactants and
the high mechanical energy that can greatly reinforce the
reaction.5c,6a,12 Notably, the product yields for 1a were obviously
higher than those for 1b, probably due to the higher reactivity
of 1a. Furthermore, no correlation could be found between the
product yield and the electronic property of the different
substituents on the phenyl ring of 2-cinnamoylpyridines. Besides
these 2-cinnamoylpyridines, other enones (4i-k) had also been
investigated to examine the scope and limitation of the reaction.
When (E)-3-phenyl-1-(pyrazin-2-yl)prop-2-en-1-one (4i) was
used as the substrate in this reaction, a lower yield (59%) was
obtained even with prolonged reaction time (3 h) (entry 16 vs
entry 1, Table 2). The reason of the lower efficiency for the
chalcone substituted with two nitrogen atoms is not clear right
now. When aliphatic substrates such as (E)-1-(pyridin-2-yl)hex-
2-en-1-one (4j) and (E)-5-methyl-1-(pyridin-2-yl)hex-2-en-1-
one (4k) were used, only moderate yields (entries 17 and 18,
Table 2) were achieved, reflecting the lower reactivity of
substrates 4j and 4k.
Compared with the Mn(OAc)3 ·2H2O and CAN-promoted
radical reactions of 1,3-dicarbonyl compounds and R,ꢀ-unsatur-
(11) (a) Roy, S. C.; Mandal, P. K. Tetrahedron 1996, 52, 2193–2198. (b)
Zhang, W.; Huo, C. D.; Liu, Z. G.; Liu, Z. L. Chin. Chem. Lett. 2004, 15, 389–
391.
a Properly characterized by FT-IR, 1H NMR, 13C NMR, and HRMS
spectra data. b The reaction time was 3 h.
(12) Janot, R.; Gue´rard, D. Prog. Mater. Sci. 2005, 50, 1–92.
7090 J. Org. Chem. Vol. 73, No. 18, 2008

SolVent-Free Cycloadditions of 1,3-Cyclohexanediones to 1-(Pyridin-2-yl)-enones
SCHEME 2. Mn(OAc)3 ·2H2O-Mediated Reaction of Dimedone 1a with 2-Cinnamoylpyridine 4a
ated compounds8,10,11 including the reaction shown in Scheme
1, reversed regioselectivity was observed for the Mn(OAc)3 ·
2H2O-mediated reactions of 1,3-cyclohexanediones with 1-(py-
ridin-2-yl)-enones. These results were quite unexpected and
interesting. In order to better understand the current solvent-
free reaction, we attempted to get some key intermediates.
Treatment of dimedone 1a (1.2 equiv) with 2-cinnamoylpyridine
4a (1.0 equiv) and Mn(OAc)3 · 2H2O (2.4 equiv) for a short
reaction time (5 min) afforded 5a in 27% yield along with
another major product (7a, 42%) (Scheme 2). Product 7a was
characterized as a Michael addition product. Compound 7a was
converted into 5a gradually with prolonged reaction time.
Compound 7a could also be obtained from the reaction of
dimedone 1a with 2-cinnamoylpyridine 4a mediated by K2CO3
and ZnCl2, which were often used in Michael reactions as a
base6a,13 and a Lewis acid,14 in 92% and 90%, further confirmed
the identity of 7a as a Michael addition product.
benzofuranones rather than as their regioisomers 3-acyl-2-aryl-
2,3,6,7-tetrahydro-4(5H)-benzofuranones. Similarly, products 5q
and 5r should also have the same regioselectivity.
The assigned regioselectivity was confirmed by the HMBC
spectrum of 5j, which clearly indicated the three-bond correla-
tion of the 2′-proton (H2′, 7.47 ppm) of the nitrophenyl moiety
with the methine carbon (C3) at 48.8 ppm, and no correlation
between the 2′-proton and the methine carbon (C2) at 91.1 ppm
bonding to the oxygen atom.
The measured coupling constants (3.4-4.2 Hz) of compounds
5a-r were close to those of compounds 3, trans-8, trans-9,
trans-10, and other trans diastereoisomers of dihydrofuran
derivatives,8 and we were confident to assign compounds 5a-r
as trans isomers. The trans stereochemistry was proved by
theoretical calculations together with the NOESY spectrum of
product 5j. The latter showed correlations between H2′/H6′ of
the nitrophenyl group and one (H2 or H3) of the two methine
protons as well as between the methine protons. The key
parameters and formation energies for the optimized structures
of the trans-5j and cis-5j isomers (Figure 2) are listed in Table
3. As seen from Table 3, the distance between the H2′ atom
and one of the two methine protons (H2-H2′) is much longer
than the other two for the cis-5j isomer, while the three key
space distances are close to each other for the trans-5j isomer.
The calculated space distances of the trans-5j isomer can explain
the observed NOESY spectrum very well, suggesting that
Compounds 5a-r were fully characterized by 1H NMR, 13
C
NMR, HRMS, and FT-IR spectra. The HRMS spectra of
products 5a-r exhibited corresponding accurate molecular ions.
In the 1H NMR spectra of 5a-p, the two methine protons (H2
and H3) of the dihydrofuran moiety had chemical shifts at
6.29-6.40 and 4.26-4.43 ppm with a coupling constant of
3.8-4.2 Hz. Their ∆δH were in the range of 1.93-2.10 ppm.
In their 13C NMR spectra, the dihydrofuran carbons showed
chemical shifts at 91.1-92.1, 48.1-49.0, 114.1-116.7, and
177.1-179.1 ppm, while the two carbonyl carbons were located
1
at 193.0-194.1, and 193.6-194.6 ppm. Whereas in the H
NMR spectra of 5q and 5r, the low-field methine proton
remained nearly the same chemical shift (6.22-6.23 ppm) as
those of 5a-p, the high-field methine proton showed drastic
upfield shift (3.24-3.26 ppm) due to the electron-donating
property of the attached alky group.
For cis and trans isomers of ethyl 5-benzoyl-2-methyl-4-
phenyl-4,5-dihydrofuran-3-carboxylate (cis-8 and trans-8, Figure
1), the ∆δH of the two methine protons of the dihydrofuran
heterocycle were pretty close, being 1.52 and 1.33 ppm,
respectively.9b In contrast, its regioisomer, i.e., trans-ethyl
4-benzoyl-2-methyl-5-phenyl-4,5-dihydrofuran-3-carboxylate(trans-
9, Figure 1), had a smaller ∆δH value (0.53 ppm).11b For
tetrahydrobenzofuranones bearing a similar dihydrofuran het-
erocycle should have the same trend for the ∆δH values. Taken
into account of the corresponding ∆δH values of trans-3-
benzoyl-2-phenyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one (3)
(0.86 ppm) and trans-3-benzoyl-2-(4-methoxyphenyl)-6,6-di-
methyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one (trans-10, Fig-
ure 1) (0.74 ppm),11b compounds 5a-p with much larger ∆δH
should be assigned as 2-acyl-3-aryl-2,3,6,7-tetrahydro-4(5H)-
FIGURE 1. Selected chemical shifts and coupling constants of cis-8,
trans-8, trans-9, and trans-10.
(13) Rosnati, V.; Saba, A.; Salimbeni, A. Tetrahedron Lett. 1981, 22, 167–
168.
(14) (a) Yamazaki, S.; Morikawa, S.; Iwata, Y.; Yamamoto, M.; Kuramoto,
K. Org. Biomol. Chem. 2004, 2, 3134–3138. (b) Ahmed, M. G.; Ahmed, S. A.;
Uddin, M. K.; Rahman, M. T.; Romman, U. K. R.; Fujio, M.; Tsuda, Y.
Tetrahedron Lett. 2005, 46, 8217–8220.
FIGURE 2. Structures of trans-5j (with chemical shift assignments)
and cis-5j.
J. Org. Chem. Vol. 73, No. 18, 2008 7091

Wang et al.
TABLE 3. Key Parameters and Formation Energies of trans-5j and cis-5ja
compound
distance (Å)b
dihedral angle (deg)c
J (Hz)d
formation energy (kcal/mol)e
trans-5j
cis-5j
H2-H3 ) 2.89; H2-H2′ ) 2.40; H3-H6′ ) 2.33
H2-H3 ) 2.28; H2-H2′ ) 4.15; H3-H6′ ) 2.29
108.7
15.7
3.0
10.6
0
1.50
a The calculation were performed at B3LYP/6-31G* level. b Shortest distances in the optimized structures. c Dihedral angle of H2-C2-C3-H3 of the
optimized structures. d Coupling constant between the two methine protons H2 and H3. e Energy relative to trans-5j.
SCHEME 3. Plausible Reaction Mechanisms for the Formation of Products 3 and 5a-r
compound 5j should have a trans stereochemistry at the C2
and C3 carbon atoms. Additional evidence for the assigned trans
stereochemistry came from the calculated coupling constants
for the two methine protons of trans-5j and cis-5j. The observed
coupling constant of 4.2 Hz was very close to the calculated
value of 3.0 Hz for the trans-5j isomer, but far away from that
(10.6 Hz) for the cis-5j isomer. Furthermore, the formation
energy of the trans isomer of 5j was lower than its cis isomer,
consistent with the fact that the trans-5j isomer was isolated as
the product.
The proposed plausible reaction mechanisms to explain the
formation of products 3 and 5a-r are shown in Scheme 3. The
formation of compound 3 probably follows the commonly
accepted pathway8,10,11 (mechanism A, Scheme 3). The addition
of radical 12, which is generated from the Mn(III)-enolate
complex of dimedone 1a, to chalcone 2 gives radical intermedi-
ate 13. Subsequent oxidative cyclization affords product 3. The
reversed regioselectivities of 1-(pyridin-2-yl)-enones and chal-
cones toward the additions of 1,3-cyclohexanediones in the
presence of Mn(OAc)3 can only be attributed to the role played
by the nitrogen atom of the pyridine ring. The plausible reaction
pathway for the formation of compounds 5a-r is shown as
mechanism B in Scheme 3. The coordination of the nitrogen
atom and oxygen atom to metal salts is well-known in the
literature.15 The concerted chelation of the pyridinyl and
carbonyl moieties of 1-(pyridin-2-yl)-enones 4 to Mn(III)
increases the electron deficiency of the CdC bond, thus
facilitates the conjugate addition of 1,3-cyclohexanedione 1, and
produces Mn(III)-complexed intermediate 16. The enolization
of intermediate 16, followed by the loss of a Mn(II) species,
gives radical 18. Oxidation of radical 18 by another molecule
of Mn(OAc)3 affords carbocation 19, which cyclizes to generate
the final product 5. Thus, Mn(OAc)3 behaves as a Lewis acid
as well as a radical initiator.
The obtained 2,3,6,7-tetrahydrobenzofuran-4(5H)-one deriva-
tives 5 bearing a dihydrofuran moiety could be further converted
into 6,7-dihydrobenzofuran-4(5H)-one derivatives oxidized by
Mn(OAc)3 ·2H2O in alcoholic solution. For instance, treatment
of compound 5a in the presence of Mn(OAc)3 ·2H2O (2.4 equiv)
in absolute ethanol under N2 protection at 60 °C for 3 h affords
product 6a in 94% yield (Scheme 4). Compound 6a was a
byproduct for the Mn(OAc)3 ·2H2O-mediated reaction of 1a and
4a in ethanol. However, product 6a was hardly detected for
the corresponding solvent-free ball-milling reaction and for the
treatment of compound 5a with Mn(OAc)3 ·2H2O (2.4 equiv)
under our ball-milling conditions.
(15) (a) Otto, S.; Boccaletti, G.; Engberts, B. F. N. J. Am. Chem. Soc. 1998,
120, 4238–4239. (b) Abu-Youseef, M. A. M.; Escuer, A.; Gatteschi, D.; Goher,
M. A. S.; Mautner, F. A.; Vicente, R. Inorg. Chem. 1999, 38, 5716–5723. (c)
Cossy, J.; Bouzide, A. Tetrahedron 1999, 55, 6483–6496. (d) Mart´ınez, A. P.;
Garc´ıa, M. P.; Lahoz, F. J.; Oro, L. A. Inorg. Chim. Acta 2003, 347, 86–98. (e)
Milios, C. J.; Stamatatos, T. C.; Kyritsis, P.; Terzis, A.; Raptopoulou, C. P.;
Vicente, R.; Escuer, A.; Perlepes, S. P. Eur. J. Inorg. Chem. 2004, 2885–2901.
(f) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157–3172. (g) Sugiura, M.;
Kobayashi, S. Angew. Chem., Int. Ed. 2005, 44, 5176–5186.
7092 J. Org. Chem. Vol. 73, No. 18, 2008

SolVent-Free Cycloadditions of 1,3-Cyclohexanediones to 1-(Pyridin-2-yl)-enones
SCHEME 4. Mn(OAc)3 ·2H2O-Mediated Oxidation of
Compound 5a
) 4.5 Hz, 1H), 8.11 (d, J ) 7.7 Hz, 1H), 7.89 (t, J ) 7.7 Hz, 1H),
7.51 (dd, J ) 7.7, 4.5 Hz, 1H), 7.36-7.23 (m, 5H), 6.40 (d, J )
3.8 Hz, 1H), 4.33 (d, J ) 3.8 Hz, 1H), 2.66 (d, J ) 17.8 Hz, 1H),
2.57 (d, J ) 17.8 Hz, 1H), 2.25 (d, J ) 16.3 Hz, 1H), 2.22 (d, J )
16.3 Hz, 1H), 1.19 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 193.9,
193.8, 177.5, 150.9, 149.1, 141.7, 137.3, 128.7 (2C), 128.0, 127.5
(2C), 127.3, 123.3, 115.2, 92.0, 51.3, 48.8, 37.8, 34.4, 29.1, 28.6;
FT-IR (KBr) ν/cm-1 2952, 1710, 1655, 1640, 1395, 1218, 1141,
1034, 951, 878, 769, 700, 617; HR-MS (+EI) calcd for C22H21NO3
(M+) 347.1521, found 347.1520.
6,6-Dimethyl-3-(4-nitrophenyl)-2-picolinoyl-2,3,6,7-tetrahy-
drobenzofuran-4(5H)-one (5b). H NMR (300 MHz, CDCl3) δ
Conclusion
1
8.56 (d, J ) 4.4 Hz, 1H), 8.22 (d, J ) 8.7 Hz, 2H), 8.14 (d, J )
7.7 Hz, 1H), 7.93 (t, J ) 7.7 Hz, 1H), 7.55 (dd, J ) 7.7, 4.4 Hz,
1H), 7.47 (d, J ) 8.7 Hz, 2H), 6.38 (d, J ) 4.1 Hz, 1H), 4.42 (d,
J ) 4.1 Hz, 1H), 2.69 (d, J ) 17.9 Hz, 1H), 2.59 (d, J ) 17.9 Hz,
1H), 2.26 (d, J ) 15.9 Hz, 1H), 2.22 (d, J ) 15.9 Hz, 1H), 1.19 (s,
3H), 1.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.7, 193.0,
178.1, 150.5, 149.2, 149.1, 147.3, 137.6, 128.5 (2C), 128.3, 124.0
(2C), 123.5, 114.5, 91.3, 51.1, 48.8, 37.8, 34.5, 29.0, 28.6; FT-IR
(KBr) ν/cm-1 2961, 1712, 1662, 1634, 1518, 1395, 1345, 1221,
1038, 945, 852, 788, 733, 700, 619; HR-MS (+EI) calcd for
C22H20N2O5 (M+) 392.1372, found 392.1374.
We have developed the synthesis of trans-2-acyl-3-aryl/alkyl-
2,3,6,7-tetrahydro-4(5H)-benzofuranone derivatives through the
radical reactions of 1-(pyridin-2-yl)-enones with 1,3-cyclohex-
anediones mediated by Mn(OAc)3 ·2H2O. The present solvent-
free radical reactions were very efficient, affording the unex-
pected products in as high as 91% yield under our ball-milling
conditions. More importantly, the reversed regioselectivity of
1-(pyridin-2-yl)-enones was uncovered for the first time.
Mn(OAc)3 ·2H2O played the role both as an oxidant and as a
Lewis acid, and thus altered the reaction pathway of 1-(pyridin-
2-yl)-enones.
3-(4-Cyanophenyl)-6,6-dimethyl-2-picolinoyl-2,3,6,7-tetrahy-
1
drobenzofuran-4(5H)-one (5c). H NMR (300 MHz, CDCl3) δ
8.56 (d, J ) 4.5 Hz, 1H), 8.13 (d, J ) 7.7 Hz, 1H), 7.92 (t, J ) 7.7
Hz, 1H), 7.64 (d, J ) 8.2 Hz, 2H), 7.54 (dd, J ) 7.7, 4.5 Hz, 1H),
7.42 (d, J ) 8.2 Hz, 2H), 6.36 (d, J ) 4.1 Hz, 1H), 4.37 (d, J )
4.1 Hz, 1H), 2.67 (d, J ) 17.8 Hz, 1H), 2.58 (d, J ) 17.8 Hz, 1H),
2.25 (d, J ) 16.5 Hz, 1H), 2.22 (d, J ) 16.5 Hz, 1H), 1.19 (s, 3H),
1.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.6, 193.1, 178.0,
150.5, 149.0, 147.1, 137.5, 132.5 (2C), 128.4 (2C), 128.3, 123.4,
118.9, 114.4, 111.2, 91.3, 51.1, 48.9, 37.8, 34.4, 29.0, 28.6; FT-IR
(KBr) ν/cm-1 2956, 2226, 1717, 1655, 1638, 1398, 1220, 1166,
1039, 941, 882, 790, 686, 554; HR-MS (+EI) calcd for C23H20N2O3
(M+): 372.1474, found 372.1467.
Experimental Section
Mn(OAc)3 ·2H2O-Catalyzed Reaction of Dimedone 1a with
Chalcone 2 by Ball Milling. A mixture of dimedone 1a (16.8 mg,
0.12 mmol), chalcone
2
(20.8 mg, 0.10 mmol), and
Mn(OAc)3 · 2H2O (64.3 mg, 0.24 mmol) along with a stainless-
steel ball (7 mm) were placed into a stainless-steel jar (10 mL).
The same mixture was introduced into another 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 milled vigorously at a rate of
1800 rpm at room temperature for 5 h (sequential intervals of 1 h
milling followed by a 1 h pause). The resulting mixtures were
extracted with ethyl acetate, and the combined solution was
evaporated to remove the solvent in vacuo. The residue was
separated by flash column chromatography on silica gel (eluent,
petroleum ether/ethyl acetate ) 3:1 v/v) to afford 3-benzoyl-6,6-
dimethyl-2-phenyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one (3, 15.9
3-(4-Chlorophenyl)-6,6-dimethyl-2-picolinoyl-2,3,6,7-tetrahy-
1
drobenzofuran-4(5H)-one (5d). H NMR (300 MHz, CDCl3) δ
8.59 (d, J ) 4.5 Hz, 1H), 8.11 (d, J ) 7.7 Hz, 1H), 7.90 (t, J ) 7.7
Hz, 1H), 7.53 (dd, J ) 7.7, 4.5 Hz, 1H), 7.31 (d, J ) 8.3 Hz, 2H),
7.23 (d, J ) 8.3 Hz, 2H), 6.35 (d, J ) 3.8 Hz, 1H), 4.29 (d, J )
3.8 Hz, 1H), 2.66 (d, J ) 17.8 Hz, 1H), 2.56 (d, J ) 17.8 Hz, 1H),
2.24 (d, J ) 16.3 Hz, 1H), 2.21 (d, J ) 16.3 Hz, 1H), 1.18 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 193.8, 193.6, 177.7, 150.8, 149.1,
140.3, 137.4, 133.1, 128.9 (2C), 128.8 (2C), 128.1, 123.4, 114.9,
91.8, 51.2, 48.4, 37.8, 34.4, 29.1, 28.6; FT-IR (KBr) ν/cm-1 2960,
1706, 1656, 1638, 1489, 1393, 1220, 1089, 948, 884, 787; HR-
MS (+EI) calcd for C22H20NO337Cl (M+) 383.1102, found 383.1096.
3-(3,4-Dichlorophenyl)-6,6-dimethyl-2-picolinoyl-2,3,6,7-tet-
rahydrobenzofuran-4(5H)-one (5e). 1H NMR (300 MHz, CDCl3)
δ 8.61 (d, J ) 4.4 Hz, 1H), 8.12 (d, J ) 7.7 Hz, 1H), 7.92 (t, J )
7.7 Hz, 1H), 7.55 (dd, J ) 7.7, 4.4 Hz, 1H), 7.42 (s, 1H), 7.40 (d,
J ) 8.2 Hz, 1H), 7.12 (d, J ) 8.2 Hz, 1H), 6.32 (d, J ) 3.9 Hz,
1H), 4.28 (d, J ) 3.9 Hz, 1H), 2.66 (d, J ) 17.8 Hz, 1H), 2.58 (d,
J ) 17.8 Hz, 1H), 2.25 (d, J ) 16.7 Hz, 1H), 2.24 (d, J ) 16.7
Hz, 1H), 1.19 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 193.7, 193.3,
178.0, 150.6, 149.1, 142.0, 137.5, 132.7, 131.3, 130.6, 129.7, 128.3,
126.9, 123.4, 114.4, 91.6, 51.2, 48.1, 37.8, 34.4, 29.0, 28.7; FT-IR
(KBr)ν/cm-1 2965, 1706, 1659, 1642, 1584, 1469, 1391, 1217,
1029, 918, 791, 684; HR-MS (+EI) calcd for C22H19NO335Cl2 (M+)
415.0742, found 415.0746.
1
mg, 23%). H NMR (400 MHz, CDCl3) δ 7.93 (d, J ) 7.5 Hz,
2H), 7.50 (t, J ) 7.2 Hz, 1H), 7.39-7.29 (m, 5H), 7.22-7.16 (m,
2H), 5.81 (d, J ) 5.7 Hz, 1H), 4.95 (d, J ) 5.7 Hz, 1H), 2.44 (d,
J ) 17.9 Hz, 1H), 2.41 (d, J ) 17.9 Hz, 1H), 2.21 (d, J ) 16.2
Hz, 1H), 2.18 (d, J ) 16.2 Hz, 1H), 1.13 (s, 3H), 1.11 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 199.2, 193.6, 177.4, 139.7, 136.5, 133.8,
129.3, 129.24 (2C), 129.20 (2C), 128.7 (2C), 125.9 (2C), 113.0,
90.3, 54.8, 51.1, 38.1, 34.6, 28.8, 28.7; FT-IR (KBr) ν/cm-1 2955,
1685, 1638, 1450, 1400, 1351, 1336, 1281, 1221, 1053, 1004, 931,
765, 695; HR-MS (+EI) calcd for C23H22O3 (M+) 346.1569, found
346.1566.
General Procedure for the Mn(OAc)3 ·2H2O-Mediated Reac-
tions of 1,3-Cyclohexanediones 1a,b with 1-(Pyridin-2-yl)-
enones 4a-k by Ball Milling. The two stainless-steel jars,
containing a mixture of 1,3-cyclohexanedione 1a (or 1b, 0.10
mmol), enone 4a (or 4b-k, 0.12 mmol), Mn(OAc)3 ·2H2O (64.3
mg, 0.24 mmol), and a stainless-steel ball in each of the two reaction
vessels, were milled vigorously at a rate of 1800 rpm at room
temperature for 1 h. The resulting mixtures were extracted with
ethyl acetate, and the combined solution was evaporated to remove
the solvent in vacuo. The residue was separated by flash column
chromatography on silica gel (eluent, petroleum ether/ethyl acetate
) 2.5:1 v/v) to afford 6,6-dimethyl-3-phenyl-2-picolinoyl-2,3,6,7-
tetrahydrobenzofuran-4(5H)-one 5a (or 5b-r).
3-(3,4-Dimethylphenyl)-6,6-dimethyl-2-picolinoyl-2,3,6,7-tet-
rahydrobenzofuran-4(5H)-one (5f). 1H NMR (300 MHz, CDCl3)
δ 8.62 (d, J ) 4.5 Hz, 1H), 8.10 (d, J ) 7.7 Hz, 1H), 7.89 (t, J )
7.7 Hz, 1H), 7.51 (dd, J ) 7.7, 4.5 Hz, 1H), 7.09 (d, J ) 7.7 Hz,
1H), 7.03 (s, 1H), 7.00 (d, J ) 7.7 Hz, 1H), 6.36 (d, J ) 3.8 Hz,
1H), 4.26 (d, J ) 3.8 Hz, 1H), 2.65 (d, J ) 17.7 Hz, 1H), 2.57 (d,
J ) 17.7 Hz, 1H), 2.29-2.17 (m, 8H), 1.19 (s, 3H), 1.18 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 194.0, 193.8, 177.2, 151.0, 149.1,
6,6-Dimethyl-3-phenyl-2-picolinoyl-2,3,6,7-tetrahydrobenzo-
1
furan-4(5H)-one (5a). H NMR (300 MHz, CDCl3) δ 8.61 (d, J
J. Org. Chem. Vol. 73, No. 18, 2008 7093

Wang et al.
139.2, 137.3, 136.7, 135.5, 130.0, 128.8, 127.9, 124.8, 123.3, 115.3,
92.1, 51.3, 48.5, 37.8, 34.4, 29.1, 28.6, 20.0, 19.5; FT-IR (KBr)
ν/cm-1 2967, 1713, 1652, 1638, 1584, 1391, 1219, 1194, 1091,
1037, 995, 960, 952, 932, 802, 776, 744, 679, 618; HR-MS (+EI)
calcd for C24H25NO3 (M+) 375.1834, found 375.1840.
(dd, J ) 7.7, 4.6 Hz, 1H), 7.31 (d, J ) 8.5 Hz, 2H), 7.22 (d, J )
8.5 Hz, 2H), 6.33 (d, J ) 4.1 Hz, 1H), 4.30 (d, J ) 4.1 Hz, 1H),
2.79-2.72 (m, 2H), 2.35 (t, J ) 6.5 Hz, 2H), 2.19-2.12 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 194.4, 193.6, 178.6, 150.8, 149.1,
140.2, 137.4, 133.1, 128.9 (2C), 128.8 (2C), 128.1, 123.3, 116.2,
91.5, 48.4, 36.8, 24.0, 21.8; FT-IR (KBr) ν/cm-1 2933, 1715, 1654,
1639, 1491, 1389, 1227, 1177, 1089, 963, 946, 795, 657, 512; HR-
MS (+EI) calcd for C20H16NO335Cl (M+) 353.0819, found 353.0818.
3-(3,4-Dimethylphenyl)-2-picolinoyl-2,3,6,7-tetrahydrobenzo-
6,6-Dimethyl-2-picolinoyl-3-p-tolyl-2,3,6,7-tetrahydrobenzo-
1
furan-4(5H)-one (5g). H NMR (300 MHz, CDCl3) δ 8.61 (d, J
) 4.4 Hz, 1H), 8.10 (d, J ) 7.7 Hz, 1H), 7.89 (t, J ) 7.7 Hz, 1H),
7.51 (dd, J ) 7.7, 4.4 Hz, 1H), 7.17 (d, J ) 8.1 Hz, 2H), 7.13 (d,
J ) 8.1 Hz, 2H), 6.37 (d, J ) 3.9 Hz, 1H), 4.28 (d, J ) 3.9 Hz,
1H), 2.65 (d, J ) 17.7 Hz, 1H), 2.56 (d, J ) 17.7 Hz, 1H), 2.34 (s,
3H), 2.24 (d, J ) 16.3 Hz, 1H), 2.21 (d, J ) 16.3 Hz, 1H), 1.18 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 194.0, 193.8, 177.3, 151.0,
149.1, 138.8, 137.3, 136.8, 129.4 (2C), 127.9, 127.3 (2C), 123.3,
115.3, 92.0, 51.3, 48.5, 37.8, 34.4, 29.1, 28.6, 21.2; FT-IR (KBr)
ν/cm-1 2961, 1707, 1659, 1632, 1394, 1223, 1038, 961, 884, 802,
746, 676, 524; HR-MS (+EI) calcd for C23H23NO3 (M+) 361.1678,
found 361.1679.
1
furan-4(5H)-one (5m). H NMR (300 MHz, CDCl3) δ 8.62 (d, J
) 4.5 Hz, 1H), 8.10 (d, J ) 7.7 Hz, 1H), 7.89 (t, J ) 7.7 Hz, 1H),
7.51 (dd, J ) 7.7, 4.5 Hz, 1H), 7.08 (d, J ) 7.7 Hz, 1H), 7.03 (s,
1H), 6.99 (d, J ) 7.7 Hz, 1H), 6.34 (d, J ) 4.0 Hz, 1H), 4.27 (d,
J ) 4.0 Hz, 1H), 2.77-2.73 (m, 2H), 2.34 (t, J ) 6.3 Hz, 2H),
2.25 (s, 3H), 2.24 (s, 3H), 2.19-2.12 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 194.6, 194.1, 178.2, 151.1, 149.1, 139.1, 137.3, 136.7,
135.5, 130.0, 128.7, 128.0, 124.8, 123.3, 116.7, 91.9, 48.5, 36.9,
24.1, 21.9, 20.1, 19.6; FT-IR (KBr) ν/cm-1 2939, 2919, 1707, 1645,
1623, 1395, 1226, 1180, 1013, 955, 932, 788, 774, 658; HR-MS
(+EI) calcd for C22H21NO3 (M+) 347.1521, found 347.1517.
2-Picolinoyl-3-p-tolyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-
one (5n). 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J ) 4.5 Hz, 1H),
8.10 (d, J ) 7.7 Hz, 1H), 7.89 (t, J ) 7.7 Hz, 1H), 7.51 (dd, J )
7.7, 4.5 Hz, 1H), 7.17 (d, J ) 8.3 Hz, 2H), 7.13 (d, J ) 8.3 Hz,
2H), 6.35 (d, J ) 3.9 Hz, 1H), 4.30 (d, J ) 3.9 Hz, 1H), 2.78-2.72
(m, 2H), 2.36-2.32 (m, 5H), 2.17-2.12 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 194.5, 194.0, 178.3, 150.9, 149.1, 138.7, 137.3,
136.8, 129.3 (2C), 127.9, 127.3 (2C), 123.2, 116.5, 91.8, 48.5, 36.9,
24.0, 21.8, 21.2; FT-IR (KBr) ν/cm-1 2951, 1707, 1646, 1625, 1394,
1228, 1168, 1015, 956, 945, 785, 767; HR-MS (+EI) calcd for
C21H19NO3 (M+) 333.1365, found 333.1359.
3-(4-Methoxyphenyl)-6,6-dimethyl-2-picolinoyl-2,3,6,7-tet-
rahydrobenzofuran-4(5H)-one (5h). 1H NMR (300 MHz, CDCl3)
δ 8.62 (d, J ) 4.4 Hz, 1H), 8.10 (d, J ) 7.7 Hz, 1H), 7.89 (t, J )
7.7 Hz, 1H), 7.51 (dd, J ) 7.7, 4.4 Hz, 1H), 7.20 (d, J ) 8.6 Hz,
2H), 6.87 (d, J ) 8.6 Hz, 2H), 6.36 (d, J ) 3.8 Hz, 1H), 4.28 (d,
J ) 3.8 Hz, 1H), 3.80 (s, 3H), 2.65 (d, J ) 17.7 Hz, 1H), 2.56 (d,
J ) 17.7 Hz, 1H), 2.24 (d, J ) 16.4 Hz, 1H), 2.22 (d, J ) 16.4
Hz, 1H), 1.18 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 194.0, 193.9,
177.3, 158.8, 151.0, 149.1, 137.3, 133.9, 128.4 (2C), 127.9, 123.3,
115.2, 114.1 (2C), 92.1, 55.3, 51.3, 48.2, 37.8, 34.3, 29.1, 28.6;
FT-IR (KBr) ν/cm-1 2961, 1707, 1647, 1631, 1608, 1509, 1394,
1249, 1224, 1174, 1031, 960, 804, 674, 535; HR-MS (+EI) calcd
for C23H23NO4 (M+) 377.1627, found 377.1621.
3-Phenyl-2-picolinoyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-
one (5i). 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J ) 4.5 Hz, 1H),
8.11 (d, J ) 7.7 Hz, 1H), 7.89 (t, J ) 7.7 Hz, 1H), 7.51 (dd, J )
7.7, 4.5 Hz, 1H), 7.36-7.24 (m, 5H), 6.38 (d, J ) 4.0 Hz, 1H),
4.34 (d, J ) 4.0 Hz, 1H), 2.79-2.72 (m, 2H), 2.35 (t, J ) 6.4 Hz,
2H), 2.19-2.12 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 194.5,
193.9, 178.4, 150.9, 149.1, 141.6, 137.3, 128.6 (2C), 128.0, 127.5
(2C), 127.3, 123.3, 116.4, 91.7, 48.8, 36.9, 24.0, 21.8; FT-IR (KBr)
ν/cm-1 2944, 1712, 1650, 1633, 1454, 1397, 1228, 1171, 944, 752,
699; HR-MS (+EI) calcd for C20H17NO3 (M+) 319.1208, found
319.1202.
3-(4-Methoxyphenyl)-2-picolinoyl-2,3,6,7-tetrahydrobenzofu-
ran-4(5H)-one (5o). H NMR (300 MHz, CDCl3) δ 8.62 (d, J )
1
4.5 Hz, 1H), 8.11 (d, J ) 7.7 Hz, 1H), 7.89 (t, J ) 7.7 Hz, 1H),
7.51 (dd, J ) 7.7, 4.5 Hz, 1H), 7.20 (d, J ) 8.6 Hz, 2H), 6.87 (d,
J ) 8.6 Hz, 2H), 6.33 (d, J ) 3.9 Hz, 1H), 4.29 (d, J ) 3.9 Hz,
1H), 3.80 (s, 3H), 2.78-2.72 (m, 2H), 2.35 (t, J ) 6.3 Hz, 2H),
2.16-2.12 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 194.6, 194.0,
178.2, 158.8, 151.0, 149.1, 137.3, 133.8, 128.4 (2C), 128.0, 123.3,
116.5, 114.1 (2C), 91.9, 55.3, 48.1, 36.9, 24.0, 21.9; FT-IR (KBr)
ν/cm-1 2936, 2920, 1719, 1637, 1609, 1511, 1392, 1243, 1226,
1178, 1036, 964, 943, 877, 795, 650; HR-MS (+EI) calcd for
C21H19NO4 (M+) 349.1314, found 349.1307.
3-(4-Nitrophenyl)-2-picolinoyl-2,3,6,7-tetrahydrobenzofuran-
1
4(5H)-one (5j). H NMR (300 MHz, CDCl3) δ 8.56 (d, J ) 4.4
6,6-Dimethyl-3-phenyl-2-(pyrazine-2-carbonyl)-2,3,6,7-tet-
rahydrobenzofuran-4(5H)-one (5p). 1H NMR (300 MHz, CDCl3)
δ 9.31 (d, J ) 1.5 Hz, 1H), 8.81 (d, J ) 2.4 Hz, 1H), 8.58 (dd, J
) 2.4, 1.5 Hz, 1H), 7.36-7.24 (m, 5H), 6.29 (d, J ) 3.9 Hz, 1H),
4.33 (d, J ) 3.9 Hz, 1H), 2.64 (d, J ) 17.7 Hz, 1H), 2.56 (d, J )
17.7 Hz, 1H), 2.25 (d, J ) 16.3 Hz, 1H), 2.22 (d, J ) 16.3 Hz,
1H), 1.18 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 193.8, 193.3,
177.1, 148.7, 145.5, 145.0, 143.6, 141.3, 128.8 (2C), 127.5, 127.4
(2C), 115.2, 91.5, 51.3, 48.8, 37.8, 34.4, 29.0, 28.7; FT-IR (KBr)
ν/cm-1 2965, 1712, 1636, 1624, 1396, 1220, 1020, 968, 947, 890,
709; HR-MS (+EI) calcd for C21H20N2O3 (M+) 348.1474, found
348.1466.
Hz, 1H), 8.21 (d, J ) 8.7 Hz, 2H), 8.14 (d, J ) 7.7 Hz, 1H), 7.93
(t, J ) 7.7 Hz, 1H), 7.55 (dd, J ) 7.7, 4.4 Hz, 1H), 7.47 (d, J )
8.7 Hz, 2H), 6.36 (d, J ) 4.2 Hz, 1H), 4.43 (d, J ) 4.2 Hz, 1H),
2.82-2.75 (m, 2H), 2.36 (t, J ) 6.4 Hz, 2H), 2.21-2.13 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 194.3, 193.1, 179.1, 150.5, 149.1,
149.0, 147.3, 137.6, 128.5 (2C), 128.3, 123.9 (2C), 123.4, 115.8,
91.1, 48.8, 36.7, 24.0, 21.8; FT-IR (KBr) ν/cm-1 2945, 1709, 1660,
1632, 1514, 1394, 1343, 1228, 1171, 1107, 957, 946, 852, 792,
751; HR-MS (+EI) calcd for C20H16N2O5 (M+) 364.1059, found
364.1053.
3-(4-Cyanophenyl)-2-picolinoyl-2,3,6,7-tetrahydrobenzofuran-
1
4(5H)-one (5k). H NMR (300 MHz, CDCl3) δ 8.56 (d, J ) 4.5
6,6-Dimethyl-2-picolinoyl-3-propyl-2,3,6,7-tetrahydrobenzo-
1
Hz, 1H), 8.13 (d, J ) 7.7 Hz, 1H), 7.92 (t, J ) 7.7 Hz, 1H), 7.64
(d, J ) 8.3 Hz, 2H), 7.54 (dd, J ) 7.7, 4.5 Hz, 1H), 7.42 (d, J )
8.3 Hz, 2H), 6.34 (d, J ) 4.2 Hz, 1H), 4.38 (d, J ) 4.2 Hz, 1H),
2.81-2.74 (m, 2H), 2.35 (t, J ) 6.4 Hz, 2H), 2.21-2.12 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 194.3, 193.2, 179.0, 150.6, 149.1,
147.1, 137.6, 132.5 (2C), 128.4 (2C), 128.3, 123.5, 119.0, 115.8,
111.2, 91.1, 49.0, 36.8, 24.0, 21.8; FT-IR (KBr) ν/cm-1 2933, 2228,
1713, 1655, 1638, 1388, 1229, 1180, 1061, 962, 939, 877, 796,
558; HR-MS (+EI) calcd for C21H16N2O3 (M+) 344.1161, found
344.1161.
furan-4(5H)-one (5q). H NMR (300 MHz, CDCl3) δ 8.68 (d, J
) 4.5 Hz, 1H), 8.05 (d, J ) 7.7 Hz, 1H), 7.87 (t, J ) 7.7 Hz, 1H),
7.51 (dd, J ) 7.7, 4.5 Hz, 1H), 6.23 (d, J ) 3.9 Hz, 1H), 3.27-3.20
(m, 1H), 2.54 (d, J ) 17.6 Hz, 1H), 2.40 (d, J ) 17.6 Hz, 1H),
2.23 (d, J ) 16.5 Hz, 1H), 2.21 (d, J ) 16.5 Hz, 1H), 1.93-1.70
(m, 2H), 1.53-1.39 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H), 0.94 (t, J
) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.8, 194.6, 177.2,
151.4, 149.0, 137.3, 127.8, 123.2, 114.6, 88.9, 51.5, 43.9, 37.9,
35.4, 34.3, 29.1, 28.5, 19.4, 14.3; FT-IR (KBr) ν/cm-1 2960, 1709,
1633, 1582, 1407, 1395, 1222, 1034, 960, 938, 742, 691; HR-MS
(+EI) calcd for C19H23NO3 (M+) 313.1678, found 313.1679.
3-Isobutyl-6,6-dimethyl-2-picolinoyl-2,3,6,7-tetrahydrobenzo-
3-(4-Chlorophenyl)-2-picolinoyl-2,3,6,7-tetrahydrobenzofuran-
1
4(5H)-one (5l). H NMR (300 MHz, CDCl3) δ 8.59 (d, J ) 4.6
1
Hz, 1H), 8.11 (d, J ) 7.7 Hz, 1H), 7.90 (t, J ) 7.7 Hz, 1H), 7.53
furan-4(5H)-one (5r). H NMR (400 MHz, CDCl3) δ 8.67 (d, J
7094 J. Org. Chem. Vol. 73, No. 18, 2008

SolVent-Free Cycloadditions of 1,3-Cyclohexanediones to 1-(Pyridin-2-yl)-enones
) 4.8 Hz, 1H), 8.05 (d, J ) 7.7 Hz, 1H), 7.87 (t, J ) 7.7 Hz, 1H),
7.51 (dd, J ) 7.7, 4.8 Hz, 1H), 6.22 (d, J ) 3.4 Hz, 1H), 3.28-3.22
(m, 1H), 2.55 (d, J ) 17.7 Hz, 1H), 2.40 (d, J ) 17.7 Hz, 1H),
2.23 (d, J ) 16.1 Hz, 1H), 2.20 (d, J ) 16.1 Hz, 1H), 2.06-1.96
(m, 1H), 1.72-1.58 (m, 2H), 1.14 (s, 3H), 1.13 (s, 3H), 0.93 (d, J
) 6.6 Hz, 3H), 0.83 (d, J ) 6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 194.5, 194.3, 177.0, 151.3, 148.9, 137.2, 127.7, 123.1,
115.5, 89.1, 51.4, 43.8, 41.9, 37.7, 34.1, 28.9, 28.3, 25.4, 23.4, 22.1;
FT-IR (KBr) ν/cm-1 2957, 1712, 1639, 1397, 1217, 1033, 939,
745, 687; HR-MS (+EI) calcd for C20H25NO3 (M+) 327.1834, found
327.1840.
Mn(OAc)3 ·2H2O-Mediated Oxidation Reaction of Com-
pound 5a. A mixture of 5a (69.4 mg, 0.20 mmol) and
Mn(OAc)3 ·2H2O (128.6 mg, 0.48 mmol) was added to absolute
ethanol (10 mL) in a round-bottomed flask wrapped with aluminum
foil, and the suspension was stirring for 3 h under the nitrogen
protection at 60 °C. After completion of the reaction, the solvent
was removed in vacuo, and the residue was separated by flash
column chromatography on silica gel (eluent, petroleum ether/ethyl
acetate ) 2.5:1 v/v) to afford 6,6-dimethyl-3-phenyl-2-picolinoyl-
1
6,7-dihydrobenzofuran-4(5H)-one 6a (64.9 mg, 94%). H NMR
(300 MHz, CDCl3) δ 8.16 (d, J ) 3.9 Hz, 1H), 7.71 (d, J ) 7.5
Hz, 1H), 7.66 (t, J ) 7.5 Hz, 1H), 7.27-7.05 (m, 6H), 2.93 (s,
2H), 2.44 (s, 2H), 1.20 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
193.0, 183.9, 169.4, 154.1, 148.6, 147.5, 136.5, 134.0, 130.4 (2C),
130.3, 128.2, 127.4 (2C), 126.0, 123.8, 119.8, 53.3, 38.1, 34.8, 28.6
(2C); FT-IR (KBr) ν/cm-1 2961, 2929, 1692, 1642, 1581, 1537,
1488, 1451, 1436, 1421, 1411, 1349, 1339, 1246, 1167, 1050, 984,
929, 770, 745, 707, 689; HR-MS (+EI) calcd for C22H19NO3 (M+)
345.1365, found 345.1362.
Synthesis of Michal Product 7a by the Mn(OAc)3 ·2H2O-
Mediated Reaction of Dimedone 1a with 2-Cinnamoylpyri-
dine 4a. The two stainless-steel jars, containing a mixture of
dimedone 1a (14.0 mg, 0.10 mmol), 2-cinnamoylpyridine 4a (25.1
mg, 0.12 mmol), Mn(OAc)3 ·2H2O (64.3 mg, 0.24 mmol), and a
stainless-steel ball in each of the two reaction vessels, were milled
vigorously at a rate of 1800 rpm at room temperature for 5 min.
The resulting mixtures were extracted with ethyl acetate, and the
combined solution was evaporated to remove the solvent in vacuo.
The residue was separated by flash column chromatography on silica
gel (gradient eluent, petroleum ether/ethyl acetate ) 2.5:1 and 1:1
v/v) to afford 6,6-dimethyl-3-phenyl-2-picolinoyl-2,3,6,7-tetrahy-
drobenzofuran-4(5H)-one 5a (18.8 mg, 27%) and 3-hydroxy-5,5-
dimethyl-2-(3-oxo-1-phenyl-3-(pyridin-2-yl)propyl)cyclohex-2-
Acknowledgment. The authors are grateful for the financial
support from National Natural Science Foundation of China
(Nos. 20621061 and 20772117), National Basic Research
Program of China (2006CB922003), and the Scientific Research
Foundation of Graduate School of USTC.
1
enone 7a (29.1 mg, 42%). 7a: H NMR (400 MHz, DMSO-d6) δ
10.32 (bs, 1H), 8.70 (bs, 1H), 7.95 (bs, 1H), 7.85 (bs, 1H), 7.61
(bs, 1H), 7.19-7.10 (m, 4H), 7.06 (t, J ) 7.0 Hz, 1H), 4.80 (bs,
1H), 4.16 (bs, 1H), 3.67 (bs, 1H), 2.27-2.11 (m, 4H), 0.95 (s, 6H);
13C NMR (100 MHz, DMSO-d6) δ 200.5, 153.1, 149.1, 144.8,
137.5, 127.7, 127.4, 125.2, 121.2, 115.8, 46.9, 33.7, 31.5, 27.8;
FT-IR (KBr) ν/cm-1 2958, 1698, 1602, 1377, 1315, 1250, 1151,
1070, 996, 764, 700; HR-MS (+EI) calcd for C22H23NO3 (M+)
349.1678, found 349.1671.
Supporting Information Available: NMR spectra of 5a-r,
1H-13C HMBC and 1H-1H NOESY spectra of 5j, and
computational details for 5j. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800870Z
J. Org. Chem. Vol. 73, No. 18, 2008 7095