Unexpected manganese(III) acetate-mediated reactions of β-enamino carbonyl compounds with 1-(pyridin-2-yl)-enones under mechanical milling conditions

Article abstract of DOI:10.1039/c2cc36360g

The solvent-free reactions of β-enamino carbonyl compounds with 1-(pyridin-2-yl)-enones in the presence of manganese(iii) acetate dihydrate unexpectedly afforded 2-acyl-3-aryl-6,7-dihydro-4(5H)-benzofuran derivatives under mechanical milling conditions.

Full text of DOI:10.1039/c2cc36360g

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COMMUNICATION
Unexpected manganese(III) acetate-mediated reactions of b-enamino
carbonyl compounds with 1-(pyridin-2-yl)-enones under mechanical
milling conditionswz
Zi Liu,a Guang-Peng Fana and Guan-Wu Wang*ab
Received 31st August 2012, Accepted 16th October 2012
DOI: 10.1039/c2cc36360g
The solvent-free reactions of b-enamino carbonyl compounds with
1-(pyridin-2-yl)-enones in the presence of manganese(III) acetate
dihydrate unexpectedly afforded 2-acyl-3-aryl-6,7-dihydro-4(5H)-
benzofuran derivatives under mechanical milling conditions.
by Mn(OAc)3ꢀ2H2O was chosen as the model reaction. Inter-
estingly, the solvent-free reaction in a molar ratio of 1 : 1 : 2 for
2 h under ball-milling conditions with two milling balls afforded
a dihydrobenzofuran derivative (3aa) in 17% yield (Table 1,
entry 1), accompanied by some byproducts. The X-ray crystal
structure of 3aa is shown in Fig. 1. With the amount of
Mn(OAc)3ꢀ2H2O increasing to 4 equiv., the yield of 3aa reached
44% (Table 1, entry 2). Further increasing the amount of 2aa to
2 equiv. did not improve the product yield (Table 1, entry 3).
Using more 1a with a molar ratio of 2 : 1 : 4 provided 3aa in 59%
yield (Table 1, entry 4). Based on the literature, Cu(II), Fe(III), and
Ce(IV) can trigger the generation of carbon-centered radicals.3a,b
Therefore, Cu(OAc)2ꢀH2O, FeCl3ꢀ6H2O and Ce(NH4)2(NO3)6
With the public’s increasing consciousness of environmental
protection, solvent-free reactions,1 which eliminate the use of
toxic organic solvents during reactions, simplify the separation
procedure and cut down the cost, have received considerable
attention in organic synthesis. One important technique employed
in solvent-free reactions is mechanical milling. Many types of
mechanochemical reactions have been investigated.2 On the other
hand, Mn(III)-promoted radical reactions have found widespread
applications in organic synthesis.3 Our group intend to solve the
poor solubility problem of Mn(OAc)3 in common organic solvents
by conducting organic reactions under solvent-free mechano-
chemical conditions.4
Table 1 Optimization of the Mn(OAc)3-mediated reaction of 3-amino-
5,5-dimethylcyclohex-2-enone with (E)-1-(pyridin-2-yl)-3-p-tolylprop-2-
en-1-one under mechanical milling conditionsa
In 2006, we have successfully realized the Mn(OAc)3-promoted
reaction of C60 with b-enamino carbonyl compounds to generate
C60-fused pyrroline derivatives.5 Shortly afterwards we have
investigated the unusual radical additions of 1,3-cyclohexane-
diones to 1-(pyridin-2-yl)-enones mediated by Mn(OAc)3 in a
ball mill affording tetrahydrobenzofurans.4c We wondered what
would happen when 1,3-cyclohexanediones were replaced by
b-enamino carbonyl compounds in the mechanochemical
reaction. In this communication, we disclose that the reactions
of b-enamino carbonyl compounds with 1-(pyridin-2-yl)-enones
afford dihydrobenzofuran derivatives instead of the expected
2-acyl-3-aryl-indole derivatives.
Ratio of
reagentb
Yieldc
Time (%)
Entry Oxidant
Base
1
2
3
4
5
6
7
Mn(OAc)3ꢀ2H2O
1 : 1 : 2
1 : 1 : 4
1 : 2 : 4
2 : 1 : 4
2 : 1 : 4
2 : 1 : 4
2 : 1 : 4
2 : 1 : 3
2 : 1 : 5
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
17
44
43
59
0
Mn(OAc)3ꢀ2H2O
Mn(OAc)3ꢀ2H2O
Mn(OAc)3ꢀ2H2O
Cu(OAc)2ꢀ2H2O
FeCl3ꢀ6H2O
0
0
The reaction of 3-amino-5,5-dimethylcyclohex-2-enone (1a)
with (E)-1-(pyridin-2-yl)-3-p-tolylprop-2-en-1-one (2a) promoted
CAN
8
9
Mn(OAc)3ꢀ2H2O
Mn(OAc)3ꢀ2H2O
39
42
67
62
51
57
43
77
76
76
40
10
11
12
13
14
15
16
17
18
Mn(OAc)3ꢀ2H2O NaHCO3
2 : 1 : 4 : 1 2 h
a Hefei National Laboratory for Physical Sciences at Microscale,
CAS Key Laboratory of Soft Matter Chemistry, and Department of
Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, P. R. China. E-mail: gwang@ustc.edu.cn;
Fax: +86 551 3607864; Tel: +86 551 3607864
Mn(OAc)3ꢀ2H2O K3PO4ꢀ3H2O 2 : 1 : 4 : 1 2 h
Mn(OAc)3ꢀ2H2O tBuOK
Mn(OAc)3ꢀ2H2O DBU
Mn(OAc)3ꢀ2H2O DABCO
Mn(OAc)3ꢀ2H2O DMAP
Mn(OAc)3ꢀ2H2O DMAP
Mn(OAc)3ꢀ2H2O DMAP
Mn(OAc)3ꢀ2H2O DMAP
2 : 1 : 4 : 1 2 h
2 : 1 : 4 : 1 2 h
2 : 1 : 4 : 1 2 h
2 : 1 : 4 : 1 2 h
3 : 1 : 4 : 1 2 h
2 : 1 : 4 : 1 3 h
2 : 1 : 4 : 1 1 h
b State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, Gansu 730000, P. R. China
w This article is part of the ChemComm ‘Mechanochemistry’ web
themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures for the synthesis, spectral data and NMR spectra of
compounds 3. CCDC 899391. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc36360g
a
All the reactions were carried out in Spex SamplePrep 5100 Mixer Mill.
For entries 1–9, the reagent ratio refers to 1a : 2a : oxidant; for entries
10–18, the reagent ratio refers to 1a : 2a : oxidant : base. c Isolated yield.
b
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11665–11667 11665

Table
1-(pyridin-2-yl)-enones promoted by Mn(OAc)3 under ball-milling
2 Reactions of b-enamino carbonyl compounds with
conditionsa
Fig. 1 X-ray structure of 3aa.
were tested in our reaction, but they all were ineffective
(Table 1, entries 5–7). Reducing the amount of Mn(OAc)3ꢀ
2H2O to 3 equiv. resulted in 39% yield (Table 1, entry 8).
However, further increasing the usage of Mn(OAc)3ꢀ2H2O
also led to poor yield (Table 1, entry 9). To improve the
product yield, we tried to add some base to the reaction
system. We were pleased to find that the addition of NaHCO3
gave a higher yield (67%, Table 1, entry 10). A comparable
efficiency was observed with K3PO4ꢀ3H2O (62%, Table 1,
t
entry 11). Other bases including BuOK, DBU and DABCO
were detrimental to the product yield (Table 1, entries 12–14).
To our satisfaction, we found that the yield was improved to
77% by using DMAP as the base (Table 1, entry 15). How-
ever, continuing to enhance the use of 1a to 3 equiv. relative to
2a, a comparable yield (Table 1, entry 16) was obtained.
Keeping the 1a
:
2a : Mn(OAc)3ꢀ2H2O : DMAP ratio as
2 : 1 : 4 : 1 and increasing the reaction time did not provide
superior yield (Table 1, entry 17), while decreasing the reaction
time deteriorated the yield to 40% (Table 1, entry 18).
With the optimized reaction conditions in hand (Table 1, entry
15), we carried out a series of reactions of b-enamino carbonyl
compounds with 1-(pyridin-2-yl)-enones (Table 2). Firstly, a range
of N-substituted b-enamino carbonyl compounds were used to
explore their reactivity towards (E)-1-(pyridin-2-yl)-3-p-tolylprop-2-
en-1-one (2a). When N-substituted b-enamino carbonyl compounds
synthesised by the condensation of 5,5-dimethyl-1,3-cyclohexane-
dione (dimedone) with different aliphatic amines (1b–1f) were
utilized, they all gave the same product 3aa in comparable
yields (61–70%), albeit lower than that from 1a. Nevertheless,
if 5,5-dimethyl-3-(p-tolylamino)cyclohex-2-enone (1g), which
was prepared from dimedone and an aromatic amine, was
used to react with 2a, 3aa was obtained in only 15% yield.
Hence 3-amino-5,5-dimethylcyclohex-2-enone (1a) was the
best reaction partner for 2a. Secondly, the substrate scope
was also investigated with respect to various 1-(pyridin-2-yl)-
enones. As shown in Table 2, a variety of functional groups from
electron-donating groups to electron-withdrawing groups, such
as –CH3 (3aa, 3ab and 3ac), –OCH3 (3ad, 3ae and 3af), –Cl (3ah
and 3ai), –CN (3ak) and –NO2 (3al and 3am), were compatible
with the reaction conditions, and provided the corresponding
products in moderate to good yields (56–78%). From 3ab, 3af
and 3ai, we can see that substitution at the ortho position of the
phenyl ring of 1-(pyridin-2-yl)-enones had a slightly negative
influence on the synthesis of dihydrobenzofuran derivatives.
Heterocyclic enones also served as suitable reaction partners,
and furnished 3an and 3ao in 72% and 77% yields, respectively.
When enones bearing a pyrazine moiety (2p and 2q) were
employed as substrates in the reaction, the corresponding products
3ap and 3aq could also be obtained in comparable yields.
c
11666 Chem. Commun., 2012, 48, 11665–11667
This journal is The Royal Society of Chemistry 2012

Table 2 (continued )
reaction showed its unique superiority over traditional liquid-
phase reaction.
To shed light on the reaction mechanism, control experi-
ments were carried out. Dihydrobenzofurans might involve
Michael intermediate 4aa formed from 1a and 2a after hydro-
lysis. Nevertheless, treatment of 4aa with Mn(OAc)3ꢀ2H2O
(4.0 equiv.) and DMAP (1.0 equiv.) in the presence of ammonium
acetate (1.7 equiv.) for 2 h afforded only tetrahydrobenzofuran
derivative 5aa (Scheme 2). Furthermore, treatment of 5aa with
Mn(OAc)3ꢀ2H2O (2.0 equiv.) and DMAP (0.5 equiv.) for 2 h
resulted in complete recovery of 5aa. Therefore, the possibility that
3aa was formed via the intermediate 4aa and 5aa can be ruled out.
Our previous study showed that the Mn(OAc)3-mediated reaction
of 1,3-cyclohexanediones with 1-(pyridin-2-yl)-enones afforded
tetrahydrobenzofurans.4c Although the attempt to isolate the
Michael intermediate of 1a and 2a failed and the detailed
pathway remains to be elucidated, the amino group in 1a must
play a crucial role in the formation of 3aa.
a
Properly characterized by FT-IR, 1H NMR, 13C NMR, and HRMS
spectral data (see ESI).
In conclusion, we have described that the solvent-free
Mn(OAc)3-mediated reactions of b-enamino carbonyl compounds
with 1-(pyridin-2-yl)-enones unexpectedly afford dihydrobenzo-
furan derivatives instead of the 2-acyl-3-aryl-indole derivatives
under mechanical milling conditions. Efforts towards under-
standing the reaction mechanism and further development of
this kind of novel cyclization reactions are underway.
We are grateful for financial support from the Knowledge
Innovation Project of the Chinese Academy of Sciences
(KJCX2.YW.H16) and the Key Project of Science and Tech-
nology of the Department of Education, Anhui Province,
China (KJ2010ZD05).
Scheme 1 Reaction of 1a with 2a promoted by Mn(OAc)3 in toluene
at 100 1C for 24 h.
Notes and references
1 (a) A. Loupy, Top. Curr. Chem., 1999, 206, 153; (b) K. Tanaka and
F. Toda, Chem. Rev., 2000, 100, 1025.
2 For reviews, see: (a) G.-W. Wang, Fullerene Mechanochemistry. in
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American Scientific Publishers, Stevenson Ranch, 2004, vol. 3, p. 557;
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Curr. Chem., 2005, 254, 185; (d) B. Rodrıguez, A. Bruckmann,
´
Scheme 2 Conversion of 4aa to 5aa in the presence of Mn(OAc)3.
T. Rantanen and C. Bolm, Adv. Synth. Catal., 2007, 349, 2213;
(e) A. Bruckmann, A. Krebs and C. Bolm, Green Chem., 2008,
10, 1131; (f) A. Stolle, T. Szuppa, S. E. S. Leonhardt and
B. Ondruschka, Chem. Soc. Rev., 2011, 40, 2317; (g) S. L. James,
Reaction of 3-aminocyclohex-2-enone (1h) with 1-(pyridin-2-yl)-
enones containing an electron-donating or electron-withdrawing
group worked as well, and afforded 3ha, 3hd, 3hl and 3hm in
68–70% yields. However, the reaction of 1a with (E)-1-phenyl-3-
p-tolylprop-2-en-1-one or (E)-4-(4-methoxy-phenyl)-but-3-en-
2-one in place of (E)-1-(pyridin-2-yl)-3-p-tolylprop-2-en-1-one
failed, indicating that the nitrogen-containing aromatic moiety
was very important in the current reaction.
C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friscic, F. Grepioni,
´
K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini,
A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steedk and
D. C. Waddelli, Chem. Soc. Rev., 2012, 41, 413; (h) R. B. N. Baig and
R. S. Varma, Chem. Soc. Rev., 2012, 41, 1559; (i) T. Friscic
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´
, Chem.
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1994, 94, 519; (b) B. B. Snider, Chem. Rev., 1996, 96, 339; (c) G.-W. Wang
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F.-B. Li, Curr. Org. Chem., 2012, 16, 1109.
4 (a) Z. Zhang, G.-W. Wang, C.-B. Miao, Y.-W. Dong and
Y.-B. Shen, Chem. Commun., 2004, 1832; (b) X. Cheng,
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The reaction was examined in organic solvents as well, but the
results were inferior to those obtained by employing the mechanical
milling technique. For example, the reaction system became
complicated and a low yield of 38% was obtained when
the reaction of 1a (3.0 equiv.) with 2a (1.0 equiv.) promoted
by Mn(OAc)3ꢀ2H2O (4.0 equiv.) in the presence of DMAP
(1.0 equiv.) was performed in toluene at 100 1C for 24 h
(Scheme 1). Therefore, the solvent-free mechanochemical
5 G.-W. Wang, H.-T. Yang, C.-B. Miao, Y. Xu and F. Liu, Org.
Biomol. Chem., 2006, 4, 2595.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11665–11667 11667