Solid-state radical reactions of 1,3-cyclohexanediones with in situ generated imines mediated by manganese(III) acetate under mechanical milling conditions

Article abstract of DOI:10.1039/b406402j

Under solid-state conditions, manganese(III) acetate-mediated radical reactions of 1,3-cyclohexanedione and 5,5-dimethyl-1,3-cyclohexanedione with in situ generated imines proceeded efficiently by mechanical milling at room temperature and good to excelle

Full text of DOI:10.1039/b406402j

Solid-state radical reactions of 1,3-cyclohexanediones with in situ
generated imines mediated by manganese(III) acetate under mechanical
milling conditions†
Ze Zhang, Guan-Wu Wang,* Chun-Bao Miao, Ya-Wei Dong and Ye-Bing Shen
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R.
China. E-mail: gwang@ustc.edu.cn; Fax: 86-551-360-7864; Tel: 86-551-360-7864
Received (in Cambridge, UK) 28th April 2004, Accepted 3rd June 2004
First published as an Advance Article on the web 21st July 2004
Under solid-state conditions, manganese(III) acetate-mediated
radical reactions of 1,3-cyclohexanedione and 5,5-dimethyl-
reactions were performed under solvent-free and one-pot condi-
tions. However, traditional Mn(OAc) -mediated radical reactions
3
1,3-cyclohexanedione with in situ generated imines proceeded
in organic solvents usually gave yields less than 70%. Our present
method could be extended to liquid starting materials as well. For
example, when aniline was employed instead of 1, a similar result
was achieved. However, an accurate yield could not be obtained
because the jar of the ball-milling apparatus was not airtight and
thus leakage occurred during the imine formation in the first
step.
efficiently by mechanical milling at room temperature and good
to excellent yields were achieved.
3
In organic chemistry, manganese(III) acetate (Mn(OAc) ) has been
most commonly used in the generation of carbon-centered radicals
from various carbonyl compounds and their oxidative addition to
1
alkenes. However, a significant drawback to the use of Mn(OAc)
3
The efficiency of the current solid-state procedure may be
ascribed to an enhanced reaction rate resulting from ultimately high
concentrations of reactants with no use of solvent, and the high
3
is the harsh reaction conditions. As Mn(OAc) has poor solubility
in organic solvents, acetic acid is almost invariably used, though
other organic solvents such as methanol, ethanol, trifluoroethanol,
acetonitrile, dichloromethane, monochlorobenzene, and toluene
4
e
mechanical energy that can greatly enforce the reaction. Fur-
thermore, the high reactivity of the substrates also contributes to
this efficiency to a great extent. This point may be understood from
2
have also been employed in some cases. Under these conditions,
1
,7
the yield is relatively low and the separation procedure at the end of
the reaction is rather tedious. In the standard workup procedure,
large quantities of water and/or aqueous sodium hydrogen
carbonate have to be used to remove the acetic acid and so
considerable amounts of aqueous waste would be generated. To
circumvent this problem, one of the best methods is to carry out this
kind of reaction under solvent-free conditions. The mechanical ball
milling technique, which is broadly used to produce alloys, metal
the reaction mechanism. Based on the related literature and the
fact that two molar equivalents of Mn(OAc) are required for the
3
completion of the reaction, a tentative mechanism for the reaction
may be formulated as shown in Scheme 2. The addition of the
Mn(III) enolate 6 to the imine 3 gives the nitrogen-centered radical
3
7, followed by oxidation with Mn(OAc) to form non-reductive
adduct 8 and subsequent enolization to afford product 5. For
1,3-cyclohexanedione and dimedone, enolization occurs readily
and thus the formation of 6 is easy and fast. For imines, the CNN
3
oxides and other inorganic materials, has been successfully
applied to some organic reactions in recent years and offers the
advantages of reduced pollution, low cost, and simplicity in process
4
and handling. On the other hand, although Mn(OAc)
3
-promoted
radical addition to alkenes has for a long time attracted research
efforts, a survey of the related literature revealed that the
corresponding radical addition to imines has not been reported.
Radical addition to the CNN bond has begun to emerge as a useful
synthetic process only since the 1980s. Among the various CNN-
containing functional groups, the most commonly used radical
receptors are oxime ethers and hydrazones. Imines are rarely used
5
due to their proneness to hydrolysis and tautomerization. Fur-
Scheme 1
thermore, in contrast to many known intramolecular reactions,
there are few reports on intermolecular radical additions to CNN
bonds.5
Table 1 Solid-state radical reactions of 1,3-cyclohexanedione and dime-
done with in situ generated imines
With a view to the above reasons and to establishing efficient and
milder reaction conditions in this field, we have investigated the
Product 5a
3 2
novel manganese(III) acetate dihydrate (Mn(OAc) ·2H O)-medi-
R
1
R
2
Yield (%)b
ated intermolecular radical additions of 1,3-cyclohexanediones to
in situ generated imines promoted by the mechanical ball milling
technique (Scheme 1).
5
5
5
5
5e
5f
a
b
c
4-NO
3-NO
4-CN
4-Cl
4-Br
3,4-Cl
2
CH
CH
CH
CH
CH3
CH
3
3
3
3
84
81
94
89
93
91
84
76
73
78
71
71
74
58
2
In our present protocol all the reactions were carried out under
solid-state conditions. The first-step reactions of 4-methylaniline 1
with aldehydes 2 could afford quantitatively imines 3, which were
directly used as radical receptors in the following process without
d
3
6
5g
3,4-OCH O
CH3
further separation. The detailed results for the radical reactions of
2
5
5
5
5
5
5
h
4-NO
3-NO
4-CN
4-Cl
4-Br
3,4-Cl
2
H
1,3-cyclohexanediones with various in situ generated imines are
i
j
k
l
m
2
H
H
H
H
H
H
summarized in Table 1.
According to the results shown in Table 1, it can be seen that
good to excellent yields have been achieved even though these
†
Electronic supplementary information (ESI) available: detailed experi-
5n
a
2
3,4-OCH O
1
13
mental procedure for the synthesis and mp, IR, H NMR, C NMR and
HRMS spectral data of compounds 5a–5n. See http://www.rsc.org/
suppdata/cc/b4/b406402j/
Properly characterized by mp, IR, H NMR, 13C NMR and HRMS spectral
data (see ESI). b Isolated yield.
1
1
832
C h e m . C o m m u n . , 2 0 0 4 , 1 8 3 2 – 1 8 3 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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group may exhibit a higher radical addition rate relative to
analogous alkene acceptors.
the National Science Foundation of China (20321101), the Anhui
5
Provincial Bureau of Personnel Affairs (2001Z019) and the Anhui
Provincial Natural Science Foundation (00045306) for financial
support.
Some of the above reactions have also been tentatively carried
out in organic solvents. But the result is much poorer than that of the
current mechanical milling procedure. In fact, it is very difficult to
obtain the imines quantitatively in the presence of organic solvents.
For example, when the reaction of 4-chlorobenzaldehyde with one
Notes and references
equivalent of 4-methylaniline was carried out in CH
temperature, it was hard to achieve completion, even overnight.
Isolation of imine 3d was attempted in the second step in CH CN
at room temperature for 6 h, but this condition led to the hydrolysis
of the imine and thus a very complicated reaction mixture, which
mainly contained the following organic compounds: unreacted
imine and dimedone, 4-chlorobenzaldehyde and 4-methylaniline
from the hydrolysis of imine 3d, condensation product from
3
CN at room
1 For reviews, see: (a) J. Iqbal, B. Bhatia and N. K. Nayyar, Chem. Rev.,
1994, 94, 519; (b) B. B. Snider, Chem. Rev., 1996, 96, 339; (c) G. G.
Melikyan, in Organic Reactions, Vol. 49, ed. L. Paquette, John Wiley,
New York, 1997, ch. 3, p. 427; ; For recent examples of Mn(III)-based
radical reactions, see: (d) D. Yang, X.-Y. Ye, M. Xu, K.-W. Pang and K.
K. Cheung, J. Am. Chem. Soc., 2000, 122, 1658; (e) B. B. Snider and R.
B. Smith, Tetrahedron, 2002, 58, 25.
3
2
(a) D. T. Davies, N. Kapur and A. F. Parsons, Tetrahedron, 2000, 56,
3
7
941; (b) J. Cossy, A. Bouzide and C. Leblanc, J. Org. Chem., 2000, 65,
257; (c) D. Yang, M. Xu and M.-Y. Bian, Org. Lett., 2001, 3, 111; (d)
4
-chlorobenzaldehyde with dimedone and a trace of desired
8
product 5d. To further investigate this reaction, we have examined
some other metal salts like those of Ce(IV) and Cu(II), which have
also been extensively studied and proved to be efficient catalysts
for the generation of carbon-centered radicals. As an example,
under these solid-state conditions, compound 5e was obtained in
only 36% yield when catalyzed by Ce(IV) ammonium nitrate
B. B. Snider and Q. L. Che, Tetrahedron, 2002, 58, 7821; (e) G. Bar, A.
F. Parsons and C. B. Thomas, Chem. Commun., 2001, 1350; (f) T.-H.
Zhang, P. Lu, F. Wang and G.-W. Wang, Org. Biomol. Chem., 2003, 1,
4
403; (g) G.-W. Wang, T.-H. Zhang, X. Cheng and F. Wang, Org.
Biomol. Chem., 2004, 2, 1160.
3
4
C. Suryanarayana, Prog. Mater. Sci., 2001, 46, 1.
(a) G.-W. Wang, K. Komastu, Y. Murata and M. Shiro, Nature, 1997,
(CAN). In the presence of Cu(OAc)
2
, compound 5e could not be
3
87, 583; (b) G. Kaupp, J. Schmeyers, A. Kuse and A. Atfeh, Angew.
generated at all.
Chem., Int. Ed., 1999, 38, 2896; (c) V. P. Balema, J. W. Wiench, M.
Pruski and V. K. Pecharsky, J. Am. Chem. Soc., 2002, 124, 6244; (d) S.
Wada, M. Urano and H. Suzuki, J. Org. Chem., 2002, 67, 8254; (e) Z.
Zhang, Y.-W. Dong, G.-W. Wang and K. Komastu, Synlett, 2004, 15,
61.
Among several modes of radical addition to the CNN bond, the
most common one is the reductive addition to obtain amines.5
Non-reductive additions had been realized to a much lesser
,9
extent.5,10 But considered from the synthetic perspective, they were
5
6
(a) G. K. Friestad, Tetrahedron, 2001, 57, 5461; (b) A. G. Fallis and I.
M. Brinza, Tetrahedron, 1997, 53, 17543.
Typical procedure is as follows: a mixture of aldehyde (0.2 mmol) and
greatly neglected and underdeveloped. Herein, the imines act as
radical acceptors for the radical addition followed by oxidation with
Mn(OAc) , thus the original CNN bond was reinstalled, which can
3
4
-methylaniline (0.2 mmol) was introduced, together with a stainless
be reasonably anticipated as a new route to subsequent synthesis of
unsymmetrical ketones and employed for further other functional-
izations. Interestingly, all the products were obtained exclusively in
an enol form under this condition. The identification of these enols
steel ball of 7.0 mm diameter, into a stainless steel jar (5 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 1 h. To the in situ generated imines in the two jars were added 0.2
1
13
is unequivocally ascertained by H NMR, C NMR, HRMS, and
6
1
FT-IR spectra. The singlet at about 14.7 ppm in the H NMR
spectra, the signal at about 195–200 ppm in the C NMR spectra
and the strong absorption at about 3440 cm21 in the IR spectra all
1
3
3 2
mmol of 1,3-cyclohexanedione and 0.4 mmol of Mn(OAc) ·2H O,
respectively. Then the reaction vessels were allowed to continue to
vibrate for 3 h. The resulting mixtures were kept overnight and extracted
with ethyl acetate and the desired product was separated by flash column
chromatography over silica gel. The spectral data for representative
compound 5a: IR (KBr) nmax 3434, 2952, 1652, 1598, 1548, 1517, 1447,
strongly support their molecular structures. It can be easily
understood that the main contribution to the remarkably high
stability of the enols is the high conjugation and thus the high
delocalization of the p electron cloud. Furthermore, the intra-
molecular hydrogen bond between the nitrogen atom in the CNN
group and the hydrogen atom in the hydroxyl group may also
contribute to stabilize this structure.
350 cm ; 1H NMR (300 MHz, CDCl
J = 8.67 Hz, 2H, Ar), 7.27 (d, J = 8.67 Hz, 2H, Ar), 6.94 (d, J = 8.31
Hz, 2H, Ar), 6.67 (d, J = 8.31 Hz, 2H, Ar), 2.58 (s, 2H, CH ), 2.31 (s,
2H, CH ), 2.23 (s, 3H, CH ), 1.11 (s, 6H, CH
3 2); 13C NMR (75 MHz,
CDCl ) d 200.78, 195.42, 167.29, 147.73, 141.20, 137.49, 133.83,
29.87 (2C), 128.91 (2C), 125.43 (2C), 123.61 (2C), 108.09, 53.20,
21
1
3
) d 14.68 (bs, 1H, OH), 8.13 (d,
2
2
3
3
In summary, we have developed a novel radical addition to
imines mediated by Mn(OAc) ·2H O under solid-state mecha-
3 2
3
1
5
+
2.53, 30.56, 28.57 (2C), 21.06; HR-MS (EI-TOF, m/z [M ]) Calc. for
378.1580, Found 378.1581.
nochemical conditions for the first time. The high efficiency and
good to excellent yield, no separation of the in situ generated
imines, no use of any solvents in carrying out the reactions and thus
the facile additional treatment make this method a potential
alternative to the traditional synthetic process. Furthermore, the
non-reductive radical addition mode and the corresponding struc-
ture of the products are intriguing, which impels us to explore other
22 22 2 4
C H N O
7
8
B. B. Snider and S. V. O’Neil, Tetrahedron, 1995, 51, 12983.
This result was obtained from a comparative evaluation on the HPLC
analyses of the mixture and each component. The measurements were
conducted on an Agilent 1100 liquid chromatograph with a diode-array
detector using a Zorbax Eclipse XDB-C18 column (4.6 mm 3 250 mm)
3 2
with CH OH/H O (4 : 1) as the eluent with monitoring at 254 nm.
9
Recent examples for reductive addition to CNN bonds: (a) N. Halland
and K. A. Jørgensen, J. Chem. Soc., Perkin Trans. 1, 2001, 1290; (b) G.
K. Friestad and J. Qin, J. Am. Chem. Soc., 2001, 123, 9922; (c) H.
Miyabe, K. Fujii and T. Naito, Org. Biomol. Chem., 2003, 1, 381; (d) M.
Ueda, H. Miyabe, M. Teramachi, O. Miyata and T. Naito, Chem.
Commun., 2003, 426; (e) M. Ueda, H. Miyabe, A. Nishimura, H. Sugino
and T. Naito, Tetrahedron: Asymmetry, 2003, 14, 2857; (f) M.
Fernandez and R. Alonso, Org. Lett., 2003, 5, 2461; (g) G. K. Friestad,
Y.-H. Shen and E. L. Ruggles, Angew. Chem., Int. Ed., 2003, 42, 5061;
1,3-dicarbonyl compounds and subsequent synthetic exploitation
on the useful functional groups that remain available in the
products. Work in this direction is under investigation.
We thank the National Science Fund for Distinguished Young
Scholars (20125205), the Fund for Innovative Research Groups of
(h) K. I. Yamada, Y. Yamamoto, M. Maekawa and K. Tomioka, J. Org.
Chem., 2004, 69, 1531.
1
0 Examples for non-reductive addition to CNN bonds: (a) A. Citterio and
L. Filippini, Synthesis, 1986, 473; (b) S. Kim, I. Y. Lee, J.-Y. Yoon and
D. H. Oh, J. Am. Chem. Soc., 1996, 118, 5138; (c) S. Kim and J.-Y.
Yoon, J. Am. Chem. Soc., 1997, 119, 5982.
Scheme 2
C h e m . C o m m u n . , 2 0 0 4 , 1 8 3 2 – 1 8 3 3
1833