Magnetically separable CuFe2O4 nanoparticles as a recoverable catalyst for the addition reaction of C(sp3)-H bond of azaarenes to aldehydes

Article abstract of DOI:10.1039/c4ra14486d

A green and efficient protocol for the copper ferrite (CuFe₂O₄) nanoparticle-catalyzed direct C(sp³)-H bond functionalization of 2-alkyl azaarenes has been developed. The magnetic catalyst can be recovered and recycled by a simple magnetic separation from the reaction solution and reused eight times without significant decrease in catalytic activity. This journal is

Full text of DOI:10.1039/c4ra14486d

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Magnetically Separable CuFe2O4 Nanoparticles as
Recoverable Catalyst for Addition Reaction of C(sp3)-
H Bond of Azaarenes to Aldehydes
Cite this: DOI: 10.1039/x0xx00000x
Zu-Li Wanga*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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formation, click reaction11 and other reactions12 were also well
A
green and efficient protocol for the copper ferrite
(CuFe2O4) nanoparticle-catalyzed direct C(sp3)-H bond
functionalization of 2-alkyl azaarenes has been developed.
The magnetically catalyst can be recovered and recycled by a
simple magnetically sepration from the reaction solution and
reused for eight times without significant decrease in catalytic
activity.
established. Although all these methods are effective,
challenges still remain, magnetic-nanoparticles catalyzed
C(sp3)-H bond functionalization has not been reported to date.
In line with our interest in C(sp3)-H bond functionalization, we
herein report the CuFe2O4-catalyzed direct C(sp3)-H bond
functionalization of 2-alkyl azaarenes: nucleophilic addition to
aldehydes.
At the outset, 2, 6-lutidine (1a) and p-nitrobenzaldehyde (2a)
were chosen as the model substrates to optimize the reaction
conditions (Table 1). Firstly, series of solvents were tested in
Aza-heterocyclic structural motifs are important components of
numerous natural products, bioactive pharmaceutical agents,
and functional organic materials.1 Because of their importance,
the presence of 0.1 equiv. of CuFe2O4 nanoparticles at 100
℃.
the functionalization of pyridines and quinolones have become
We found that ethylene glycol (EG) gave the highest yield
(65%) (entry11). Water afforded the lowest yield for this
reaction (entry 6), the reason may come from the low solubility
of the substrates in water. Only 22% yield was obtained when
nonplar solvent toluene was used (entry 5). A little higher
yields than that of toluene were obtained when polar solvent
such as DMF, DMSO were used (entries 2, 4). Furthermore,
when the amount of the catalyst was increased, the yield of
reaction showed no significant increase (entries 11-13).
However, the yield of the reaction decreased noticeably (entry
14) when the amount of the catalyst was reduced to 5mol%.
The effect of temperature on this reaction was also investigated,
but the yields of the reaction remain unchanged when the
a hot topic in organic transformations. One of the most efficient
methods for obtaining pyridine and quinoline derivatives is the
direct C(sp3)–H functionalization of alkyl-substituted azaarene.
In 2010, Huang, Xia and co-workers disclosed the palladium-
catalyzed addition reaction of C(sp3)–H bond of alkyl-
substituted azaarenes to imines.2 Then lots of efforts were made
on this area. At present, examples catalyzed by other transition
metal were realized,3 successful examples include Yb(OTf)3,3g
Sc(OTf)3,3c Cu(OTf)23k-catalyzed addition reaction of benzylic
C-H bond of azaarenes to double bonds reported by Huang,
Kanai and Rueping. Additionally, Bronsted acids4 and
microwave5 could also promote these reactions efficiently. In
some special circumstances, reactions could also be carried out
without catalyst.6 However, there are rare reports3a, 4a, 4g, 5a in
the addition of 2-alkylazaarenes to aldehyde. A green and
efficient method for C(sp3)–H of azaarenes functionalization
and nucleophilic addition to aldehydes under mild conditions
would be highly desired.
temperature was increased to 110
℃ and 120℃(entries15-16).
To examine the effect of the ligand on the reaction, several
ligands were subjected to this reaction. But the result was
disappointing (entries 17-19), all the ligand we examined
showed no improvement on this reaction. It is worth noting that
the addition of tetrabutylammonium chloride (TBAC) could
significantly improve the yield of 3a to 77% (entry 20). When 2
equiv. TBAC was added, there was no significant improvent on
the yield (entry 21). When the catalyst of CuFe2O4 was not
added, there was little desired products (entry 22). We also used
other catalyst such as Fe2O3 for this reacton, but only 10% yield
was obtained (entry 23).
Because of its inexpensive, air-stable, magnetically separable,
and recyclable merits, magnetic nanoparticles (MNPs) have
been extensively used in organic transformations.7 For
examples, Brahmachariet and co-workers presented an elegant
work for the synthesis of 2-substituted benzimidazoles and
quinoxalines using MnFe2O4 as a heterogeneous catalyst.8
Copper ferrite (CuFe2O4) catalyzed C-N,9 C-O10 bond
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Under the optimized conditions, the substrate scope of this pyridines, 2-methylbenzothiazole was also good substrate for
CuFe2O4-catalyzed C(sp3)-H functionalization of azaarenes this reaction (3p 3r). Good to excellent yields were obtained
were explored. As shown in Table 2, most of substrates we when 2-methylbenzothiazole reacted with p-
-
m
,
o
,
examined provided good to excellent yields. Substituted nitrobenzaldehyde. Among these various substituted
benzaldehydes with the electron-withdrawing group (such as benzaldehydes, 1, 4-phthalaldehyde could also reacted well
nitro-, cyano-) attached to benzene rings could react with 2- with 2,6-lutidine (3u) and the other formyl group remained
methyl pyridine or 2-methyl quinoline derivatives smoothly to intact, which provides a useful handle for further chemical
generate the corresponding products in good to excellent yields manipulations. It is worthwhile to note that heteroaromatic
(
3a
-
3l,
3n-
3o). When 2-methylpyrazine was used, good yield of aldehyde (3s) and aliphatic aldehyde (3t) were also well
tolerated in this system.
Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of the 2-alkyl azaarenes and aldehydea
OH
OH
OH
N
N
N
Catalyst
(equiv)
Entry
Solvent
T (℃)
Yield(%)b
O2N
O2N
3b,65%
O2N
3a,77%
3c
,90%
1
2
3
4
5
6
7
8
CuFe2O4 (0.1) THF
CuFe2O4 (0.1) DMF
CuFe2O4 (0.1) Dioxane
CuFe2O4 (0.1) DMSO
CuFe2O4 (0.1) Toluene
CuFe2O4 (0.1) H2O
CuFe2O4 (0.1) Ethanol
CuFe2O4 (0.1) DCE
CuFe2O4 (0.1) DME
CuFe2O4 (0.1) Glycerin
CuFe2O4 (0.1) EG
100
100
100
100
100
100
100
100
100
100
100
100
100
30
41
33
38
22
11
36
25
29
45
65
65
67
F
Br
OH
OH
OH
N
N
N
b
O2N
3f,90%
3d
O2N
,75%
3e,84%
O2N
OH
OH
N
OH
N
N
N
NO2
O2N
b
O2N
3i
,84%
3g,72%
OH
3h,73%
OH
O2N
9
OH
10
11
12
13
N
N
N
CuFe2O4 (0.2) EG
CuFe2O4 (0.3) EG
3k,80%
3j
,70%
3l
,84%
NO2
NO2
OH
CN
N
N
OH
CuFe2O4
(0.05)
OH
14
EG
100
50
N
N
NC
15
CuFe2O4 (0.1) EG
CuFe2O4 (0.1) EG
CuFe2O4 (0.1) EG
110
120
100
62
63
60
NC
3o,95%
O2N
3n,75%
3m
,70%
16
17c
OH
S
OH
S
OH
S
N
N
18d
CuFe2O4 (0.1) EG
100
46
N
NO2 3q
O2N
,89%
3p
,81%
3r
,88%
19e
20f
21g
22f
23f
CuFe2O4 (0.1) EG
CuFe2O4 (0.1) EG
CuFe2O4 (0.1) EG
100
100
100
100
100
57
77
75
trace
10
NO2
OH
N
HO
HO
CO2Et
N
N
N
none
Fe2O3(0.1)
EG
EG
OHC
3u
,71%
3s
,76%
3t,75%
aUnless otherwise stated, all reactions were carried out with 1 (0.5 mmol), 2
(0.25 mmol), CuFe2O4(0.1 equiv) and TBAC (1equiv) in EG (0.5 ml) at 100℃
for 24 h. bIn dioxane.
aUnless otherwise stated, all reactions were carried out with 1a (0.5 mmol),
2a (0.25 mmol), CuFe2O4 (0.1 equiv.), solvent (0.5ml) reacted at 100℃ for
24 h. b The yield of isolated product is reported. c 2,2’-Dipyridyl (0.2 equiv.)
was added. d1,10-Phenanthroline,4,7-diphenyl (0.2 equiv.). eNeocuproine (0.2
equiv.) was added. f TBAC(1 equiv.) was added. g TBAC(2 equiv.) was added.
We also studied the recyclability of the catalyst. For this, we
investigated the CuFe2O4-catalyzed reaction of 2, 6- lutidine
(
1a) with 4-nitrobenzaldehyde (2a) under the optimized
conditions. After completion of the reaction, the reaction
mixture was cooled to room temperature, and the catalyst was
magnetically separated from the reaction medium. The
separated catalyst was washed with ether for five times and
dried at 100
℃ for 2 h, then the recycled catalyst could be used
directly for further catalytic reactions. The catalyst could be
reused eight times without significant loss in catalytic activity
(Table 3). In addition, the SEM-analysis of CuFe2O4
nanoparticles used for this reaction showed that the morphology
of the catalyst were unchanged even after eight catalytic cycles,
which correlates well with retention of catalytic activity even
after reused eight times.
(a)
(b)
Fig. 3 SEM images of CuFe2O4 nanoparticles before (a) and after (b)
8th cycle.
the product was obtained (3m). Besides alkyl-substituted
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DOI: 1C0.O10M39M/CU4RNAI1C4A48T6IDON
E-mail: wangzulichem@163.com; wangzuli09@tsinghua.org.cn
†
Footnotes should appear here. These might include comments
a
Table 3 Recovery and Reuse of Recoverable CuFe2O4
relevant to but not central to the matter under discussion, limited
experimental and spectral data, and crystallographic data.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
Entry
Yield a (%)
Entry
Yield a (%)
1
2
3
4
77
75
76
74
5
6
7
8
76
75
74
75
a
Unless otherwise stated, all reactions were carried out with 1a (0.5 mmol),
2a (0.25 mmol), CuFe2O4(0.1 equiv.) and TBAC (1equiv.) in EG (0.5 ml) at
1
(a) M. C. Bagley, C. Glover, E. A. Merritt, Synlett 2007, 2459; (b) G.
D. Henry, Tetrahedron 2004, 60, 6043; (c) J. P. Michael, Nat. Prod.
Rep. 2005, 22, 627. (d) P. N. W. Baxter, J. M. Lehn, J. Fischerand
and M. T. Youinou, Angew. Chem. Int. Ed. Engl., 1994, 33, 2284; (e)
J. M. Lehn, Science 2002, 295, 2400; (f) D. Henry, Tetrahedron
2004, 60, 6043; (g) M. C. Bagley, C. Gloverand and E. A. Merritt,
Synlett 2007, 2459.
100℃for 24 h.
2
3
B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia and H. Huang, J.
Am. Chem. Soc., 2010, 132, 3650.
(a) J.-J. Jin, H.-Y. Niu, G.-R. Qu, H. M. Guo and J. S. Fossey, RSC
Adv., 2012, 2, 5968; (b) H. Komai, T. Yishino, S. Matsunaga and M.
Kanai, Org. Lett. 2011, 13, 1706; (c) B. Qian, S. Guo, C. Xia and H.
Huang, Adv. Synth. Catal. 2010, 352, 3195; (d) B. Qian, P. Xie, Y.
Xie and H. Huang, Org. Lett. 2011, 13, 2580; (e) V. B. Graves and A.
Shaikh, Tetrahedron Lett. 2013, 54, 695; (f) B. Qian, S. Guo, J. Shao,
Scheme 1. Proposed mechanism of addition of C (sp3)–H bond to
aldehyde
We presume the mechanism of this reaction maybe as shown
in Scheme 1. In the presence of CuFe2O4, 2-methyl azaarene
Q. Zhu, L. Yang, C. Xia and H. Huang, J. Am. Chem. Soc. 2010, 132
,
3650; (g) B. Qian, D. J. Shi, L. Yang and H. Huang, Adv. Synth.
Catal. 2012, 354, 2146; (h) B. Qian, L. Yang and H. Huang,
Tetrahedron Lett. 2013, 54, 711; (i) J. Y. Liu, H. Y. Niu, S. Wu, G. R.
Qu and H. M. Guo, Chem. Commun. 2012, 9723; (j) Y. Yan, K. Xu,
Y. Fang and Z. Wang, J. Org. Chem. 2011, 76, 6849; (k) M. Rueping
and N. Tolstoluzhsky, Org. Lett. 2011, 13, 1095; (l) A. Kumar, P. L.
tends to isomerization and the enamine intermediate
B is
formed. Then the nucleophilic addition of the enamine
intermediate to aromatic aldehyde which was activated by
CuFe2O4 would occur to afford the desired adduct.
Conclusions
Gupta and M. Kumar, RSC Adv. 2013, 3, 18771.
4
(a) F. F. Wang, C.-P. Luo, Y. Wang, G. Deng and Yang, L. Org.
Biomol. Chem. 2012, 10, 8605; (b) R. Niu, J. Xiao, T. Liang and X.
Li, Org. Lett. 2012, 14, 676; (c) S. V. N. Vuppalapati and Y. R. Lee,
Tetrahedron 2012, 68, 8286; (d) X. Gao, F. Zhang, G. Deng and L.
Yang, Org. Lett. 2014, 16, 3664; (e) S. A. R. Mulla, M. Y. Pathan
In conclusion, for the first time, we demonstrated the
application of magnetic copper ferrite nanoparticle for the
synthesis of the azaarenes derivatives via C(sp3)-H bond
activation. The magnetic nature of CuFe2O4 nanoparticles is
particularly advantageous for easy, quick, and quantitative
separation from the reaction medium. The catalyst can be
recycled and reused for eight times without significant decrease
in activity. The magnetically nanoparticles catalyzed other
reactions and mechanistic studies are ongoing in our lab.
and S. S. Chavan, RSC Adv. 2013, 3, 20281; (f) M. Raghua, M.
Rajasekhar, B. C. O. Reddy, C. S. Reddy and B. V. S. Reddy,
Tetrahedron Lett. 2013, 54, 3503. (g) X.-Y. Zhang, D.-Q. Dong, T.
Yue, S.-H. Hao and Z.-L. Wang, Tetrahedron Lett, 2014, 55, 5462.
(a) N. N. Rao and H. M. Meshram, Tetrahedron Lett. 2013, 54, 5087;
(b) N. N. Rao and H. M. Meshram, Tetrahedron Lett. 2013, 54, 1315;
(c) H. M. Meshram, N. N. Rao, L. C. Rao and N. S. Kumar,
Tetrahedron Lett. 2012, 53, 3963;
5
Acknowledgements
Financial support from the National Natural Science
Foundation of China (21402103), the research fund of Qingdao
Agricultural University’s high-level Person [631303], the
Scientific Research Foundation of Shandong Province
Outstanding Young Scientist Award [BS2013YY024] were
gratefully acknowledged.
6
7
(a) H. Y. Li, L. J. Xing, T. Xu, P. Wang, R. H. Liu and B. Wang,
Tetrahedron Lett. 2013, 54, 858. (b) Y. Yan, K. Xu, Y. Fang and Z.
Wang, J. Org. Chem. 2011, 76, 6849.
(a) M. B. Gawande, P. S. Brancoa and R. S. Varma, Chem. Soc. Rev.
,
We thank Xue-Yan Zhang for helping us to prepare the
compounds and supporting information.
2013, 42, 3371; (b) R. B. Nasir Baig and R. S. Varma, Chem.
Commun., 2013, 49, 752, and references therein; (c) M. B. Gawande,
A. K. Rathi, P. S. Branco, I. D. Nogueira, A. Velhinho, J. J.
Shrikhande, U. U. Indulkar, R. V. Jayaram, C. A. A. Ghumman, N.
Bundaleski and O. M. N. D. Teodoro, Chem. Eur. J., 2012, 18, 12628;
(d) M. B. Gawande, A. K. Rathi, I. D. Nogueira, R. S. Varmaand and
P. S. Branco, Green Chem., 2013, 15, 1895; (e) M. B. Gawande, V. D.
Notes and references
a
College of Chemistry and Pharmaceutical Sciences, Qingdao
Agricultural University, Qingdao, 266109, P.R.China
B. Bonif
á
cio, R. S. Varma, I. D. Nogueira, N. Bundaleski, C. A. A.
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA14486D
Ghumman, O. M. N. D. Teodoro and P. S. Branco, Green Chem.
,
2013, 15, 1226; (f) C. Ò. D laigh, S. A. Corr, Y. Gun'ko and S. J.
á
Connon, Angew. Chem., Int. Ed., 2007, 46, 4329.
8
9
G. Brahmachari, S. Laskar and P. Barik, RSC Adv., 2013, 3, 14245.
N. Panda, A. K. Jena, S. Mohapatra and S. R. Rout. Tetrahedron Lett.
2011, 52, 1924
10 R. Zhang, J. Liu, S. Wang, J. Niu, C. Xia and W. Sun. ChemCatChem
2011, , 146
3
11 (a) B. S. P. A. Kumar, K. H. V. Reddy, B. Madhav, K. Ramesh and Y.
V. D. Nageswar. Tetrahedron Lett. 2012, 53, 4595. (b) S. Ishikawa, R.
Hudson, A. Moores and C.-J. Li. Heterocycles, 2012, 86, 1023; (c) A.
S. Kumar, M. A. Reddy, M. Knorn, O. Reiser and B. Sreedhar. Eur. J.
Org. Chem. 2013, 4674; (d) R. Hudson, C.-J. Li and A. Moores.
Green Chem., 2012, 14, 622;
12 (a) V. Srinivas, V. S. Rawat, K. Konda and B. Sreedhar. Adv. Synth.
Catal. 2014, 356, 805; (b) D. Kundu, T. Chatterjee and B. C. Ranu.
Adv. Synth. Catal. 2013, 355, 2285; (c) K. Swapna, S. N. Murthy, M.
T. Jyothi and Y. V. D. Nageswar. Org. Biomol. Chem. 2011,
(d) R. Hudson, S. Ishikawa, C.-J. Li and A. Moores. Synlett 2013, 24
1637. (e) S. M. Baghbanian and M. Farhang. RSC Adv. 2014,
9, 5989.
,
,
4
11624; (e) A. S. Kumar, T. Ramani and B. Sreedhar, Synlett 2013, 24
938; (f) K. Pradhan, S. Paul and A. R. Das. Catal. Sci. Technol. 2014,
, 822-831 (g) A. Dandia, A. K. Jain and S. Sharma. RSC Adv.
2013, , 2924; (h) D. Yang, X. Zhu, W. Wei, N. Sun, L. Yuan, M.
Jiang, J. You and H. Wang. RSC Adv. 2014, , 17832; (i) B. Sreedhar,
,
4
；
3
4
A. S. Kumar and D. Yada. Tetrahedron Lett. 2011, 52, 3565. (j) R.
Parella, Naveen, A. Kumar and S. A. Babu. Tetrahedron Lett. 2013,
1738.
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