Noncovalent catalysis of glucose-containing imidazolium salt in solvent-free one-pot synthesis of Ortho-aminocarbonitriles

Article abstract of DOI:10.1016/j.tetlet.2015.06.094

Abstract A glucose-containing imidazolium salt β-1-imidazole-2,3,4,6-tetraacetyl-D-glucopyranosyl bromide was firstly used as efficient noncovalent organocatalyst to promote the solvent-free preparation of ortho-aminocarbonitriles via a four-component con

Full text of DOI:10.1016/j.tetlet.2015.06.094

Accepted Manuscript
Noncovalent Catalysis of Glucose-containing Imidazolium Salt in Solvent-free
One-pot Synthesis of Ortho-aminocarbonitriles
Li-zhuo Zhang, Yu Wan, Xiao-xiao Zhang, Hao Cui, Huan Zou, Qiu-ju Zhou,
Hui Wu
PII:
S0040-4039(15)01113-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.094
TETL 46486
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 May 2015
22 June 2015
29 June 2015
Please cite this article as: Zhang, L-z., Wan, Y., Zhang, X-x., Cui, H., Zou, H., Zhou, Q-j., Wu, H., Noncovalent
Catalysis of Glucose-containing Imidazolium Salt in Solvent-free One-pot Synthesis of Ortho-aminocarbonitriles,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.094
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A glucose-containing imidazolium salt β-
Noncovalent Catalysis of Glucose-containing
Imidazolium Salt in Solvent-free One-pot
Synthesis of Ortho-aminocarbonitriles
1-imidazole-2,3,4,6-tetraacetyl-D-gluco-
pyranosyl bromide was firstly used as
efficient noncovalent organocatalyst to
promote the solvent-free preparation of
Li-zhuo Zhanga, Yu Wanb,*, Xiao-xiao Zhanga, Hao
Cuia, Huan Zoua, Qiu-ju Zhoua, Hui Wua,b,*
ortho-aminocarbonitriles via
component condensation of aromatic
aldehyde, cyclohexanone and two
a
four-
a
School of Chemistry and Chemical Engineering, Jiangsu
Normal University, Xuzhou 221116, P. R. China
equivalents of malononitrile at room
temperature. Seven bonds were cleaved
while four new bonds were formed and a
six-membered ring was constructed in one-
pot.
b
State Key Laboratory Cultivation Construction Base of
Biotechnology on Med-edible Plant of Jiangsu Province,
Jiangsu Normal University, Xuzhou, 221116, P. R. China
Scheme 1. The synthesis of ortho-aminocarbonitriles.

Tetrahedron Letters
1
Tetrahedron Letters
journal homepage: www.elsevier.com
Noncovalent Catalysis of Glucose-containing Imidazolium Salt in Solvent-free
One-pot Synthesis of Ortho-aminocarbonitriles
Li-zhuo Zhanga, Yu Wanb,*, Xiao-xiao Zhanga, Hao Cuia, Huan Zoua, Qiu-ju Zhoua, Hui Wua,b,∗
a School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou 221116, P. R. China
b State Key Laboratory Cultivation Construction Base of Biotechnology on Med-edible Plant of Jiangsu Province, Jiangsu Normal University, Xuzhou, 221116,
P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
A glucose-containing imidazolium salt β-1-imidazole-2,3,4,6-tetraacetyl-D-glucopyranosyl
bromide was firstly used as efficient noncovalent organocatalyst to promote the solvent-free
preparation of ortho-aminocarbonitriles via a four-component condensation of aromatic
aldehyde, cyclohexanone and two equivalents of malononitrile at room temperature. Seven
bonds were cleaved while four new bonds were formed and a six-membered ring was
constructed in one-pot.
Received in revised form
Accepted
Available online
Keywords:
glucose-containing imidazolium salt
noncovalent organocatalyst
ortho-aminocarbonitriles
2015 Elsevier Ltd. All rights reserved.
1. Introduction
Ortho-aminocarbonitriles, an important intermediate in organic
synthesis,9 is widely used in the preparation of various heterocyclic
compounds.10-11 Therefore, their synthesis attracted the attention of
organic chemists.12-16 However, most methods have their limitations.
Specific conditions such as organic solvents (MeOH, HOAc),13-14
strong basic catalyst (1,2-diamine,14 Et3N,15 morpholine,16 etc),
complex substrate13-16 and tedious post-processing were necessary.
Compared with colvant catalysts, noncolvant catalysts has many
advantages such as the lower kinetic barriers, less directional and
less distance dependent,1-2 especially, unnecessary additive and
rigorous conditions and easier removing of catalyst.3-5 The main
reason is that the formation of interdiate from the substrate and the
noncovalent cataltyst is easier than the covalent one due to the low
orbital overlap between the substrate and the noncovalent cataltyst.4,6
To obtain these potential units efficiently and environment-
friendly, and to expand the application of glucose-containing
imidazolium salt in organic synthesis, we herein report an efficient,
solvent-free one-pot method to successfully synthesize a series of 2-
amino-4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-tricarbonitriles via
four-component reaction of one equivalents of aromatic aldehyde,
cyclohexanone and two equivalents of malononitrile catalyzed by a
new glucose functionalized noncolvant catalyst β-1-imidazol-2,3,4,6-
tetraacetyl-D-glucopyranosyl bromide ([Bmim-G]+[Br]-) at room
temperature (Scheme 2).
Glucose is an important nature product bearing five hydroxyl
groups. It is envisioned that the poly-hydroxyl glucose-
containing H-bond donor would be the efficient noncovalent
catalyst 7-8
of glucose-containing imidazolium salt catalysts
were investigated in this paper.
.
Based on this idea, the catalystic activity of a series
(Scheme 1)
1-6
Scheme 1 Catalysts been tested
Scheme 2 The synthesis of ortho-aminocarbonitriles
∗ Corresponding author. Tel.: +86051683536977; fax: +86051683536977; e-mail: wuhui72@aliyun.com

2
Tetrahedron Letters
and regular influence on the yield. Both electro-withdrawing and
electro-dondring in aromatic aldehydes could afford high yield.
2. Results and discussion
Malononitrile is one of the most versatile reagents to be used
Table 2 Synthesis of 10 under optimum conditions
in MCRs because of the high reactivity of both the methylene
and the cyano groups.17 Traditionally, it is a very useful molecule
to prepare heterocyclic compounds which have medical and
industrial utility.18
Entry
R
Product
10a
10b
10c
Time/ h
Yield/%
1
H
4
4
4
4
4
4
5
5
5
5
4
5
5
5
5
5
4
83
2
4-F
85
In the solvent-free synthesis of 10a, reaction conditions such
as the type and amount of catalysts (Scheme 2), reaction
temperature and reaction time were tested firstly to explore the
optimum (Table 1). Catalysts illustrated in Scheme 1 synthesized
in our lab (Experimental section) were tested firstly. It was found
that the reaction could not run smoothly without catalyst (Table
3
4-Cl
89
4
4-Br
10d
10e
87
5
4-I
91
6
4-CN
10f
92
7
4-OH
10g
10h
10i
84
1,
Entry
1).
N-methylimidazole
and
1-butyl-3-
methylimidazolium bromide ([Bmim]+Br-) could promote this
reaction but with lower yield (Table 1, Entries 2-3). Interestingly,
in the catalysts mentioned above, only 1 and 4 which containing
bromide ion could promoted the reaction and 1 gave the best
yield (Table 1, Entries 4-9). It seems that the counteranion of Br-
plays more determinative role in controlling the overall reaction.
However, inorganic bromide ion from sodium bromide could not
improve the reaction (Table 1, Entry 10). It means the catalytic
activity of 1 is the result of synergistic effect of all parts of the
catalyst which was supposed in the mechanism (Scheme 3).
8
2-Cl
89
9
2-Br
87
10
11
12
13
14
15
16
17
3-F
10j
82
3-NO2
2,4-Cl2
4-CH3
2-CH3O
2,3-(CH3O)2
3,4-(CH3O)2
3,4,5-(CH3O)3
10k
10l
88
84
10m
10n
10o
10p
10q
90
89
86
85
Table 1 Synthesis of 10a under different conditionsa
83
X
Time
/ h
Temp.
/ °C
Yield
/ % b
Entry
Cat.
/mol%
1
2
--
--
8
8
8
8
8
8
8
8
8
8
4
12
4
4
4
4
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
Nrc
The catalyst recyclability has been investigated for the
synthesis of 10f (Table 3). The catalyst was recovered by
extraction with CH2Cl2 (3 × 15 mL) from the aqueous phase.
After removed the water under vacuum, the organic phase was
dried in infrared drying oven and reused for subsequent runs. It
was observed that the catalyst can be used for five times with
minimal loss of activity.
N-methylimidazole
20
20
20
20
20
20
20
20
20
20
20
5
23
3
[Bmim]Br
70
4
1 (pH=4.63)19
85
5
2 (pH=3.67)19
NPd
NPd
70
6
3 (pH=4.10)19
4 (pH=10.09) 19
Table 3 Recyclability of catalyst for the synthesis of 10f
7
8
5 (pH=9.12)19
NPd
NPd
NPd
83
Number of times the
Isolated yield / %
catalyst was reused
9
6 (pH=1.44)19
92
86
84
79
70
55
1
2
3
4
5
6
10
11
12
13
14
15
16
17
Sodium bromide
1
1
1
1
1
1
1
86
22
10
30
10
10
83
75
25
50
84
The possible mechanism was proposed in Scheme 3. We
supposed that the catalyst had two functions: 1) to provide a
nucleophilic bromide ion to start the nucleophilic addition of
malononitrile with cyclohexylene via capturing a proton of
malononitrile; 2) to provide an electrophilic imidazolium cation
meanwhile to accept the transfered electron to complete the
reaction cycle. 2-Cyclohexylene malononitrile I was then formed
through the dehydration of the condensation product of
cyclohexanone and malononitrile. After that, I transformed to II
promoted by the catalyst. The concerted stereospecific Diels-
Alder reaction of II and III which was formed from the
condensation of malononitrile and aromatic aldrhyde promoted
by the catalyst similarly afforded intermediate IV. The
isomerization of IV gave the final product 10. The sugar part
may provide the solubility overall polarity pH etc.
aReactions were performed in 1:1:2 (benzaldehyde : cyclohexanone :
b
malononitrile) in different conditions. Isolated yields. No reaction. No
c
d
product 4a.
As shown in Table 1, the suitable reaction time was 4h and the
appreciable amount of catalyst 1 was 10 mol%. But the
increasing of catalytic loading could not enhance the yield of the
product (Table 1, Entry 14). Finally, the results in Table 1
indicated the optimal temperature was room temperature.
Therefore, 10 mol% of 1 as the catalyst under solvent-free
condition and at room temperature for 4 h were the optimal
reaction condition.
To explore the application of this method, the scope of the
substrates was evaluated with a variety of aromatic aldehydes
under the optimal condition (Table 2). The electro effict and
steric hindrance of group in aromatic aldehydes had no obvious

Tetrahedron Letters
3
3. Conclusion
In summary, we reported a high yield one-pot solvent-free
synthesis of trans-2-amino-4a,5,6,7-tetrahydronaphthalene-
1,3,3(4H)-tricarbo nitriles from readily available aromatic
aldehyde, cyclohexanone and malononitrile catalyzed by β-1-
imidazole-2,3,4,6-tetraacetyl-D-glucopyranosyl
bromide
([Bmim-G]+[Br]-). In the one-pot process, four new bonds formed
while seven bonds breakaged to built a new six-membered ring.
The role of catalyst in this reaction was supposed. It is expected
to expand this kind of new and effective sugar-containing
organocatalysts, providing valuable supplement for organic
catalytic reaction.
4. Experimental section
4.1. General remarks
IR spectra were recorded with a Varian FTIR-Tensor-27
spectrophotometer using KBr optics. 1H NMR spectra were
recorded at 400 MHz on a Bruker DPX 400 spectrometer using
TMS as an internal standard and DMSO-d6 as solvent. Mass was
determined by using a Bruker TOF-MS high resolution mass
spectrometer.
Scheme 3 A supposed mechanism
4.2. General procedure for the preparation of [Bmim-G]+[Br]-.
Theoretically, trans- is the more stable configuration of
product 10 (Figure 1). The X-ray singal crystal structure of 10h
(Figure 2, 3) confirmed it. However, the enantioselectivity of
chiral product was not detected. A possible reason is that the
chiral centre on sugar ring of 1 is wraped up by outside groups,
which prevented it from binding with reactants very well. It is
necessary to modify the structure of 1 if we want to use it and its
derivatives as chiral catalyst in asymmetric synthesis. There is
still a long way to go.
1-Bromo-2,3,4,6-tetraacetyl-glucopyranose (10 mmol) and
N-methyl-imidazole (20 mmol) were placed in 50 mL round
bottom flask and then acetonitrile (1 mL) was added. The
reactants were stirred for 2 h at room temperature to give the
white viscous solid, which was washed with acetone and filtered
to give a white solid 1 ([Bmim-G]+[Br]-).
4.3. General procedure for the preparation of 2-amino-4a,5,6,7-
tetrahydronaphthalene-1,3,3(4H)-tricarbonitriles 10.
A mixture of aromatic aldehyde 7 (1 mmol), cyclohexanone 8
(1 mmol), malononitrile 9 (2 mmol), and [Bmim-G]+[Br]- (10
mol%) were stirred at room temperature. After completion of the
reaction (monitored by TLC), distilled water (20 mL) was added,
the organic layer was extracted with dichloromethane. Removed
dichloromethane of organic phase under vacuum, recrystallized
the residue with 95% EtOH/DMF (1/4, v/v) to provide the pure
product 10.
Figure 1 The stable configuration of compound 10
Acknowledgments
We are grateful to the foundation of the "National Natural
Sciences Foundation of China" (No. 31300067), "Major Project
of Natural Science Research of University in Jiangsu" (No.
14KJA430003), "Natural Sciences Foundation of Jiangsu Normal
University" (No. 13XLA01) for financial support.
References and notes
Figure 2 The crystal structure of 10h
1. Pousse, G.; Cavelier, F. L.; Humphreys, L.; Rouden, J.;
Blanchet, J. Org. Lett. 2010, 12, 3582-3585.
2. Yang, Y.; Zheng, K.; Zhao, J.; Shi, J.; Lin, L.; Liu, X.;
Feng, X. J. Org. Chem. 2010, 75, 5382-5384.
3. Wurtz, C. A. J. Prakt. Chem. 1872, 5, 457-464.
4. Allu, S.; Molleti, N.; Panem, R.; Singh, V. K.
Tetrahedron Lett. 2011, 52, 4080-4083.
5. Guo, Q. S.; Bhanushali, M.; Zhao, C. G. Angew. Chem.
Int. Ed. 2010, 49, 9460-9464.
6. (a) Samanta, S.; Zhao, C. G. Tetrahedron Lett. 2006, 47,
3383-3386; (b) Mahrwald, R. Chem. Rev. 1999, 99,
1095-1120. (c) Wang, L. M.; Jiao, N. J.; Qiu, J. J.; Yu, J.
Figure 3 Crystal packing diagram of 10h

4
Tetrahedron Letters
Q.; Liu, F.; Guo, L.; Liu, Y. Tetrahedron. 2010, 66,
339-343. (d) Cassani, C.; Melchiorre, P. Org. Lett. 2012,
14, 5590-5593.
15. Al-Matar, H. M.; Khalil, K. D.; Meier, H.; Kolshorn, H.;
Elnagdi, M. H. Arkivoc. 2008, (16), 288-301.
16. Wang, X. S.; Wu, J. R.; Zhou, J.; Tu, S. J. J. Comb.
Chem. 2009, 11, 1011.
7. Tharun, J.; Hwang, Y.; Roshan, R.; Ahn, S.;
Kathalikkattil A. C.; Park D.W. Catal. Sci. Technol.
2012, 2, 1674–1680.
8. Sun, J.; Wang, J. Q.; Cheng, W. G.; Zhang, J. X.; Li, X.
H.; Zhang S. J.; She. Y. B. Green Chem. 2012, 14, 654-
660.
17. (a) Freeman, F. Chem. Rev. 1969, 69, 591. (b) Fatiadi,
A. J. Synthesis. 1978, (3), 165. (c) Fatiadi, A. J.
Synthesis. 1978, (4), 241.
18. (a) Ohashi, M.; Nakatani, K.; Maeda, H.; Mizuno, K.
Org. Lett. 2008, 10, 2741. (b) Alberola, A.; Calvo, L. A.;
Ortega, A. G.; Sanudo-Ruiz, M. C.; Yustos, P.; Granda,
S. G.; Garcia-Rodriguez, E. J. Org. Chem. 1999, 64,
9493. (c) Evdokimov, N. M.; Magedov, I. V.; Kireev, A.
S.; Kornienko, A. Org. Lett. 2006, 8, 899.
9. (a) Enders, D.; Huettl, M. R. M.; Grondal, C.; Raabe, G.
Nature. 2006, 441, 861-863. (b) Padwa, A. Chem. Soc.
Rev. 2009, 38, 3072-3081.
10. Takumi, M.; Noriaki, O.; Takatoshi, I.; Toshiyuki, M.
Tetrahedron Lett. 2000, 41, 1051-1053.
19. Zhang, X. X. Synthesis and applications of new glucose
functionalized catalysts [D]. Xuzhou: Jiangsu Normal
University. 2013.
11. Takumi, M.; Yoshio, I. Tetrahedron. 2002, 58, 3155-
3158.
12. Wan, Y.; Zhang, X. X.; Zhao, L. L.; Wang, C.; Chen, L.
F.; Liu, G. X.; Huang, S. Y.; Yue, S. N.; Zhang, W. L.;
Wu, H. J. Heterocycl. Chem. 2015, 52, 623-627.
13. Kurbatov, E. S.; Krasnikov, V. V.; Mezheritskii, V. V.
Russ. J. Org. Chem. 2006, 42, 460-462.
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file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
14. Wang, J. F.; Li, Q.; Qi, C.; Liu, Y.; Ge, Z.; Li, R. Org.
Biomol. Chem. 2010, 8, 4240.