Regioselective N-allylation and N-cinnamylation of indoles using CuI-exchanged hierarchical nanoporous material

Article abstract of DOI:10.1016/j.catcom.2015.07.022

Regioselective N-allylation and N-cinnamylation of indoles are achieved using a novel catalyst of Cu^I-exchanged hierarchically architectured nanoporous material (MMZ_Cu^I_Y). The catalyst was characterized by electron microscopy and X-ray methods. Other advantages like functional tolerance, easy separation and reusability of the catalyst are also highlighted.

Full text of DOI:10.1016/j.catcom.2015.07.022

Regioselective N-allylation and N-cinnamylation of indoles using CuI-
exchanged hierarchical nanoporous material
S. Senthilkumar, M. Kumarraja
PII:
DOI:
Reference:
S1566-7367(15)30031-5
doi: 10.1016/j.catcom.2015.07.022
CATCOM 4394
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
25 May 2015
22 July 2015
29 July 2015
Please cite this article as: S. Senthilkumar, M. Kumarraja, Regioselective N-allylation
and N-cinnamylation of indoles using CuI- exchanged hierarchical nanoporous material,
Catalysis Communications (2015), doi: 10.1016/j.catcom.2015.07.022
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ACCEPTED MANUSCRIPT
Regioselective N-allylation and N-cinnamylation of indoles using CuI-
exchanged hierarchical nanoporous material
S. Senthilkumar, M. Kumarraja*
Centre for Research and Post-graduate Studies in Chemistry,
Ayya Nadar Janaki Ammal College (Autonomous), Sivakasi 626 124, Tamilnadu, India.
Abstract: Regioselective N-allylation and N-cinnamylation of indoles are achieved using a
I
novel catalyst of CuI-exchanged hierarchically architectured nanoporous material (MMZCu Y).
The catalyst was characterized by electron microscopy and X-ray methods. Other advantages
like functional tolerance, easy separation and reusability of the catalyst are also highlighted.
Keywords: hierarchical nanoporous zeolite; regioselectivity; N-allylation; N-cinnamylation.
1. INTRODUCTION
Indole containing compounds are best known for their medicinal properties in the
pharmaceutical industry [1]. Notably indolic aminoacid tryptophan is the precursor of the
neurotransmitter serotonin. In last few years, it was reported that indole and its derivatives have
antimicrobial activity against gram(+) and gram(-) bacteria and shows other biological activities
those including anti-cancer drugs, anti-hypertensive drugs, antipsychotic agents, antiasthmatic
drug, inhibitor of RNA polymerase-11 and for treating sexual dysfunction [2]. Lewis and
Bronsted acid promoted Friedel-Crafts reaction [3] and metal complex/salts catalyzed alkylation
of indole processes proved to be remarkably effective under homogeneous and heterogeneous
*Corresponding author: Tel: +91-9443570835; Fax: +91-4562 254970
E-mail address: dr.kumarraja@gmail.com
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conditions [4-6]. Although the alkylation of indoles with allyl halides, allyl acetates or allyl
carbonates provides a valuable method for the direct allylation of indoles. However, most of the
described procedures generally suffer from problems associated with the regiochemistry of
alkylation at the N1, C2 or C3 positions of the indole nucleus. Thus the functionalization of
indole ring system is an area of great interest and challenging task, because of the discrimination
between the N- alkylated product and the C3-alkylated product with unsubstituted indoles.
Regioselective C-2 allylation of indoles has also been achieved by the use of catalysts such as
Potassium organotrifluoroborate salts [7], Pd [8] and Rh [9] catalysts. Similarly selective
synthesis of C-3 allylated indoles includes the use of catalysts such as H2SO4 [10], Ru [11],
amberlyst-15 [12], Et3B [13], Pd [14-15]. Recently, N-allylation of amines and O-allylation of
phenols have been reported with allyl acetate using Pd Catalyst [16-17]. However, a clean
regioselective N-allylation of indoles has rarely been explored due to its weak acidity of the
N-H group [18-20]. But many of the reports generally suffer from the disadvantages such as use
of expensive catalysts, low yield, longer reaction time and functional intolerance. As its
consequence, the challenging task of selective N-allylation welcomes newer methods and
catalysts particularly those involve the efficient, inexpensive and environmentally benign
catalyst for the allylation of indoles with higher yield.
In recent years, hierarchical nanoporous materials [21-24] have been emerging with
significant scientific interest because of its potential application in its multidisciplinary field of
study, hydrocarboncracking [25], adsorption/separation [26], drug delivery [27],
microelectronics, biomolecular separation and dye sensitized solar cells [28]. However, the
catalytic applications of nanoporous materials in fine chemical synthesis are very few in number.
In catalysis, the active sites of hierarchical nanoporous materials are often located in the
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micropores and mesopores, whereas the macropores favor mass transfer and reduce transport
limitations and the micropores enhances the selectivity [29] due to their high surface area and
unique pore size [30] and also they having high thermal stability [31].
We have been involved in showing the hierarchically ordered nanoporous material as a
versatile catalyst for the organic transformations due to its nature of ease of preparation, handling
and separation, environmental benign nature, high selectivity. Herein, we report the selective
NH-allylic alkylation of indoles and its derivatives at room temperature in a shorter time.
2. Experimental Section
I
Synthesis and Characterization of Hierarchical Nanoporous Zeolite (MMZCu Y):
MMZY zeolite was synthesized from the commercially available NH4-Y zeolite according
to the procedure reported by Ryoo et. al [21]. A mixture of CuCl and MMZY was ground by
pestle and mortar, it was heated in flowing nitrogen atmosphere at a heating rate of 10°C/min.
The ion-exchange of Cu(I) in solid CuCl with H+ in MMZY zeolite occured at over 300°C and
the maximum ion-exchange rate was reached at 340°C with the consequent release of HCl
I
gas [32-34]. After the preparation was over, the MMZCu Y was kept under vaccum. The as
prepared catalyst was characterized by SEM, TEM, EDAX and powder XRD analysis. Scanning
Electron Microscopy (SEM) and EDAX images were taken by using FEI Quanta FEG 200-High
Resolution Scanning Electron Microscope, and X–ray diffraction (XRD) patterns were taken
with a Bruker D8 advance, Cu Kα radiation (40 kV, 30 mA). Transmission Electron Microscopy
I
(TEM) image of MMZCu Y was obtained using a JEOL JEM-2100 LaB6 instrument equipped
with the high-resolution (HRP), style objective-lens pole piece at an acceleration
voltage of 200 kV.
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General procedure for the synthesis of N-allyl and N-cinnamyl indole derivatives (3a-l)
I
using MMZCu Y zeolite:
I
A 100mg of hierarchical MMZCu Y zeolite was taken in a reaction tube contains DMF
(3mL) as a solvent and K2CO3 (1mmol) as base. A mixture of indole 1a (1mmol) and
allylbromide 2a (1.2mmol) were added simultaneously to the reaction tube. The reaction mixture
was placed onto a magnetic stirrer for 10 hours at room temperature and the proceedings of the
reaction was constantly monitored by TLC carried out on silica plates with iodine and UV light
for visualization. After dilution with dichloromethane (15 mL), the mixture was washed with
brine solution. The organic layer was separated, dried and concentrated in vacuo, and the residue
was subjected to column chromatography over silica gel (silica gel 60-120 mesh, hexane 99%
and ethyl acetate 1%) to give 3a as a colourless oil.
3. Results and discussion
Our earlier studies [35] particularly the use of CuIY in Click Chemistry and
MMZY in chemoselective synthesis of benzimidazoles [36], have prompted us to prepare
I
MMZCu Y and employ as a novel catalyst in the present study. The morphology of the as prepared
I
hierarchical nanoporous MMZCu Y zeolite was characterized by XRD, SEM and TEM methods.
It clearly shows the uniform formation of Cu(I) species in the MMZY framework of the catalyst
I
with the particle size range of 0.5–1μm . The XRD pattern of the MMZCu Y are found to be in
good agreement with the parent zeolite framework structure. It clearly reveals that there is no
change in crystallinity.
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The optimization and screening study of reaction was performed by having indole and
allylbromide using different materials and the results are summarized in table1.
(a)
(b)
(c)
(d)
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Fig. 1. (a) SEM, (b) TEM, (c) p-XRD and (d) EDAX spectrum of MMZCu Y Zeolite.
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Table 1
Optimization of reaction conditions for the selective N-allylation of indolesa
catalyst
+
+
Br
K2CO3, rt
N
N
N
H
H
2
1
4
3
Yieldb (%)
Entry
Catalyst
Time
(3)
(4)
1.
2.
3.
4.
5
CuCl2
CuCl
24
24
10
10
10
--
--
C
16
18
69
91
15
NaY
21
28
--
Cu(I)Y
I
MMZCu Y
aReaction conditions: 1(1mmol), 2(1.2 mmol), catalyst(100 mg), DMF(3 mL), base(1mmol), rt, 10h.
bIsolated Yields.
cTrace amount of diallylated product also noted (confirmed by GC-MS).
In the absence of zeolite, there was no significance in selectivity and also in the yield of
allylated indole as in the case of CuCl2 in this reaction (entry 1). In the presence of CuCl alone as
a catalyst, only 31% of allylated products were obtained but with no selectivity. In sharp contrast
to entries 2 and 3, the use of CuIY affords 68% of N-allylated product however along with the
notable amount of C-3 allylated product. The use of Cu(I)-exchanged hierarchically architectured
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MMZY afforded regioselectively an excellent amount of N-allylated product (Table 1, entry 5).
I
To check the functional tolerance of MMZCu Y towards the selective N-allylation, we have also
employed the substituted indoles for allylation and the obtained results are summarized in
table 2. We have extended our present investigation into the cinnamylation of indoles also, which
was actually failure to achieve by the Pd/PPh3 system [15] and the interesting results are
presented in table 2.
Table 2
I
Synthesis of N-allyl and N-Cinnamyl indoles using MMZCu Y Zeolitea
R'
I
R'
MMZCu Y, K2CO3
-
Br
R
+
rt, 10h
N
N
H
R
R = H, C6H5; R’ = H, 2-Me, 3-Me, 5-CN, 5-Br, 3-CH2COOH.
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S. No
Substrate
Allylating agent
Product
Yieldb (%)
1.
N
91
N
H
Br
(3a)
N
Br
Br
2.
3.
89
93
N
H
(3b)
N
N
H
(3c)
COOH
COOH
Br
4.
90
N
N
H
(3d)
Br
Br
5.
6.
97
94
N
N
H
Br
Br
(3e)
NC
NC
N
N
H
(3f)
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Br
N
7.
8.
88
82
N
H
(3g)
Br
N
N
H
(3h)
Br
N
9.
91
N
H
(3i)
COOH
COOH
Br
N
10.
11.
12.
87
93
90
N
H
(3j)
Br
Br
N
Br
N
H
(3k)
NC
Br
NC
N
N
H
(3l)
a
I
Reaction conditions: 1(1mmol), 2(1.2 mmol), MMZCu Y(100mg), DMF(3mL), K2CO3(1mmol),
rt, 10h.
b Isolated Yields.
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The present catalytic system shows an excellent tolerance toward the sterically crowded
cinnamylation also and gives the N-cinnamylated indole in high yields. In the presence of both
indoles bearing electron releasing and electron withdrawing groups, the reaction with allyl
bromide/cinnamyl bromide proceeded effectively and
yielding regioselectively
N-allylated/N-cinnamylated products (82-97%) in higher yields. We have also examined the
recycling of the catalyst which afforded the same result even after two time usage.
It is believed that this reported reaction supports and proceeds through the proposed
mechanism [18] which involves the addition of a base favours proton abstraction from the
heteroatom followed by the catalyst coordination through its Cu(I) sites. The high polar solvent
favours the N-allylation, because of dissociation of the N-Cu bond by the stronger solvation of
the counter ion, is subsequently attacked by the allylbromide and gives regioselectively
N- allylated product in higher yield.
4. Conclusions
In summary, we have developed a simple procedure for the clean regioselective
N-allylation and N-cinnamylation of indoles by a one pot strategy promoted by an inexpensive,
I
reusable, non-toxic and environmentally benign novel catalytic system MMZCu Y zeolite. These
reactions encompass a broad range of indole substituents as well as simple and bulkier allylating
agents. The other advantages of this procedure are no need of external stabilizing ligand for CuI
metal ion, use of a simple base, shorter reaction time and excellent regioselectivity with higher
I
yield. Further works are now in progress to explore the catalytic system of MMZCu Y for other
organic synthesis.
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Acknowledgements
The authors thank the Principal and the Management of ANJA College, Sivakasi as well
as the University Grants Commission, New Delhi (F. No. 41-334/2012 (SR)) for financial
support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at ……………………………
These data include NMR files of all reported compounds described in this article.
References
[1]
[2]
R. J. Sundberg, Indoles, Academic Press: San Diego, 1996.
C. Praveen, A. Ayyanar, P. T. Perumal, Bioorg. Med. Chem. Lett. 21 (2011) 4072.
[3]
[4]
S. You, Q. Cai and M. Zeng, Chem. Soc. Rev. 38 (2009) 2190.
G. Helmchen, A. Dahnz, P. Dibbon, M. Schelwies, R. Weihofen, Chem. Commun. (2007)
675.
[5]
[6]
[7]
[8]
[9]
X. Zhang, W. Liu, Q. Wu, S. You, Org. Lett. 15 (2013) 3746.
Y. Lian, H. M. L. Davies, Org. Lett. 14 (2012) 1934.
F. Nowrouzi, R. A. Batey, Angew. Chem. Int. Ed. 52 (2013) 892.
Y. Wei, I. Deb, N. Yoshikai, J. Am. Chem. Soc. 134 (2012) 9098.
M. Kim, J. Park, S. Sharma, S. Ham, S. H. Han, J. H. Kwak, Y. H. Jung, I. N. Kim, Org.
Biomol. Chem. 11 (2013) 7427.
11

ACCEPTED MANUSCRIPT
[10] M. Wang, S. Sun, D. Liang, B. Liu, Y. Dong, Q. Liu, Eur. J. Org. Chem. (2011) 2466.
[11] A. B. Zaitsev, S. Gruber, P. S. Pregosin, Chem. Commun. (2007) 4692.
[12] Z. Liu, D. Wang, Y. Wu, Y. Chen, Synth. Commun. 42 (2012) 1813.
[13] M. Kimura, M. Futamata, R. Mukai, Y. Tamaru, J. Am. Chem. Soc. 127 (2005) 4592.
[14] P. Y. Choy, C. P. Lau, F. Y. Kwong, J. Org. Chem. 76 (2010) 80.
[15] W. E. Billups, R. S. Erkes, L. E. Reed, Synth. Commun. 10 (1980) 147.
[16] R. B. N. Baig, B. R. Vaddula, M. A. Gonzalez, R.S. Varma, RSC Adv. 4 (2014) 9103.
[17] R. B. N. Baig, R. S. Varma, Ind. Eng. Chem. Res. 53 (2014) 18625.
[18] M. Bandini, A. Melloni, A. Umani-Ronchi, Org. Lett. 6 (2004) 3199.
[19] L. M. Stanley, J. F. Hartwig, Angew. Chem. Int. Ed. 48 (2009) 7841.
[20] W. Liu, X. Zhang, L. Dai, S. You, Angew. Chem. Int. Ed. 51 (2012) 5183.
[21] K. Na, M. Choi, R. Ryoo, Micropor. Mesopor. Mater. 166 (2013) 3.
[22] C. N. R. Rao, A. Müller, A. K. Cheetham, The Chemistry of Nanomaterials: Synthesis,
Properties and Applications, Wiley-VCH, Weinheim, 2004.
[23] K. Na, C. Jo, J. Kim, K. Cho, J. Jung, Y. Seo, R. J. Messinger, B. F. Chmelka, R. Ryoo,
Science, 333 (2011) 328.
[24] Y. Sue, J. Wu, S. Chung, C. Kang, K. Tung, K. W. Wu, F. Shieh, Appl. Mater. Interfaces.
6 (2014) 5192.
12

ACCEPTED MANUSCRIPT
[25] J. Francis, E. Guillon, N. Bats, C. Pichon, A. Corma, L. J. Simon, Appl. Catal. A: Gen. 409
(2011) 140.
[26] B. Coasne, A. Galarneau, C. Gerardin, F. Fajula, F. Villemot, Langmuir, 29 (2013) 7864.
[27] A. Tiwari, Nanomaterials in Drug Delivery, Imaging, and Tissue Engineering, Wiley-VCH,
Weinheim, 2013.
[28] H. Chen, D. Kuang, C. Su, J. Mater. Chem. 22 (2012) 15475.
[29] J. Zhang, C. M. Li, Chem. Soc. Rev. 41 (2012) 7016.
[30] S. Sattayasamitsathit, A. M. O’Mahony, X. Xiao, S. M. Brozik, C. M. Washburn, D. R.
Wheeler, W. Gao, S. Minteer, J. Cha, D. B. Burckel, R. Polsky, J. Wang, J. Mater. Chem.
22 (2012) 11950.
[31] Y. Tong, T. Zhao, F. Li, Y. Wang, Chem. Mater. 18 (2006) 4218.
[32] Z. Li, K. Xie, R. C. T. Slade. Appl. Catal. A: Gen. 209 (2001) 107.
[33] S. Chassaing, M. Kumarraja, A. S. S. Sido, P. Pale, J. Sommer, Org. Lett. 9 (2007) 883.
[34] S. Chassaing, A. S. Sido, A. Alix, M. Kumarraja, P. Pale, J. Sommer, Chem. Eur. J. 14
(2008) 6713.
[35] K. Namitharan, M. Kumarraja, K. Pitchumani, Chem. Eur. J. 15 (2009) 2755.
[36] S. Senthilkumar, M. Kumarraja, Tetrahedron Lett. 55 (2014) 1971.
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Regioselective N-allylation and N-cinnamylation of indoles using CuI-
exchanged hierarchical nanoporous material
S. Senthilkumar, M. Kumarraja*
*Centre for Research and Post-graduate Studies in Chemistry,
Ayya Nadar Janaki Ammal College (Autonomous), Sivakasi 626 124, Tamilnadu, India.
E-mail: dr.kumarraja@gmail.com
GRAPHICAL ABSTRACT
R'
I
R'
MMZCu Y, K2CO3
-
Br
R
+
rt, 10h
N
N
H
R
Where R = H, C6H5; R’ = H, 2-Me, 3-Me, 5-CN, 5-Br, 3-CH2COOH
Abstract: Regioselective N-allylation and N-cinnamylation of indoles are achieved using a
I
novel catalyst of CuI-exchanged hierarchically architectured nanoporous material (MMZCu Y).
The catalyst was characterized by electron microscopy and X-ray methods. Other advantages
like functional tolerance, easy separation and reusability of the catalyst are also highlighted.
Keywords: hierarchical nanoporous zeolite; regioselectivity; N-allylation; N-cinnamylation.
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Highlights of the Work:
I
 Prepared a new and novel catalyst MMZCu Y and achieved a
regioselective N-allylation and N-cinnamylation.
 The catalyst would find extensive applications in organic synthesis filed.
 No external stabilizing ligand was required for Cu(I).
 Catalyst was reused for two times and which afforded the same yield.
 Simple experimental conditions were followed.
 Catalyst was characterized by the instrumental methods like SEM, TEM,
XRD, EDAX.
 Products are well characterized by NMR and MS.
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