Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.3762/bjoc.12.288

A new series of spiropyrrolidine compounds containing indole/indazole moieties as side chains have been accomplished via a one-pot multicomponent synthesis. The method uses the 1,3-dipolar cycloaddition reaction between N-alkylvinylindole/indazole and azomethine ylides, prepared in situ from cyclic/acyclic amino acids. The 1,3-dipolar cycloaddition proceeds efficiently under thermal conditions to afford the regio- and stereospecific cyclic adducts.

Full text of DOI:10.3762/bjoc.12.288

Multicomponent synthesis of spiropyrrolidine analogues
derived from vinylindole/indazole by a
1,3-dipolar cycloaddition reaction
Manjunatha Narayanarao1, Lokesh Koodlur2, Vijayakumar G. Revanasiddappa3,
Subramanya Gopal2 and Susmita Kamila*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2893–2897.
1East Point College of Engineering and Technology,
VisvesvarayaTechnological University, Aavalahalli, Bangalore-560
049, India, 2Department of Studies and Research in Chemistry,
Vijayanagara Sri Krishnadevaraya University, Bellary-583105, India
and 3Department of Chemistry, University College of Science, Tumkur
University, BH Road, Tumakuru-572103 India
doi:10.3762/bjoc.12.288
Received: 12 October 2016
Accepted: 13 December 2016
Published: 29 December 2016
Associate Editor: T. J. J. Müller
Email:
Susmita Kamila* - sushkam@yahoo.co.in
© 2016 Narayanarao et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
L-proline; ninhydrin; sarcosine; spiropyrrolidine; 5-vinylindazole;
5-vinylindole
Abstract
A new series of spiropyrrolidine compounds containing indole/indazole moieties as side chains have been accomplished via a one-
pot multicomponent synthesis. The method uses the 1,3-dipolar cycloaddition reaction between N-alkylvinylindole/indazole and
azomethine ylides, prepared in situ from cyclic/acyclic amino acids. The 1,3-dipolar cycloaddition proceeds efficiently under ther-
mal conditions to afford the regio- and stereospecific cyclic adducts.
Introduction
The [3 + 2] cycloaddition between azomethine ylides and ized spiranes. The earlier works reveal the use of different reac-
olefins/acetylene as dipolarophiles is an important reaction to tion conditions to prepare functionalized spiroindane, spiropy-
access a number of novel heterocyclic spiro scaffolds of biolog- rolidine, spiropyrrolizidine and spirooxindole derivatives.
ical importance [1,2]. The regio- and stereoselective construc- Among them, the 1,3-dipolar cycloaddition based route is
tion of spiro compounds by utilizing the 1,3-dipolar cycloaddi- preferred due to multiple advantages [7-10].
tion reaction of azomethine ylides has been reported [3-6].
However, unlike the previous reports, the present method is Indole and indazolyl subunits are central to numerous alkaloids
concise and facilitates the one-pot synthesis of multifunctional- and are constituents of many classes of compounds that display
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Beilstein J. Org. Chem. 2016, 12, 2893–2897.
a wide range of bioactivities such as antimycobacterial, anti- The applicability of the cycloaddition reaction was explored
inflammatory, antihypertensive, anticancer, antidepressant, first for indole derivatives 7a–d and then extended to the syn-
antidiabetic, antimalarial, antitubercular, anticonvulsant and thesis of indazole analogues 7e–k under similar reaction condi-
cardiovascular activities [11-16].
tions. Based on the same logic of vinylindole, regioisomers of
N-alkylvinylindazole were considered. So, this 1,3-dipolar
As part of our interest in the exploration of 1,3-dipolar cycload- cycloaddition reaction could be well applied to both derivatives
dition reactions [17] for the synthesis of polycyclic molecules, which afforded a range of differentially substituted final prod-
N-alkylated vinylindoles are applied as dipolarophiles in view ucts in yields ranging from 60 to 93% (Table 1, entries 1–11).
of the challenges that still pose in the construction of functional- Unfortunately the product 7 with X–R = NCOCH3, Y = N could
ized spiro compounds. We report herein the facile synthesis of not be synthesized due to low amounts of the required regio-
novel spiropyrrolidine compounds through a one-pot three- isomer of the N-acylated indazole. In both cases of vinylic
component reaction involving N-substituted vinylindole/inda- indole and indazoles, we have shown that the cyclic adducts
zole, ninhydrin and sarcosine/L-proline. The present multicom- were favored with dipoles and highly reactive dipolarophiles
ponent reaction (MCR) leads to five-membered spiropyrroli- (vinylindole and -indazole). The increase in the reactivity could
dine derivatives 7 and 8 substituted with indole or indazole be attributed to the presence of electron-donating groups on the
moieties, respectively. The synthesis being described is the dipolarophile.
first on the usage of N-alkylated vinylindole or indazole deriva-
tives.
Encouraged by the success with the acyclic amino acid sarco-
sine (5), the reaction was extended to the cyclic amino acid
L-proline (6) which was reacted with 3 under the optimized
Results and Discussion
Our studies started with the synthesis of 5-bromo-N-alkylindole reaction conditions. The corresponding stereo- and regiospe-
and indazole derivatives 2 that can be obtained from 5-bromo- cific isomers of spiropyrrolidines 8 were obtained in good
indoles/indazoles (1). The latter compounds were synthesized yields (Table 1, entries 12–22). The stereochemical assign-
according to procedures described in the literature [18-20]. The ments for compounds 8 were supported by 2D NMR data which
regioisomers of N-alkylated 5-bromoindazoles were isolated by showed NOE interactions between H1 and H2 on the asym-
column chromatography using a hexane–ethyl acetate mixture. metric carbon atoms correlated to the syn-configuration
The resulting 5-bromo-N-alkyl derivatives 2 were then treated (Figure 1). Upon irradiation of H1 the NOE enhancement was
with potassium vinyltrifluoroborate and PdCl2(dppf)CH2Cl2 in observed for H3 and H4 and the same was observed by irradia-
DMF at 90 °C to afford the vinyl-substituted products 3 in tion of the ring-junction proton H2. The regioselectivity of
excellent yields (Scheme 1) [21,22].
cyclic adducts could be explained by secondary orbital interac-
tion as described in earlier reports [4,23]. All compounds were
In the next step, the one-pot three component reaction was comprehensively characterized by spectroscopic methods (IR,
carried out by reacting N-alkylvinyl products 3 with azo- 1H, 13C NMR and LC–MS). The general procedure for the syn-
methine ylide, generated in situ through decarboxylative con- thesis of 7a–k and 8a–k including the spectral characterization
densation of ninhydrin (4) and sarcosine (5). The 1,3-dipolar of the compounds are provided in Supporting Information
cycloaddition of the ylide with the olefin 3 yielded spiropyrro- File 1.
lidines 7 with regiospecificity (Table 1, entries 1–4). The for-
mation of the azomethine ylide intermediate and a plausible The 1H NMR spectrum of compound 7a (X–R = CH, Y–R =
reaction pathway for the formation of the spiranes is depicted N–CH3) proved the formation of the desired product which
following the retrosynthetic strategy in Scheme 2.
showed a characteristic doublet of doublets for the H1 proton at
Scheme 1: Synthesis of N-alkyl vinylindoles and N-alkyl vinylindazoles (3).
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Beilstein J. Org. Chem. 2016, 12, 2893–2897.
Table 1: Synthesis of spiropyrrolidine compounds 7a–k and 8a–k.a
Entry
X–R
Y–R
Product
Yieldb (%)
1
C–H
N–CH3
7a
7b
7c
7d
7e
7f
90
93
87
91
85
82
78
79
70
65
60
86
80
83
85
86
68
70
82
68
68
68
2
C–H
N–CH2CH(CH3)2
N–COCH3
N–CH2C6H5
N–CH3
3
C–H
4
C–H
5
N
6
N
N–CH2CH(CH3)2
N–COCH3
N–CH2C6H5
N
7
N
7g
7h
7i
8
N
9
N–CH3
10
11
12
13
14
15
16
17
18
19
20
21
22
N–CH2CH(CH3)2
N
7j
N–CH2C6H5
N
7k
8a
8b
8c
8d
8e
8f
C–H
N–CH3
C–H
N–CH2CH(CH3)2
N–COCH3
N–CH2C6H5
N–CH3
C–H
C–H
N
N
N–CH2CH(CH3)2
N–COCH3
N–CH2C6H5
N
N
8g
8h
8i
N
N–CH3
N–CH2CH(CH3)2
N–CH2C6H5
N
8j
N
8k
aReaction conditions: 3 (1 mmol, 1 equiv), 4 (1.2 mmol, 1.2 equiv), 5/6 (1.2 mmol, 1.2 equiv), methanol (5 mL), 60 °C, 30 min. bIsolated yield.
Scheme 2: Retrosynthetic strategy used for the synthesis of 7 and 8.
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Supporting Information
Supporting Information File 1
Experimental and characterization data of all new
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-288-S1.pdf]
Acknowledgements
Manjunatha K. Narayanarao is grateful to VTU for providing
facility to carry out the work. The authors acknowledge Dr.
Suchetan P A, UCS, TU for elucidating structures from the
single crystal XRD data. We thank Dr. Narendra N, UCS, TU
for language correction and proof reading.
Figure 1: NOE interactions in compound 8c supporting the stereo-
chemical assignments for 8a–k. H1 and H2 on the asymmetric carbon
atoms were found to be syn oriented.
δ 3.99 ppm. The CH2 group adjacent to the pyrrolidine nitrogen
appeared as a triplet of doublets (δ 3.42 ppm) and multiplet
(δ 3.59 ppm), and the N–CH3 of the pyrrolidine ring as a singlet
at δ 2.36 ppm. Further, the structures of 7a and 7f were con-
firmed by single crystal X-ray diffraction studies and the corre-
sponding ORTEP representations are given in Figure 2.
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