Multicomponent Dipolar Cycloaddition Strategy: Combinatorial Synthesis of Novel Spiro-Tethered Pyrazolo[3,4-b]quinoline Hybrid Heterocycles

Article abstract of DOI:10.1021/acscombsci.6b00003

The stereoselective syntheses of a library of novel spiro-tethered pyrazolo[3,4-b]quinoline-pyrrolidine/pyrrolothiazole/indolizine-oxindole/acenaphthene hybrid heterocycles have been achieved through the 1,3-dipolar cycloaddition of azomethine ylides generated in situ from α-amino acids and 1,2-diketones to dipolarophiles derived from pyrazolo[3,4-b]quinoline derivatives.

Full text of DOI:10.1021/acscombsci.6b00003

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Article
Multicomponent Dipolar Cycloaddition Strategy: Combinatorial Synthesis
of Novel Spiro Tethered Pyrazolo[3,4-b]quinoline Hybrid Heterocycles
Remani Vasudevan Sumesh, Muthumani Muthu, Abdulrahman I Almansour, Raju Suresh Kumar,
Natarajan Arumugam, S Athimoolam, E. Arockia Jeya Yasmi Prabha, and Raju Ranjith Kumar
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00003 • Publication Date (Web): 30 Mar 2016
Downloaded from http://pubs.acs.org on March 31, 2016
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Multicomponent Dipolar Cycloaddition Strategy: Combinatorial Synthesis of Novel Spiro
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Tethered Pyrazolo[3,4ꢀb]quinoline Hybrid Heterocycles
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Remani Vasudevan Sumesh,† Muthumani Muthu,† Abdulrahman I. Almansour,§ Raju Suresh
Kumar,§ Natarajan Arumugam,§ S. Athimoolam,‡ E. Arockia Jeya Yasmi Prabha‡ and Raju
Ranjith Kumar*,†
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†Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai
625 021, Tamil Nadu, India
§Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh
11451, Saudi Arabia
‡Department of Physics, University College of Engineering, Anna University Constituent
College, Nagercoil 629 004, Tamil Nadu, India
ABSTRACT:
The stereoselective syntheses of a library of novel spiro tethered pyrazolo[3,4ꢀ
b]quinoline–pyrrolidine/pyrrolothiazole/indolizine–oxindole/acenaphthene hybrid heterocycles
have been achieved through the 1,3ꢀdipolar cycloaddition of azomethine ylides generated in situ
from αꢀamino acids and 1,2ꢀdiketones to dipolarophiles derived from pyrazolo[3,4ꢀb]quinoline
derivatives.
Keywords: 1,3ꢀDipolar cycloaddition, Azomethine ylide,
αꢀAmino acid, Isatin, Pyrazolo[3,4ꢀ
b]quinoline, Spiroꢀoxindole, Spiroꢀpyrrolidine
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INTRODUCTION
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Pyrazolo[3,4ꢀb]quinoline ring systems are privileged class of nitrogen containing
heterocycles endowed with profound biological activities. For instance pyrazolo[3,4ꢀb]quinoline
derivatives have been investigated for their antimicrobial,1 antimycobacterial2 and antiviral3
activities. Among the several methods available for the synthesis of pyrazolo[3,4ꢀb]quinolines,
the threeꢀcomponent reactions of 1,3ꢀdiketones, 5ꢀaminopyrazoles and aromatic aldehydes or
isatins have received much attention.4 Moreover, in spite of their significances pyrazolo[3,4ꢀ
b]quinoline derivatives have been less explored as precursors for further transformations. To the
best of our knowledge these compounds have been used in the VilsmeierꢀHaack formylation
reaction and for the synthesis of bispyrazolo[3,4ꢀb:4,3ꢀf]quinolines5 and pyrazolo[3,4ꢀ
b]quinoline ribofuranosides.6 Further, the analogous derivatives have been used to synthesize
quinoxalineꢀfused benzo[h]isoxazolo[5,4ꢀb]quinolines7 and benzo[a]pyrazolo[4′,3′:5,6]pyridoꢀ
[2,3ꢀc]phenazine.8 In this context, we envisaged to investigate the feasibility of pyrazolo[3,4ꢀb]ꢀ
quinoline derivatives as dipolarophiles in the 1,3ꢀdipolar cycloadditions of azomethine ylides
with a view to construct spiro tethered pyrazolo[3,4ꢀb]quinoline–pyrrolidine/pyrrolothiazole/
indolizine–oxindole/acenaphthene hybrids.
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The syntheses of spiro compounds have received much attention in view of their wide
range of applications.9 For example spiro compounds have been shown to inhibit cholesteryl
ester transfer protein, aspartyl proteases BACE1, acetylcholinesterase, bacterial typeꢀII
topoisomerase and kinesin spindle protein.10 These compounds have also been investigated for
their anticancer and antimicrobial activities apart from being identified as histamineꢀ3 receptor
and TRPM8 antagonists.11 Among the various protocols reported for the synthesis of spiro
compounds, the 1,3ꢀdipolar cycloadditions involving dipolarophiles with exoyclic olefins have
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occupied an eminent position.12 This strategy allows the stereoselective construction of complex
spiro heterocyclic hybrids in a single transformation with ease.12 In particular the cycloaddition
of azomethine ylides generated in situ from the decarboxylative condensation of αꢀamino acids
and isatins, acenaphthenequinone or ninhydrin with dipolarophiles with exocyclic olefins have
received substantial amount of attention as they lead to the synthesis of spiro
oxindole/acenaphthene/indanone and pyrrolidine/pyrrolizine/pyrrolothiazole/indolizine hybrid
heterocycles. It is noteworthy that spiro oxindoleꢀpyrrolidine or pyrrolizine hybrids form the core
of several bioactive natural products such as horsfiline13 and elacomine,14 whereas
rhynchophylline15 comprises spiro oxindoleꢀindolizine unit and spirotryprostatins comprise spiro
oxindoleꢀpyrrolopyrazine motif.16
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RESULTS AND DISCUSSION
Initially, the precursors 2ꢀ((dimethylamino)methylene)cyclohexaneꢀ1,3ꢀdione 3{1} and
2ꢀ((dimethylamino)methylene)ꢀ5,5ꢀdimethylcyclohexaneꢀ1,3ꢀdione 3{2} were synthesized from
the reaction of 1,3ꢀcyclohexanedione 1{1} or dimedone 1{2} with DMFꢀDMA 2, respectively
following literature procedure (Scheme 1).17
Seheme 1. Synthesis of precursors 3
Subsequently, the pyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 7 were synthesized via a oneꢀpot threeꢀ
component sequential procedure in water (Scheme 2). First of all, 3ꢀaminocrotononitrile 4 and
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the appropriate arylhydrazines 5{1–6} were refluxed in water for 1 h in the presence of Lꢀproline
(40 mol%) to obtain 3ꢀmethylꢀ1ꢀarylꢀ1Hꢀ5ꢀpyrazolamines 6{1–6}. Then without isolating 6, the
previously synthesized 3{1} or 3{2} was added and the reflux continued for another 1 h, which
resulted in quantitative yields of 7{1–6} or 7{2–5}, respectively. The formation of 7 presumably
occurred via a similar pathway as depicted by Perumal et al.8 It is to be noted that Zheng et al.
reported the synthesis of 7{2,1} in 15% yield from a twoꢀstep reaction.4b Later, Dzvinchuk et
al.4c synthesized 7{1,1} in 87% yield from the reaction of 1,3ꢀcyclohexanedione 1, 3ꢀmethylꢀ1ꢀ
phenylꢀ1Hꢀ5ꢀpyrazolamine 6 and 4ꢀ(dimethylamino)ꢀbenzaldehyde in boiling acetic acid for 2 h.
In this reaction N,Nꢀdimenthylaniline was obtained as a byꢀproduct. Moreover, the protocol
employed by us for the synthesis of 7 is more advantageous than the literature reports in terms of
several green chemical aspects. The structure of all the pyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 7 was
elucidated using NMR spectroscopy. In addition, in two cases, 7{1,1} and 7{2,5}, the structure
was also confirmed from their single crystal Xꢀray studies (Figure 1).18
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In the next step we chose 3ꢀmethylꢀ1ꢀphenylꢀ1,6,7,8ꢀtetrahydroꢀ5Hꢀpyrazolo[3,4ꢀb]ꢀ
quinolinꢀ5ꢀone 7{1,1} and 3,7,7ꢀtrimethylꢀ1ꢀphenylꢀ1,6,7,8ꢀtetrahydroꢀ5Hꢀpyrazolo[3,4ꢀb]ꢀ
quinolinꢀ5ꢀone 7{2,1} to investigate the baseꢀpromoted Knoevenagel condensation with
aromatic aldehydes 8{1–7} in order to induct an exocyclic alkene at position Cꢀ6 of the
pyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 7. In the case of 7{1,1}, the reaction occurred at ambient
temperature in the presence of KOH in ethanol affording novel (E)ꢀ3ꢀmethylꢀ6ꢀ(arylidene)ꢀ1ꢀ
phenylꢀ1,6,7,8ꢀtetrahydroꢀ5Hꢀpyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 9 in quantitative yields (Scheme
3). However, under these and several other conditions the reaction of 7{2,1} with aromatic
aldehydes 8{1–7} failed to occur, presumably due to the steric hindrance exerted by the methyl
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groups at Cꢀ7. Further, in both the cases of 7{1,1} and 7{2,1}, the reaction failed to occur with
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6
aliphatic aldehydes.
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9
O
5
NH2
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4
4a
8a
3a
9a
3
6
CN
4
N2
N1
N
N
7
9
N
3
3
{1} or {2}
R1
R1
L-Proline
8
NH2
NH
H2O
reflux, 1 h
R2
reflux, 1 h
quantitative
H2N
R2
5
7
R2
6
Entry Comp
R1
H
H
H
H
H
H
Me
Me
Me
Me
Me
R2
Yield (%) Mp (oC)
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7{1,1}
7{1,2}
7{1,3}
7{1,4}
7{1,5}
7{1,6}
7{2,1}
7{2,2}
7{2,3}
7{2,4}
7{2,5}
H
98 (87)4b 123–124
Cl
Br
F
CN
Me
H
Cl
Br
F
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98
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98
97
149–150
153–154
165–166
175–176
128–129
98 (15)4c 165–166
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140–141
164–165
208–209
10
11
CN
Scheme 2. Synthesis of pyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 7
7{1,1}
7{2,5}
Figure 1. ORTEP diagrams of 7{1,1} and 7{2,5}
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Entry Comp
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2
R1
9{1,1,1} H
9{1,1,2} H
R2
4ꢀMe
4ꢀMeO 97
4ꢀCl
4ꢀF
2ꢀCl
3ꢀBr
2,4ꢀCl2 96
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
Yield (%) mp (oC)
98
182–183
158–159
179–180
159–160
180–181
207–208
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199–200
198–199
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9{1,1,3} H
9{1,1,4} H
9{1,1,5} H
9{1,1,6} H
9{1,1,7} H
9{1,2,3} Cl
9{1,4,3} F
9{1,5,3} CN
9{1,6,3} Me
98
96
98
96
98
97
98
98
Scheme 3. Synthesis of 6ꢀarylideneꢀpyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 9
The structure of these 6ꢀarylideneꢀpyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 9 was elucidated with
the help of FTꢀIR, ESIꢀmass and NMR spectroscopic techniques. In general, the NMR spectra of
9 was found to be similar to that of 7{1,1} apart from the presence of arylidene ꢀCH and
aromatic ring protons and the absence of one ꢀCH2 signal in the aliphatic region. The mass
spectrum of 9{1,1,1} had a characteristic molecular ion peak at 380.18 [M+H]+. The IR spectrum
of 9{1,1,1} showed strong absorption at 1686 cmꢀ1 due to the carbonyl group. In the 1H NMR of
9{1,1,1}, the methyl protons at Cꢀ3 and phenyl ring appeared as singlets at 2.70 and 2.41 ppm,
respectively. The singlet at 3.26 ppm accounting for 4 protons was assigned to the 7ꢀ and 8ꢀCH2
protons. The arylidene CH and 4ꢀCH protons appeared as singlets at 7.95 and 8.85 ppm,
respectively while the remaining protons of the aromatic rings appeared as multiplets in the
range 7.25–8.31 ppm.
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Having synthesized the 6ꢀarylideneꢀpyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 9, we then
concentrated on the solvent optimization for the 1,3ꢀdipolar cycloaddition of azomethine ylide
generated in situ from the decarboxylative condensation of αꢀamino acids and nonꢀenolizable
1,2ꢀdiketones to the above diplarophiles. For this we selected the reaction of 9{1,1,1}, sarcosine
10{1} and isatin 11{1} that presumably affords 1',3ꢀdimethylꢀ1ꢀphenylꢀ4'ꢀ(pꢀtolyl)ꢀ7,8ꢀdihydroꢀ
dispiro[indolineꢀ3'',2'ꢀpyrrolidineꢀ3',6ꢀpyrazolo[3,4ꢀb]quinoline]ꢀ2'',5(1H)ꢀdione 12{1,1,1,1,1},
as a model reaction, under reflux in various solvents (Table 1). From the data in Table 1 we
observed that either methanol or ethanol was the optimal solvent for this cycloaddition reaction,
wherein quantitative yield of 12{1,1,1,1,1} was obtained (>90%). After completion of the
reaction as evident from the TLC, the reaction mixture was poured into ice cold water and the
resultant precipitate was filtered and dried to obtain the product 12{1,1,1,1,1}. It is noteworthy
that the crude reaction product was clean enough to be purified just by crystallization, thereby
obviating the need for column chromatography, which is the main source of waste.
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Table 1. Solvent optimization for the cycloaddition
Entry Solvent
Time (h) Yield (%)a
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2
3
4
5
MeOH
EtOH
4
3
6
6
8
>90
>90
40b
55b
40b
iꢀPrOH
1,4ꢀDioxane
MeCN
aIsolated yield; bYield after column chromatography
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The structure of the isolated product was elucidated with the help of FTꢀIR, ESIꢀmass
and NMR spectroscopic studies. The mass spectrum of 12{1,1,1,1,1} had a characteristic
molecular ion peak at 554.22 [M+H]+. The IR spectrum of 12{1,1,1,1,1} showed strong
absorptions at 1686 and 1670 cmꢀ1 due to the Cꢀ5 and C2'' carbonyl groups, respectively. The 1H
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13
and C NMR chemical shifts of 12{1,1,1,1,1} are shown in Figure 2. The discussion on the
complete assignment of H and 13C NMR chemical shifts of 12{1,1,1,1,1} are given in the
1
supporting information.
7.13, d, J = 7.8Hz, 128.9
7.38-7.43, m, 130.2
2.37, s, 21.0
4.99, t, J = 9.1Hz, 47.7
H3C
H
136.5
3.52, t, J = 8.5Hz,
4.01, t, J = 9.7Hz, 57.7
8.74, s, 131.8
H
H
135.5
2.11, s, 34.6
2.65, s,12.5
145.0
O
197.7
H
CH3
N
H3C
H
116.6
N76.2
6.96, d, J = 7.8Hz, 127.2
6.87, t, J = 7.7Hz, 129.3
61.0
162.6
150.3
O
H
H
123.3 N
7.38-7.43, m, 130.2
N
141.1
177.4
H
138.6
NH
125.9
8.05, d, J = 8.7Hz, 121.1
7.20, t, J = 7.4Hz, 126.1
H
H
6.62, t, J = 7.6Hz, 122.3
6.45, d, J = 7.5Hz, 109.5
H
8.32, s
2.82-3.03, m, 29.6
1.43, td, J = 5.1, 14.1Hz
2.50, br dt, J = 15.0Hz, 29.4
Figure 2. 1H and 13C chemical shifts of 12{1,1,1,1,1}
The formation of 12{1,1,1,1,1} can be rationalized through the pathway depicted in
Scheme 4. Initially, the condensation of sarcosine 10{1} and isatin 11{1} forms the azomethine
ylide dipole 13 via spontaneous decarboxylation. Subsequently, the 1,3ꢀdipole 13 undergoes
cycloaddition with the exocyclic dipolarohile 9{1,1,1}, which may be visualized in two different
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pathways viz. path A and B. However, the exclusive formation of dispiroꢀoxindoleꢀpyrrolidineꢀ
pyrazoloquinoline 12{1,1,1,1,1} discloses that this cycloaddition occurs through Path A, wherein
the carbonyls of the dipole and the dipolarophile are trans to each other. Path B, which leads to
the formation of 14{1,1,1,1,1}, is presumably less favored in view of the electrostatic repulsion
between the cis carbonyls.
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Scheme 4. Formation of 12{1,1,1,1,1}
Furthermore, it is evident that the cycloaddition proceeded regioselectively involving the
addition of electron rich carbon of the dipole 13 to the βꢀcarbon of the α,βꢀunsaturated
1
dipolarophile 9{1,1,1} (Scheme 4). This is also evident form H NMR spectrum of
12{1,1,1,1,1}, wherein three triplets appeared in the range between 3.52–4.99 ppm due to 4′ꢀCH
and 5′ꢀCH2 protons. If the other regioisomer 12′{1,1,1,1,1} was formed (Figure 3), a singlet and
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two doublets would have been expected for these protons. Moreover, this regiochemistry is in
accord with the polarization of the C=C bond with a more electronꢀdeficient βꢀcarbon in
9{1,1,1}, which could preferentially react with the electronꢀrich site of the approaching 1,3ꢀ
dipole 13. In addition, the cycloaddition occurred diastereoselectively to afford a single
diastereoisomer exclusively in quantitative yields, albeit more than one contiguous stereocentres
are present in the cycloadduct 12{1,1,1,1,1}.
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Figure 3. The regioisomer of 12{1,1,1,1,1} not formed in the reaction
With the optimized reaction condition established and the structure arrived at for
12{1,1,1,1,1}, we then explored the viability of this protocol for library generation. It is pertinent
to
note
that
fortyꢀtwo
novel
spiro
tethered
pyrazolo[3,4ꢀb]quinoline–
pyrrolidine/pyrrolothiazole/indolizine–oxindole/acenaphthene hybrids 12 and 15–19 were
synthesized employing eleven 6ꢀarylideneꢀpyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 9, three αꢀamino
acids 10 and two 1,2ꢀdiketones 11 (Figure 4, Scheme 5 and Table 2). From the data in Table 2 it
is apparent that the cycloaddition works well with all the substrates affording quantitative yields
of the products. The structure of all the dispiro hybrid heterocycles 12 and 15–19 was elucidated
unambiguously as done for 12{1,1,1,1,1}. In the case of 12{1,1,7,1,1} the structure was further
confirmed from single crystal Xꢀray analysis (Figure 5).18 The ORTEP diagram of 12{1,1,7,1,1}
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discloses that Cꢀ5 and C2′′ carbonyls are trans, providing conclusive evidence to the proposed
reaction pathway (Scheme 4). In addition, the C–N bond lengths of pyrazolo[3,4ꢀb]quinoline
ring varied from 1.312 (7) to 1.381 (8) Å. These distances were observed to be shorter than the
relevant single bond length (1.443 Å) and longer than the double bond length (1.269 Å). The
variation in bond length may be due to the electron delocalization around the ring. The
pyrrolidine and the oxindole rings were oriented nearly perpendicular to each other at an angle of
87.01 (1)°. Further the pyrrolidine ring was making an angle of 75.22 (1)° with the
dichlorophenyl plane.
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CONCLUSIONS
We have developed an environmentally benign threeꢀcomponent sequential protocol for
the synthesis of pyrazolo[3,4ꢀb]quinolinꢀ5ꢀones 7 in water. The baseꢀpromoted Knoevenagel
reaction of 7 with aromatic aldehydes afforded novel 6ꢀarylideneꢀpyrazolo[3,4ꢀb]quinolinꢀ5ꢀones
9. Subsequently, the 1,3ꢀdipolar cycloaddition of azomethine ylides generated in situ from the
decarboxylative condensation of sarcosine, thiazolidineꢀ4ꢀcarboxylic acid or piperidineꢀ2ꢀ
carboxylic acid and isatin or acenaphthenequinone to these exocyclic alkenenic dipolarophiles 9
led to the stereoselective formation of novel structurally intriguing spiro tethered pyrazolo[3,4ꢀ
b]quinoline–pyrrolidine/pyrrolothiazole/indolizine–oxindole/acenaphthene hybrids 12 and 15–
19, in quantitative yields. As the products were obtained in pure form just by filtration, additional
purification steps such as column chromatography, which is the main source of waste generation,
was avoided. The quantitative yield of the product in combination with the high atom economy
observed (>90%) makes this protocol efficient and green. Ultimately, we have demonstrated that
pyrazolo[3,4ꢀb]quinoline derivatives are potential precursors for further transformations into
complex heterocycles via 1,3ꢀdipolar cycloaddition.
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Figure 4. Diversity of reagents
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Scheme 5. Synthesis of dispiro hybrid heterocycles
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Table 2. Yield and melting point of 12, 15–19
5
6
7
8
Entry Comp
R1
H
H
H
H
H
H
H
R2
Yield (%) mp (oC)
1
12{1,1,1,1,1}
4ꢀMe
4ꢀMeO
4ꢀCl
4ꢀF
2ꢀCl
3ꢀBr
2,4ꢀCl2
4ꢀCl
98
96
98
97
95
96
98
94
92
93
96
97
98
96
94
96
95
97
95
93
96
97
95
96
93
94
96
93
98
98
97
94
96
93
92
98
97
98
95
94
96
93
249–250
230–231
238–239
258–259
209–210
258–259
242–243
250–251
250–251
228–229
242–243
232–233
210–211
233–234
215–216
185–186
238–239
243–244
236–237
254–256
258–259
208–209
105–106
210–211
190–191
130–131
192–193
158–159
168–169
137–138
138–139
148–149
160–161
162–163
203–204
230–231
205–206
220–221
226–227
215–216
210–211
225–226
2
3
4
5
6
7
12{1,1,2,1,1}
12{1,1,3,1,1}
12{1,1,4,1,1}
12{1,1,5,1,1}
12{1,1,6,1,1}
12{1,1,7,1,1}
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
12{1,2,3,1,1} Cl
9
12{1,5,3,1,1} CN 4ꢀCl
12{1,6,3,1,1} Me 4ꢀCl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
15{1,1,1,2,1}
15{1,1,2,2,1}
15{1,1,3,2,1}
15{1,1,4,2,1}
15{1,1,5,2,1}
15{1,1,6,2,1}
15{1,1,7,2,1}
16{1,1,3,3,1}
16{1,1,5,3,1}
16{1,1,6,3,1}
16{1,1,7,3,1}
17{1,1,1,1,2}
17{1,1,2,1,2}
17{1,1,3,1,2}
17{1,1,4,1,2}
17{1,1,5,1,2}
17{1,1,6,1,2}
17{1,1,7,1,2}
18{1,1,1,2,2}
18{1,1,2,2,2}
18{1,1,3,2,2}
18{1,1,4,2,2}
18{1,1,5,2,2}
18{1,1,6,2,2}
18{1,1,7,2,2}
19{1,1,1,3,2}
19{1,1,2,3,2}
19{1,1,3,3,2}
19{1,1,4,3,2}
19{1,1,5,3,2}
19{1,1,6,3,2}
19{1,1,7,3,2}
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4ꢀMe
4ꢀMeO
4ꢀCl
4ꢀF
2ꢀCl
3ꢀBr
2,4ꢀCl2
4ꢀCl
2ꢀCl
3ꢀBr
2,4ꢀCl2
4ꢀMe
4ꢀMeO
4ꢀCl
4ꢀF
2ꢀCl
3ꢀBr
2,4ꢀCl2
4ꢀMe
4ꢀMeO
4ꢀCl
4ꢀF
2ꢀCl
3ꢀBr
2,4ꢀCl2
4ꢀMe
4ꢀMeO
4ꢀCl
4ꢀF
2ꢀCl
3ꢀBr
2,4ꢀCl2
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Figure 5. ORTEP diagram of 12{1,1,7,1,1}
EXPERIMENTAL SECTION
General
The melting points were measured in open capillary tubes and are uncorrected.
Electronspray ionization mass spectrometry (ESIꢀMS) analyses were recorded in LCQ Fleet,
Thermo Fisher Instrument in negative or positive ion mode. The collision voltage and ionization
voltage were +35 V and +5 kV, respectively, using nitrogen as atomization and desolvation gas.
The desolvation temperature was set at 300o C. The scan range of mass spectrum was 300ꢀ2000
m/z. The relative amount of each component was determined from the LCꢀMS chromatogram,
using the area normalization method. Infrared spectra were recorded on a Thermo Scientific FTꢀ
IR instrument by ATR method. The 1H, 13C and the 2D NMR spectra were recorded on a Bruker
(Avance) 300 MHz NMR instrument (1H: 300 MHz, 13C: 75 MHz) using TMS as internal
standard and CDCl3 as solvent. Standard Bruker software was used throughout the spectral
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analysis. Chemical shifts are given in parts per million (δꢀscale) and the coupling constants are
given in Hertz. Elemental analyses were performed on Perkin Elmer 2400 Series II CHNS
analyzer. The single crystal Xꢀray data set for compounds 7{1,1}, 7{2,5} and 12{1,1,7,1,1} was
collected on Bruker AXS KAPPA APEXꢀ2 diffractometer equipped with graphite
monochromator. The structure was solved by direct methods and refined by fullꢀmatrix leastꢀ
squares calculations using SHELXL–2014.19 Silica gelꢀG plates (Merck) were used for TLC
analysis with a mixture of nꢀhexane and ethyl acetate as eluent. All the chemicals were
purchased from commercial sources and used without any further purification.
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11
12
13
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General procedure for the synthesis of 7
A mixture of 3ꢀaminocrotononitrile 4 (1 mmol), arylhydrazine 5 (1 mmol) and Lꢀproline
(0.4 mmol) was taken in water (10 mL) and heated to reflux. After 1 h of continuous reflux,
methyleneꢀcyclohexaneꢀ1,3ꢀdione 3 (1 mmol) was added and the reflux continued for another 1
h. Upon addition of 3 the mixture turns homogeneous. The completion of the reaction was
evident from the formation of precipitate, which was filtered, washed with water and dried under
vacuum to obtain pure 7.
1
Compound 7{1,2}. Obtained as Pale yellow solid; Yield 97%; m.p. 149–150°C; H NMR (300
MHz, CDCl3) δH: 2.25 (qui, J = 5.0 Hz, 2H), 2.65 (s, 3H), 2.77 (t, J = 6.5 Hz, 2H), 3.28 (t, J =
6.1 Hz, 2H), 7.47 (dd, J = 6.9, 2.1 Hz, 2H), 8.30 (d, J = 9.0 Hz, 2H), 8.74 (s, 1H) ppm. 13C NMR
(75 MHz, CDCl3) δC: 12.4, 21.8, 33.6, 36.7, 116.7, 121.4, 123.0, 128.9, 130.3, 130.8, 137.7,
145.2, 150.9, 163.8, 197.2 ppm.
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General procedure for the synthesis of 9
5
6
7
8
9
To an equimolar mixture of 7 (1 mmol) and aromatic aldehyde (8, 1 mmol) in ethanol (5
mL) was added 10 mL of ethanolic solution of KOH (5%). The mixture was stirred at ambient
temperature for about 1 h. The completion of the reaction was noted when the product 9
precipitated out of the reaction mixture, which was filtered, washed with water and dried.
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Compound 9{1,1,1}. Obtained as pale yellow solid; Yield 98%; m.p. 182–183°C; 1H NMR (300
MHz, CDCl3) δH: 2.41 (s, 3H), 2.70 (s, 3H), 3.26 (s, 4H), 7.26 (d, J = 8.1 Hz, 3H), 7.32 (dt, J =
8.4, 1.2 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.53 (tt, J = 8.4, 1.2 Hz, 2H), 7.95 (s, 1H), 8.30 (dt, J
13
= 7.5, 1.2 Hz, 2H), 8.85 (s, 1H) ppm. C NMR (75 MHz, CDCl3) δC: 12.5, 21.4, 26.2, 32.7,
116.9, 120.8, 123.7, 125.8, 129.0, 129.2, 130.1, 131.2, 132.6, 133.6, 137.6, 139.0, 139.1, 145.0,
150.9, 162.5, 187.0 ppm. Anal. Calcd. for C25H21N3O: C, 79.13; H, 5.58; N, 11.07. Found: C,
79.22; H, 5.48; N, 11.19. ESIꢀMS m/z calcd [M + H]+ 379.17, found 380.18. FT IR (cm–1): 1686,
3022.
General procedure for the synthesis of dispiro hybrid heterocycles 12 and 15–19.
A mixture of 9 (1 mmol), sarcosine/thiazolidineꢀ4ꢀcarboxylic acid/piperidineꢀ2ꢀ
carboxylic acid (10, 1.1 mmol) and isatin/acenaphthenequinone (11, 1.1 mmol) was taken in 10
mL of ethanol in a 50 mL round bottom flask and heated to reflux on a boiling water bath for 1–4
h. After completion of the reaction as evident from TLC, the reaction mixture was poured into
ice cold water (50 mL). The precipitated solid was filtered, washed with water and dried to get
the dispiro hybrid heterocycles 12 or 15–19. The crude product was purified through
crystallization from ethanol.
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Compound 12{1,1,1,1,1}: Obtained as pale yellow solid; Yield 98%; m.p. 249–250°C; 1H NMR
(300 MHz, CDCl3) δH: 1.43 (td, J = 14.0, 5.1 Hz, 1H), 2.12 (s, 3H), 2.32 (s, 3H), 2.50 (d, J =
14.9 Hz, 1H), 2.65 (s, 3H), 2.81–3.00 (m, 2H), 3.52 (t, J = 8.5 Hz, 1H), 4.01 (t, J = 9.7 Hz, 1H),
4.92–5.05 (m, 1H), 6.45 (d, J = 7.7 Hz, 1H), 6.62 (t, J = 7.6 Hz, 1H), 6.87 (t, J = 7.7 Hz, 1H),
6.96 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.5 Hz,
3
4
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13
4H), 8.05 (d, J = 8.4 Hz, 2H), 8.32 (s, 1H), 8.74 (s, 1H) ppm. C NMR (75 MHz, CDCl3) δC:
12.5, 21.0, 29.4, 29.6, 34.6, 47.7, 57.7, 61.0, 76.2, 109.5, 116.6, 121.1, 122.3, 123.3, 126.0,
126.1, 127.2, 129.0, 129.2, 130.3, 131.8, 135.6, 136.5, 138.7, 141.1, 145.0, 150.3, 162.7, 177.4,
197.8 ppm. Anal. Calcd. for C35H31N5O2: C, 75.93; H, 5.64; N, 12.65. Found: C, 75.83; H, 5.52;
N, 12.54. ESIꢀMS m/z calcd [M + H]+ 553.67, found 554.22. FT IR (cm–1): 3735, 2864, 1688,
1591.
1
15{1,1,1,2,1}: Obtained as yellow solid; Yield 96%; m.p. 242–243°C; H NMR (300 MHz,
CDCl3) δH: 1.51 (td, J = 13.5, 5Hz, 1H), 2.32 (s, 3H), 2.60 (s, 3H), 2.77 (d, J = 12.3 Hz, 1H),
2.87–2.03 (m,3H), 3.15 (td, J = 15.8, 5 Hz, 1H), 3.45 (d, J = 6.1 Hz, 1H), 3.57 (d, J = 6.1 Hz,
1H), 4.64 (d, J = 10.0 Hz, 1H), 4.83 (ddd, J = 10.0, 7.7, 5.5 Hz, 1H), 6.46 (d, J = 7.7 Hz, 1H),
6.76 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.18–7.25(m, 2H),
7.34 (d, J = 8.0 Hz, 2H), 7.40–7.47 (m, 2H), 7.55 (s, 1H), 8.12 (d, J = 7.6 Hz, 2H), 8.45 (s, 1H)
13
ppm. C NMR (75 MHz, CDCl3) δC: 12.3, 20.9, 27.8, 33.0, 46.8, 51.0, 66.7, 66.9, 69.1, 71.7,
109.8, 116.3, 120.6, 120.8, 121.8, 123.1, 125.0, 125.7, 127.4, 128.8, 128.9, 129.0, 129.3, 129.8,
134.1, 136.7, 141.1, 144.8, 162.2, 177.4, 196.1 ppm. Anal. Calcd. for C36H31N5O2S: C, 72.34; H,
5.23; N, 11.72. Found: C, 72.20; H, 5.10; N, 11.61. ESIꢀMS m/z calcd [M + H]+ 597.74, found
554.22.
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16{1,1,3,3,1}: Pale yellow solid; Yield 97%; m.p 243–244oC; H NMR (300 MHz, CDCl3) δ
1.18–1.57 (m, 6H), 1.77 (s, 2H), 2.20 (s, 2H), 2.63 (s, 3H), 2.91–3.04 (m, 2H), 3.85 (t, J = 9.1
Hz, 1H), 4.49 (d, J = 9.8 Hz, 1H), 6.46 (d, J = 7.7 Hz, 1H), 6.62 (t, J = 7.5 Hz, 1H), 6.85 (t, J =
7.4 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 7.17–7.25 (m, 2H), 7.29–7.56 (m, 5H), 7.98 (s, 1H), 8.07
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1
(d, J = 7.9 Hz, 2H), 8.63 (s, 1H) ppm. C NMR (300 MHz, CDCl3) δC: 12.1, 23.6, 25.1, 28.8,
29.5, 30.6, 44.9, 53.9, 59.3, 62.4, 75.3, 109.3, 116.1, 120.3, 121.4, 123.1, 125.4, 125.9, 126.6,
127.9, 128.5, 131.0, 132.0, 137.0, 138.6, 141.7, 144.5, 150.1, 162.2, 177.2, 196.8 ppm. Anal.
Calcd. for C37H32ClN5O2: C, 72.36; H, 5.25; N, 11.40. Found: C, 72.27; H, 5.13; N, 11.30.
1
17{1,1,1,1,2}: Obtained as yellow solid; Yield 97%; m.p. 208–209°C; H NMR (300 MHz,
CDCl3) δH: 1.40 (td, J = 14.3, 4 Hz, 1H), 2.04 (s, 3H), 2.24 (td, J = 15.0, 5.0 Hz, 1H), 2.33 (s,
3H), 2.40 (s, 1H), 2.54 (s, 1H), 2.63 (s, 3H), 3.59 (t, J = 8.5 Hz, 1H), 4.10 (t, J = 9.8 Hz, 1H),
5.09 (t, J = 9.0 Hz, 1H), 7.18 (t, J = 8.7 Hz, 3H), 7.28–7.43 (m, 4H), 7.50 (dd, J = 16.7, 7.6 Hz,
13
3H), 7.60–7.68 (m, 1H), 7.81–8.05 (m, 4H), 8.67 (s, 1H) ppm. C NMR (75 MHz, CDCl3) δC:
12.5, 21.0, 29.2, 30.4, 34.5, 48.1, 58.3, 62.5, 79.2, 116.4, 120.6, 123.4, 124.1, 125.1, 125.7,
127.9, 128.2, 128.8, 129.0, 130.1, 130.2, 131.3, 131.7, 131.9, 135.7, 136.4, 136.5, 138.7, 142.0,
144.8, 150.3, 162.4, 198.1, 206.7 ppm. Anal. Calcd. for C39H32N4O2: C, 79.57; H, 5.48; N, 9.52.
Found: C, 79.61; H, 5.36; N, 9.42. ESIꢀMS m/z calcd [M + H]+ 588.71, found 589.24. FT IR
(cm–1): 2843, 2162, 1703, 1678, 1596.
18{1,1,1,2,2}: Obtained as pale orange solid; Yield 98%; m.p. 168–169°C; 1H NMR (300 MHz,
CDCl3) δH: 1.51–1.62 (m, 1H), 2.33 (s, 3H), 2.53 (s, 3H), 2.66–2.72 (m, 2H), 2.8 (dt, J = 15.0,
3.0 Hz, 1H), 2.96 (dd, J = 9.8, 6.5 Hz, 1H), 3.10 (dd, J = 9.9, 5.8 Hz, 1H), 3.44 (d, J = 6.8 Hz,
1H), 3.60 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 10.1 Hz, 1H), 4.89–4.98 (m, 1H), 7.17 (d, J = 7.9 Hz,
2H), 7.23 (d, J = 7.4 Hz, 1H), 7.38 (s, 1H), 7.43 (d, J = 8.2 Hz, 3H), 7.45–7.51 (m, 2H), 7.58 (s,
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1H), 7.60–7.69 (m, 2H), 7.79 (d, J = 4.9 Hz, 1H), 7.81 (d, J = 6.3 Hz, 1H), 7.99 (d, J = 7.8 Hz,
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2H), 8.12 (s, 1H) ppm. C NMR (75 MHz, CDCl3) δC: 12.3, 21.0, 26.8, 29.8, 33.9, 48.3, 52.1,
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67.8, 69.8, 76.4, 116.1, 120.6, 121.3, 123.5, 124.8, 125.3, 125.8, 127.7, 128.1, 128.9, 129.2,
129.9, 130.0, 130.4, 131.1, 131.7, 134.1, 134.9, 136.9, 138.7, 141.2, 144.5, 150.5, 161.6, 196.6,
205.0 ppm. Anal. Calcd. for C40H32N4O2S: C, 75.93; H, 5.10; N, 8.85. Found: C, 75.83; H, 5.03;
N, 8.79. ESIꢀMS m/z calcd. [M + H]+ 632.78, found 633.18. FT IR (cm–1): 3040, 2035, 1701,
1590.
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19{1,1,1,3,2}: Obtained as brown solid; Yield 98%; m.p. 230–231°C1H NMR (300 MHz,
CDCl3) δH: 1.20–1.52 (m, 6H), 1.74 (d, J = 12.7 Hz, 1H), 1.86 (d, J = 13.1 Hz, 1H), 2.02–2.19
(m, 2H), 2.33 (s, 3H), 2.38–2.51 (m, 2H), 2.60 (s, 3H), 3.99 (t, J = 9.1 Hz, 1H), 4.58 (d, J = 10.0
Hz, 1H), 7.09–7.23 (m, 3H), 7.28–7.43 (m, 5H), 7.48 (d, J = 7.7 Hz, 2H), 7.57–7.64 (m, 1H),
7.86 (t, J = 7.5 Hz, 2H), 7.94 (d, J = 7.9 Hz, 2H), 8.54 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3)
δC: 12.4, 21.0, 24.0, 25.7, 28.8, 30.6, 31.2, 45.4, 55.0, 61.5, 63.0, 79.1, 116.3, 120.4, 120.6,
123.7, 123.9, 124.8, 125.7, 127.9, 128.2, 128.9, 129.0, 129.9, 131.0, 131.7, 131.8, 135.4, 136.3,
137.2, 138.8, 141.9, 144.7, 150.3, 162.3, 197.7, 206.6 ppm. Anal. Calcd. for C42H36N4O2: C,
80.23; H, 5.77; N, 8.91. Found: C, 80.11; H, 5.68; N, 8.82. ESIꢀMS m/z calcd [M + H]+ 628.78,
found 629.22.
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AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail: raju.ranjithkumar@gmail.com. Phone: +919655591445
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FUNDING
R.R.K., R.V.S and M.M. thank the University Grants Commission, New Delhi, for funds
through Major Research Project F. No. 42ꢀ242/2013 (SR) and Department of Science and
Technology, New Delhi, for funds under IRHPA program for the high resolution NMR facility
and PURSE programme. The authors acknowledge the Deanship of Scientific Research at King
Saud University for the Research Grant No. RGPꢀVPPꢀ026.
ASSOCIATED CONTENT
Supporting Information
Experimental details and spectroscopic characterization of all the compounds. 1H and 13C
spectra for all products. This material is available free of charge via the Internet at
http://pubs.acs.org.
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[18] Crystallographic data (excluding structure factors) for compounds 7{1,1}, 7{2,5} and
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supplementary publication numbers CCDC 1445689, 1445690 and 1445688,
respectively. Copy of these data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 762911 or eꢀmail:
deposit@ccdc.cam.ac.uk].
[19] Sheldrick, G. M. Crystal Structure refinement with SHELXL. Acta Cryst. 2015, C71, 3–
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