Efficient Protocol for the Synthesis of Novel Spiro[acenaphthylene-1,2′-pyrrolidin]-2-one Compounds

Article abstract of DOI:10.1080/00397911.2015.1066390

An efficient catalyst-free synthesis of 3′-benzoyl-4′,5′-diphenyl-2H-spiro[acenaphthylene-1,2′-pyrrolidin]-2-one derivatives via one-pot 1,3-dipolar cycloaddition of acenaphthenequinone, arylmethyl amines, and chalcones with high regioselectivity is described. The structure of the cycloadducts were characterized by infrared, high-resolution mass spectrometry (electrospray ionization), ¹H NMR, and ¹³C NMR spectra, and the structure of 4a was confirmed using x-ray single-crystal structure analysis.

Full text of DOI:10.1080/00397911.2015.1066390

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An Efficient Protocol for the Synthesis of Novel
Spiro[Acenaphthylene-1,2′-pyrrolidin]-2-one
Compounds
Yan Lina, Zhijie Fua, Tianhua Shena, Fengfeng Chea & Qingbao Songa
a College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, P. R. China
Accepted author version posted online: 17 Jul 2015.
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To cite this article: Yan Lin, Zhijie Fu, Tianhua Shen, Fengfeng Che & Qingbao Song (2015): An Efficient Protocol for the
Synthesis of Novel Spiro[Acenaphthylene-1,2′-pyrrolidin]-2-one Compounds, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1066390
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An Efficient Protocol for the Synthesis of Novel
Spiro[Acenaphthylene-1,2'-pyrrolidin]-2-one Compounds
Yan Lin1, Zhijie Fu1, Tianhua Shen1, Fengfeng Che1, Qingbao Song1
1College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, P. R.
China
Corresponding author: Qingbao Song, Email: qbsong@zjut.edu.cn
Abstract
An efficient catalyst-free synthesis of
3'-benzoyl-4',5'-diphenyl-2H-spiro[acenaphthylene-1,2'-pyrrolidin]-2-one derivatives via
one-pot 1,3-dipolar cycloaddition of acenaphthenequinone, arylmethyl amines, and
chalcones with high regioselectivity is described. The structure of the cycloadducts were
characterized by IR, HRMS (ESI), 1H-NMR, 13C-NMR spectra and the structure of 4a
was confirmed using X-ray single crystal structure analysis.
Graphical Abstract:
1

KEYWORDS: [3+2]-cycloaddition; spiropyrrolidine; acenaphthenequinone; arylmethyl
amine; chalcone
INTRODUCTION
Spirocyclic compounds containing five membered rings represent a significant class of
natural products characterized by a wide range of biological activities.[1] The key step to
achieve such skeleton is the construction of the five-membered ring, especially nitrogen
containing five-membered heterocycles. Among numerous strategies, the intermolecular
[3+2] cycloaddition is regarded to be a straightforward one.[2] Generally, azomethine
ylides would react with electron-deficient olefinic dipolarophiles to form nitrogen
containing five-membered rings. This kind of reaction is highly desirable in terms of
efficiency and selectivity. A lot of protocols have been developed for the generation of
azomethine ylides, including the ring opening of aziridines, the desilylation of various
silylamino derivatives, the decarboxylation condensation of amino acids, the
1,2-prototropy/metallo-azomethine ylides of amino acid-derived imines and the
deprotonation of iminium salts.[3] Recently, the azomethine ylides generated in situ by the
reaction of isatins or acenaphthenequinone with amino acids have been reported widely,
which provide possibilities for tandem cyclizations.[4]
On the other hand, chalcone is a kind of aromatic ketone which forms the central skeleton
for a number of useful biologically active products.[5] They have been reported to possess
2

numerous important properties, including antioxidant, antifungal, anti-inflammatory,
antimicrobial, and anticancer activities.[6] The incorporation of the chalcone moiety in the
target products is expected to enhance their biological properties. In continuation of our
research on the synthesis of spirocyclic compounds,[7] we herein develop a catalyst-free
three component one-pot reaction to construct
3'-benzoyl-4',5'-diphenyl-2H-spiro[acenaphthylene-1,2'-pyrrolidin]-2-one derivatives,
which includes the initial reaction of acenaphthenequinone and terminal amides to form
azomethine ylides, and the following intermolecular [3+2] cycloaddition with chalcones
(Scheme 1).
RESULTS AND DISCUSSION
Initially, the reaction of acenaphthenequinone 1, benzylamine 2a and chalcone 3a was
chosen as the model reaction. By simply stirring the starting reagents in ethanol under
reflux condition for 90 min, the desired
3'-benzoyl-4',5'-diphenyl-2H-spiro[acenaphthylene-1,2'-pyrrolidin]-2-one 4a was
obtained in good yield (Table 1, entry 1). Then, a variety of solvents were tested, and the
best yield was observed in ethanol (Table 1, entries 2-10). When the reaction was carried
out in water, no product was detected due to the insolubility of starting materials (Table 1,
entry 10). With temperature decreased, the yields of 4a were obviously reduced (Table 1,
entries 11-13).
3

With the optimal reaction conditions established, this protocol was applied to a series of
arylmethyl amines and chalcones in order to obtain the corresponding spiro-compounds 4
in a regio-controlled manner. As summarized in Table 2, chalcones bearing
electron-withdrawing groups or electron-donating groups could afford the corresponding
products in good to excellent yields. This cycloaddition is regioselective with the
electron-rich carbon of the dipole attacking the β-carbon of the α,β-unsaturated moiety of
3. To our delight, the [3+2] cycloaddition affords a racemic mixture exclusively, despite
the presence of four stereocenters and eight possible racemates in the products as found
in many similar cycloaddition studies.[8] The regioselective outcome of the
spiro[acenaphthylene-1,2'-pyrrolidin]-2-one derivatives 4 was confirmed by using IR,
HRMS (ESI), 1H-NMR, and 13C-NMR spectra and the structure of 4a was confirmed
using X-ray single crystal structure analysis (Fig. 1).[9]
For example, the IR spectrum of 4a showed an absorption peak at 3317 cm-1 which was
assigned to N–H bond of pyrrolidine ring, and two absorption peaks at 1702 and 1685
cm-1 indicating the carbonyl groups of acenaphthenone and benzoyl, respectively. The
1H-NMR spectrum of 4a displayed a doublet at δ = 5.25 ppm for Hc, a doublet at δ = 4.89
ppm for Ha and a triplet at δ = 4.42 ppm for Hb. The value of δ (Ha) is smaller than δ (Hc)
because the electron-withdrawing effect of nitrogen atom is stronger than that of benzoyl.
The NH proton of the pyrrolidine ring appeared as a broad singlet at δ= 2.80 ppm. The
13C-NMR spectrum of 4a showed a peak at δ = 72.4 ppm which was assigned to the
spiro-carbon. The signals at δ = 208.4 and 197.8 ppm confirmed the presence of
4

acenaphthenone and benzoyl carbonyl carbons, respectively. Moreover, the presence of a
molecular ion peak at m/z 480.1967 [M+H]+ in the HRMS spectrum confirmed the
formation of 4a (Calculated for 4a C34H26NO2 [M+H]+: 480.1964).[10]
In the molecule of chalcone，due to the electron-withdrawing effect of benzoyl group, the
β-carbon is more electrophilic than the α-carbon. Therefore, the β-carbon is preferred
position for a nucleophilic attack by carbanion of the azomethine ylides. This clearly
indicated the regioselective outcome of product 4a. Another reason may be owing to
unfavorable steric interactions between the carbonyl group of acenaphthenone moiety and
the benzoyl of dipolarophile.[11]
A plausible mechanism for the synthesis of spiroadducts 4 is proposed in Scheme 2. The
reaction of acenaphthenequinone 1 with arylmethyl amines 2 led to the formation of the
azomethine ylides 5, which served as dipoles. The carbanion of azomethine ylides 5 then
attacked the electrophilic β-carbon of chalcones in a concerted manner, the products 4
were obtained because of electronic effect and steric-hindrance effect.
CONCLUSIONS
In conclusion, we have developed a simple one-pot protocol for the facile synthesis of
functionalized spiro[acenaphthylene-1,2'-pyrrolidin]-2-one derivatives via 1,3-dipolar
cycloaddition of the azomethine ylides with chalcones. The reactions were carried out
under mild conditions without using catalysts, and possess the advantages of high atom
5

efficiency and wide substrate scopes. All cycloadducts were obtained in a highly
regioselective manner and were characterized by IR, HRMS (ESI), 1H-NMR, and
13C-NMR spectra, and the structure of 4a was confirmed by X-ray single crystal structure
analysis.
EXPERIMENTAL
1H-NMR spectra and 13C-NMR spectra were recorded on a Bruker Avance III 500 MHz
spectrometer, using CDCl3 as solvent (500 MHz for 1H or 126 MHz for 13C, respectively).
IR spectra (KBr) were recorded on a Nicolet 6700 spectrometer. Melting points were
taken on Büchi M-560 apparatus in open capillary tubes and are uncorrected. HRMS
were carried out on DECAX-60000 LCQ Deca XP. X-ray crystallographic intensity data
were collected using Bruker SMART APEX II instrument. The reaction mixtures were
monitored by TLC on silica gel plates (60 F-254). All chemicals were purchased from
Aladdin (Shanghai, China) chemical company.
General Procedure For The Synthesis Of Chalcones 3
A solution of 0.01 mol of aryl aldehyde and 0.01 mol of acetophenone in 10 mL of
ethanol was taken in a 25-mL flask equipped with a magnetic stirring bar. To this solution
10 mL of 2 M NaOH solution was added with the help of a dropping funnel keeping the
flask in an ice water bath. Then, the reaction mixture was stirred for 4-5 h at room
temperature, subsequently the crude product was filtered and recrystallized from ethanol.
6

General Procedure For Preparation Of
Spiro[Acenaphthylene-1,2'-Pyrrolidin]-2-Ones 4
A mixture of acenaphthenequinone 1 (0.5 mmol), arylmethyl amine 2 (0.5 mmol) and
chalcone 3 (0.5 mmol) in ethanol (5 mL) was stirred at reflux for 90 min, as indicated by
TLC. After completion of the reaction, the mixture was cooled to room temperature.
Then the precipitate formed in the reaction mixture was filtered and recrystallized from
ethanol to obtain the pure product.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
REFERENCES
1. (a) Chande, M. S.; Verma, R. S.; Barve, P. A.; Khanwelkar, R. R. Eur. J. Med. Chem.
2005, 40, 1143; (b) Dandia, A.; Sati, M.; Arya, K.; Sharma, R.; Loupy, A. Chem. Pharm.
Bull. 2003, 51, 1137.
2. (a) Harwood, L. M.; Vickers, R. J. In Synthetic Applications of 1,3-dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A.; Pearson,
W. H. (Eds.); Wiley; Hoboken, NJ, 2002, pp. 169–252; (b) Bridges, R. J.; Lovering, F. E.;
Humphrey, J. M.; Stanley, M. S.; Blakely, T. N.; Cristofaro, M. F.; Chamberlin, A. R.
Bioorg. Med. Chem. Lett. 1993, 3, 115; (c) Pellissier, H. Tetrahedron. 2007, 63, 3235; (d)
Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2006, 13, 2873; (e) Pandey, G.; Banerjee, P.;
7

Gadre, S. R. Chem. Rev. 2006, 106, 4484; (f) Coldham, I.; Hufton, R. Chem. Rev. 2005,
105, 2765.
3. Pellissier, H. Tetrahedron. 2007, 63, 3235.
4. (a) Jain, R.; Sharma, K.; Kumar, D. Tetrahedron Lett. 2012, 53, 1993; (b)
Alimohammadi, K.; Sarrafi, Y.; Tajbakhsh, M.; Yeganegi, S.; Hamzehloueian, M.
Tetrahedron. 2011, 67, 1589; (c) Purushothaman, S.; Prasanna, R.; Lavanya, S.;
Raghunathan, R. Tetrahedron Lett. 2013, 54, 5744; (d) Naga Siva Rao, J.; Raghunathan,
R. Tetrahedron Lett. 2013, 54, 6568; (e) Rajesh, R.; Suresh, M.; Selvam, R.;
Raghunathan, R. Tetrahedron Lett. 2014, 55, 4047; (f) Lanka, S.; Thennarasu, S.;
Perumal, P. T. RSC Adv. 2014, 4, 2263; (g) Revathy, K.; Lalitha, A. RSC Adv. 2014, 4,
279.
5. Yarishkin, O. V. Bioorg. Med. Chem. Lett. 2008, 18, 137.
6. (a) Dimmock, J. R.; Elias, D. W.; Beazely, M. A.; Kandepu, N. M. Curr. Med. Chem.
1999, 6, 1125; (b) Go, M. L.; Wu, X.; Liu, X. L. Curr. Med. Chem. 2005, 12, 483.
7. (a) Yu, J. X.; Zhou, Y. B.; Shen, T. H.; Mao, W. G.; Chen, K.; Song, Q. B. J. Chem.
Res. 2013, 37, 365; (b) Shen, T. H.; Fu, Z. J.; Che, F. F.; Dang, H. B.; Lin, Y.; Song, Q. B.
Tetrahedron Lett. 2015, 69, 1072–1075.
8. (a) Badru, R.; Shah, S.; Singh, B. J. Heterocyclic. Chem. 2012, 49, 336; (b) Sarrafi,
Y.; Hamzehloueian, M.; Alimohammadi, K.; Yeganegi, S. J. Mol. Struct. 2012, 1030, 168;
(c) Kaur, A.; Singh, B.; Vyas, B.; Silakari, O. Eur. J. Med. Chem. 2014, 79, 282.
8

9. CCDC 1045858 contains the supplementary crystallographic data for this paper. Data
can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
10. 3'-benzoyl-4',5'-diphenyl-2H-spiro[acenaphthylene-1,2'-pyrrolidin]-2-one (4a).
Yellow powder; m.p. 218–220 °C; IR (KBr, ν, cm-1): 3317, 3060, 1707, 1685, 1601, 1281,
783, 699; 1H-NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 7.5, 2.2 Hz, 2H), 7.64 (t, J = 7.1
Hz, 2H), 7.58 (dt, J = 7.2, 5.1 Hz, 2H), 7.51 (d, J = 7.4 Hz, 2H), 7.43 (d, J = 7.1 Hz, 2H),
7.31 – 7.28 (m, 4H), 7.26 – 7.17 (m, 2H), 7.13 (d, J = 7.3 Hz, 2H), 7.00 (t, J = 7.4 Hz,
1H), 6.82 (t, J = 7.8 Hz, 2H), 5.25 (d, J = 10.5 Hz, 1H, Hc), 4.89 (d, J = 10.5 Hz, 1H, Ha),
4.42 (t, J = 10.5 Hz, 1H, Hb), 2.80 (s, 1H). 13C-NMR (126 MHz, CDCl3) δ 208.4, 197.8,
141.5, 140.7, 139.3, 139.1, 136.9, 132.1, 131.8, 131.2, 129.9, 128.7, 128.5, 128.5, 128.3,
127.9, 127.7, 127.6, 127.2, 127.1, 126.9, 124.8, 122.8, 121.7, 72.4, 68.4, 62.7, 55.7.
HRMS (ESI): Calculated for C34H26NO2 [M+H]+: 480.1964; Found: 480.1967.
11. (a) Ghandi, M.; Taheri, A.; Abbasi, A. Tetrahedron. 2010, 66, 6744; (b) Sureshbabu,
A.; Raghunathan, R.; Satiskumar, B. Tetrahedron Lett. 2009, 50, 2818.
9

Table 1. Optimization of reaction conditionsa
Entry Solvent
Temp (ºC) Yieldb(%)
1
EtOH
78
89
2
1,4-dioxane 101
75
3
AcOEt
THF
77
69
4
66
63
5
toluene
CH3CN
CH3OH
n-PrOH
n-BuOH
H2O
110
80
Trace
77
6
7
65
82
8
97
87
9
117
100
20
85
10
11
12
13
NR
45
EtOH
EtOH
40
67
EtOH
60
73
aReactions were performed with acenaphthenequinone 1 (0.5 mmol), benzylamine 2a (0.5
mmol), chalcone 3a (0.5 mmol) and solvents (5 mL).
bIsolated Yield.
10

Table 2. Synthesis of spiro[acenaphthylene-1,2'-pyrrolidin]-2-one derivatives
a
Entry Ar1
Ar2
Ar3
Yield (%)b
89
4
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4a
4b
4c
4d
4e
4f
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-Cl-C6H4
2-NO2-C6H5
4-NO2-C6H5
4-F-C6H5
4-Cl-C6H5
4-Br-C6H5
4-I-C6H5
68
3
84
4
76
5
80
6
92
7
91
4g
4h
4i
8
4-OCH3-C6H5 C6H5
67
9
4-OCH3-C6H5 2,4-Cl2-C6H3
4-OCH3-C6H5 4-Br-C6H4
79
10
11
12
13
14
15
16
17
18
19
20
21
87
4j
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-NO2-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CH3-C6H4
4-OCH3-C6H4
C10H7
83
4k
4l
84
89
4m
4n
4o
4p
4q
4r
4s
4t
71
75
80
C6H5
82
4-OCH3-C6H4 C6H5
C6H5
69
2-Br-C6H4
C4H3O
C6H5
C6H5
C6H5
C6H5
86
C6H5
78
C5H4N
C6H5
93
4u
aReaction of acenaphthenequinone 1, arylmethyl amines 2 and chalcones 3 in ethanol
reflux for 90 min.
bIsolated Yield.
11

Fig. 1. ORTEP diagram of 4a
12

Scheme 1. Regioselective synthesis of spiro[acenaphthylene-1,2'-pyrrolidin]-2-one
derivatives.
13

Scheme 2. Plausible mechanism of the formation of
spiro[acenaphthylene-1,2'-pyrrolidin]-2-one derivatives.
14