Catalyst-free concise synthesis of imidazo[1,2-a]pyrrolo[3,4-e]pyridine derivatives

Article abstract of DOI:10.1039/c3ra45485a

An eco-benign and highly efficient aza-ene reaction for preparing imidazo[1,2-a]pyrrolo[3,4-e]pyridine derivatives from heterocyclic ketene aminals (HKAs) and 2,3-dioxopyrrolidines has been developed in environmentally benign solvent systems, as well as in the absence of any catalyst. The procedures feature excellent yields, short reaction times, a convenient one-pot method, and simple purification that not only minimise the generation of waste but also simplify the work-up procedure.

Full text of DOI:10.1039/c3ra45485a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Catalyst-free concise synthesis of imidazo[1,2-a]-
pyrrolo[3,4-e]pyridine derivatives†
Cite this: RSC Adv., 2014, 4, 9926
*
*
Xuebing Chen, Li Zhu, Li Fang, Shengjiao Yan and Jun Lin
An eco-benign and highly efficient aza–ene reaction for preparing imidazo[1,2-a]pyrrolo[3,4-e]pyridine
derivatives from heterocyclic ketene aminals (HKAs) and 2,3-dioxopyrrolidines has been developed in
environmentally benign solvent systems, as well as in the absence of any catalyst. The procedures
feature excellent yields, short reaction times, a convenient one-pot method, and simple purification that
not only minimise the generation of waste but also simplify the work-up procedure.
Received 30th September 2013
Accepted 24th January 2014
DOI: 10.1039/c3ra45485a
www.rsc.org/advances
Introduction
The imidazo[1,2-a]pyridine derivatives and its analogues are
some of the most important heterocycles as they are not only
broadly used in material science1 but also have widespread
applications in medicinal chemistry; these compounds have a
wide range of biologic activities such as insecticidal,2 antitu-
berculosis,3 antiviral,4 antiprotozoal,5 antibacterial,6 antiulcer,7
and anti-inammatory behaviours.8 They have also been char-
acterised as the inhibitors of b-amyloid plaques formation,9
selective cyclin-dependent kinase,10 and they constitute a novel
class of orally active non-peptide bradykinin B2 receptor
antagonists.11 In addition to the before mentioned bio-activi-
ties, many marketed drugs including zolpidem,12 zolimidine,
olprinone13 (Fig. 1), optically-active GSK812397 (Fig. 1) candi-
date14 and saripidem15 are derived from imidazo[1,2-a]pyridine
core entities. Consequently, these have attracted considerable
interest for synthetic chemists and stimulated the development
of numerous methods for their preparation.16
Fig.
1 Biologically active imidazo[1,2-a]pyridines, pyrrolin-2-one,
imidazopyrrolopyridines and the target compounds.
On the other hand, the pyrrolin-2-ones core is featured in a
number of natural products (e.g., epolactaene17 and
UCS1025A18) (Fig. 1) and biologically active drug candidates.19
Compounds carrying the pyrrolin-2-ones moiety exhibit anti-
inammatory20 activities, and are found to inhibit cyclo-
oxygenase-2,21 vascular endothelial growth factor receptor
(VEGF-R)22 and protein kinase C.23
Further, the fused imidazo-pyrrolopyridines contain both
imidazo-pyridine and pyrrole cores displaying a variety of bio-
logical activities. For example, AG110 (Fig. 1) displayed a strong
antiviral activity against the bovine viral diarrhea virus.24
Moreover, imidazo-pyrrolopyridines has used as the inhibitors
of IkB-kinase (IKK)25 and Janus protein tyrosine kinase (JAKs).26
Numerous methods for the synthesis of imidazo[1,2-a]pyridine
and pyrrolin-2-ones have been reported, but the preparation of
fused imidazo-pyrrolopyridines are rarely.27
Heterocyclic ketene aminals (HKAs), as a type of versatile
building block, are widely used for the synthesis of a variety of
fused heterocyclic compounds, including anticancer agents,28
herbicides, pesticides,29 anti-anxious agents,30 anti-leishmanial
agents31 and antibacterial and anti-therapeutic drugs.32 Our
group has been pursuing the diversied synthesis of natural
product-like heterocycles33 with potential bioactivities through
one-pot reactions based on HKAs. This is part of our research
program, which aims to develop new efficient and environ-
mentally friendly methodologies for the preparation of hetero-
cycles. Herein, we investigated a one-pot reaction of HKAs and
2,3-dioxopyrrolidines to afford a novel series of imidazo[1,2-a]-
pyrrolo[3,4-e]pyridine derivatives.
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University),
Ministry Education, School of Chemical Science and Technology, Yunnan University,
Kunming, 650091, P. R. China. E-mail: yansj@ynu.edu.cn; linjun@ynu.edu.cn; Fax:
+86 871 65033215
† Electronic supplementary information (ESI) available. CCDC 962808. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra45485a
9926 | RSC Adv., 2014, 4, 9926–9934
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 2 Catalyst-free synthesis of imidazo[1,2-a]pyrrolo[3,4-e]-pyri-
dine derivatives 4a
Results and discussion
The aza–ene reaction represents one of the most powerful
methods for the formation of carbon–nitrogen bonds in organic
synthesis, and has been applied to make a range of heterocycles.
The aza–ene reactions of heterocyclic ketene aminals have
recently been explored with a variety of bis-electrophilic
reagents.34
In this paper, a series of imidazo[1,2-a]pyrrolo[3,4-e]pyridines
4–5 were easily prepared by a new aza–ene reaction of HKAs 1–2
and dioxopyrrolidines 3 in the absence of catalyst in ethanol
with good to excellent yields (81–95%).
Entry
1/EWG
3
4
Yieldb (%)
To test the success of our strategy, we rst used the reaction
of HKAs 1a and dioxopyrrolidines 3a as a representative to
optimise the experimental conditions; and the results are
summarized in Table 1. No reaction occurred in the solvent of
ethanol at room temperature even for 12 h (Table 1, entry 1), but
at 40 ꢀC and 60 ꢀC the product 4a was obtained in 93% and 90%
yields, respectively (Table 1, entries 2 and 3). We only obtain a
nal product with moderate yield in acetonitrile or 1,4-dioxane
1
2
3
4
5
6
7
8
1a (NO2)
1a (NO2)
3a
3b
3a
3b
3c
3d
3a
3b
3d
3a
3b
3c
3d
3a
3b
3c
3d
3a
3b
3c
3d
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
93
95
94
93
94
90
89
87
84
94
94
92
90
94
93
90
89
91
90
89
89
89
86
86
84
1b (p-FPhCO)
1b (p-FPhCO)
1b (p-FPhCO)
1b (p-FPhCO)
1c (o-FPhCO)
1c (o-FPhCO)
1c (o-FPhCO)
1d (p-ClPhCO)
1d (p-ClPhCO)
1d (p-ClPhCO)
1d (p-ClPhCO)
1e (PhCO)
ꢀ
at 40 C. However, the results indicate that the reaction could
9
not proceed in water even at reux temperature (Table 1, entry
6). The reaction temperature and solvents are key to product
yields. It was realised that the ethanol was the best solvent for
the reaction to furnish 4a. The temperature of 40 ꢀC is benecial
for the reaction. Inspired by these results, we continued to
optimise reaction conditions to further improve the chemical
yield; different basic and acidic catalysts such as TFA, HOAc,
L-proline, p-TSA, piperidine, Et3N, DABCO were added in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1e (PhCO)
1e (PhCO)
1e (PhCO)
1f (p-MePhCO)
1f (p-MePhCO)
1f (p-MePhCO)
1f (p-MePhCO)
1g (p-MeOPhCO)
1g (p-MeOPhCO)
1g (p-MeOPhCO)
1g (p-MeOPhCO)
4s
4t
4u
4v
4w
4x
4y
Table 1 Optimisation conditions for the formation of 4aa
a
The reaction was performed with 1 (1 mmol), 3 (1.1 mmol) and the
solvent (15 mL). b Isolated yields, isolated yield based on HKA 1.
ethanol, but the results showed that these catalysts could not
promote this reaction efficiently (Table 1, entries 7–13). Thus, it
was concluded that the optimum reaction conditions were the
Entry
Solvent
Catalyst
t (ꢀC)
Time/min
Yieldb (%)
ꢀ
use of ethanol under catalyst-free conditions at 40 C.
With the optimised conditions, we investigated the scope of
this aza–ene strategy for the construction of a library of imidazo
[1,2-a]pyrrolo[3,4-e]pyridines (Table 2).
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
CH3CN
Dioxane
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
—
—
—
—
—
—
TFA
HOAc
L-Proline
p-TSA
Piperidine
Et3N
DABCO
rt
40
60
40
40
Reux
40
40
40
40
40
40
40
12
6
6
6
6
12
6
6
6
6
n.r.
93
90
87
78
Trace
77
81
85
83
We rst explored variations in the dioxopyrrolidines 3; the
results demonstrate that the reaction tolerates signicant
functionalisation of the dioxopyrrolidines both electron-
donating and electron-withdrawing groups can be accommo-
dated, and substituents ortho or para to the aromatic group can
all be generated. It is observed that the substituents on the
aromatic rings had slightly inuence on the yields. The
aromatics with electron-withdrawing groups p-chloro, 2,4-
dichloro groups gave higher yields than those with electron-
donating groups or no substituted ones (compare Table 2,
entries 3, 4, 5 & 6).
9
10
11
12
13
6
6
6
89
89
79
a
The reaction was performed with 1a (1 mmol), 3a (1.1 mmol) and the
solvent (15 mL). b Isolated yields, isolated yield based on HKA 1a. n.r. ¼
no reaction.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 9926–9934 | 9927

View Article Online
RSC Advances
Paper
Table
3 Catalyst-free synthesis of pyrimido[1,2-a]pyrrolo[3,4-e]-
pyridines derivatives 5a
Entry
2/EWG
5
Yieldb (%)
1
2
3
4
5
2a (p-FPhCO)
2b (p-ClPhCO)
2c (PhCO)
2d (p-MePhCO)
2e (p-OMePhCO)
5a
5b
5c
5d
5e
85
84
84
84
81
Scheme 1 The proposed mechanism of the reaction.
economy and ecologically benign process since no molecule was
lost; (2) the environmentally friendly process which included
green solvents, was catalyst-free, and used a mild reaction
temperature; and (3) the convenient workup which only
required simple ltration rather than column chromatography
or recrystallisation.
a
The reaction was performed with 2 (1 mmol), 3a (1.1 mmol) and the
solvent (15 mL). b Isolated yields, isolated yield based on HKA 2.
Subsequently, the substrate 1 was also extended by using
other ve-membered HKAs; the similar reactions were observed
(Table 2, entries 7–25). The results revealed that the ve-
membered HKAs, with various substituents, were all good
substrates for the aza–ene reaction. Similarly, it was clearly
shown that the electron-withdrawing aromatic rings of HKAs 1
can encourage the yield of the reaction (compare Table 2, entries
1, 3, 10, 14, 18, and 22). What is more, the HKAs with substituents
at para-positions afforded higher yields than those counterparts
at the ortho-positions (compare Table 2, entries 3 and 7).
In order to further investigate the scope of HKAs, the ring
size was also examined in our work. Thus, ve six-membered
HKAs 2a–e were also employed in this process; the corre-
sponding products 5 were obtained (Table 3). On the whole, the
six-membered HKAs provided lower yields than those of the
ve-membered HKAs (Table 3 vs. 2). It could be concluded that
the ring size of HKAs can inuence the yields of the reaction.
Compared with other aza–ene reactions, the present reaction
showed the following attractive characteristics: (1) a high atom
The structures of imidazo[1,2-a]pyrrolo[3,4-e]pyridines 4 and
pyrimido[1,2-a]pyrrolo[3,4-e]pyridines 5 were identied by their
1
IR, H NMR, 13C NMR and HRMS spectra. In order to further
conrm the crystal structure of the product imidazo[1,2-a]pyr-
rolo[3,4-e]pyridine, 5a was selected as
a representative
compound and characterized by X-ray crystallography, as shown
in Fig. 2.35
A proposed mechanism for the aza–ene reaction is depicted
in Scheme 1. First, HKA 1a reacts with dioxopyrrolidine 3a
through an aza–ene reaction36 to form the intermediate 6, which
undergoes a rapid imine–enamine tautomerisation to give 7.
Then, intra-molecular cyclisation of 7 forms imidazo[1,2-a]-
pyrrolo[3,4-e]pyridines 4a.
Conclusions
In conclusion, we developed an eco-benign, mild, and highly
efficient method for the synthesis of fused tricyclic heterocycles
containing imidazo[1,2-a]pyrrolo[3,4-e]pyridines & pyrimido
[1,2-a]pyrrolo[3,4-e]pyridines via an aza–ene reaction of HKAs
and dioxopyrrolidines. Our work presents a very simple reaction
which is performed under neutral conditions without any
catalyst in the green solvent ethanol. All products were easily
isolated (ltration) and obtained in good to excellent yields.
Features of this procedure include ease of execution, exibility,
and substantial minimisation of waste. Moreover, these special
fused tricyclic heterocycles may be directly useful for drug
design, discovery and development.
Experimental
General information
All compounds were fully characterised by spectroscopic data.
The NMR spectra were recorded on Bruker DRX500 (1H: 500
Fig. 2 X-ray crystal structures of 5a; ellipsoids are drawn at the 30%
probability level.
9928 | RSC Adv., 2014, 4, 9926–9934
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
MHz, 13C: 125 MHz) or Bruker AVIII-400 (1H: 400 MHz, 13C: 100 ArH), 6.50 (br, 1H, OH), 4.47 (d, J ¼ 15.0 Hz, 1H, ArCH2), 4.32 (d,
MHz), chemical shis (d) are expressed in ppm, and J values are J ¼ 15.0 Hz, 1H, ArCH2), 3.76 (d, J ¼ 10.3 Hz, 1H, CH), 3.66–3.74
given in Hz, DMSO-d6 was used as solvent. IR spectra were (m, 2H, NCH2), 3.54–3.60 (m, 2H, NCH2), 3.27–3.31 (m, 1H, CH),
recorded on a FT-IR Thermo Nicolet Avatar 360 using a KBr 3.01–3.08 (m, 1H, NCH2), 2.57–2.65 (m, 1H, NCH2); 13C NMR
pellet. The reactions were monitored by thin-layer chromatog- (100 MHz, DMSO-d6): d ¼ 188.1, 169.7, 161.8 (d, J ¼ 243.0 Hz),
raphy (TLC) using silica gel GF254. The melting points were 159.9, 142.1, 139.4, 136.7, 133.0, 132.4, 131.6; 129.3, 128.5,
determined on XT-4A melting point apparatus and are uncor- 128.0, 127.3, 115.0 (d, J ¼ 22.0 Hz), 114.8 (d, J ¼ 22.0 Hz), 82.4,
rected. HRMs were performed on a Agilent LC/Msd TOF and 82.2, 46.8, 46.2, 45.2, 43.4, 42.8, 36.2; HRMS (ESI-TOF): m/z
Monoisotopic Mass instrument. All chemicals and solvents calcd for C29H25Cl2FN3O3 [(M + H)+], 552.1252; found, 552.1253.
were used as received without further purication unless
2-Benzyl-4-(4-chlorophenyl)-5-(4-uorobenzoyl)-9a-hydroxy-
otherwise stated. The raw material 1–2 was synthesized 2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-
according to the literature.37 For the method of synthesis of pyridin-1-one (4d). White solid; Mp 224–226 ꢀC; IR (KBr): 3312,
compound 3 see the literature.38
1703, 1595, 1512, 1215, 837, 580 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d ¼ 9.55 (br, 1H, NH), 7.35–7.40 (m, 2H, ArH), 7.28–
7.33 (m, 1H, ArH), 7.20 (d, J ¼ 7.7 Hz, 4H, ArH), 7.02 (d, J ¼ 8.0
Hz, 2H, ArH), 6.93–6.99 (m, 2H, ArH), 6.87–6.92 (m, 2H, ArH),
General procedure
HKAs 1–2 (1 mmol), dioxopyrrolidines 3 (1.1 mmol), solvent 6.42 (br, 1H, OH), 4.44 (d, J ¼ 15.0 Hz, 1H, ArCH2), 4.38 (d, J ¼
EtOH (15 mL) were charged into a 25 mL round-bottom ask, 15.0 Hz, 1H, ArCH2), 3.71–3.74 (m, 1H, CH), 3.66–3.90 (m, 2H,
and the mixture was stirred at 40 ꢀC until the HKA 1–2 was NCH2), 3.58–3.62 (m, 2H, NCH), 3.34–3.37 (m, 1H, CH), 3.04 (t,
completely consumed. The mixture was cooled to room J ¼ 9.5 Hz, 1H, NCH2), 2.74–2.80 (m, 1H, NCH2); 13C NMR (100
temperature. Then the precipitation was ltered and succes- MHz, DMSO-d6): d ¼ 188.0, 170.0, 162.0 (d, J ¼ 242.0 Hz), 159.9,
sively washed by ethanol to afford the pure products 4–5 in a 145.5, 139.7, 136.8, 130.6, 130.2, 129.3, 128.6; 128.6, 128.1, 115.0
good yield (81–95%). The products were further identied by (d, J ¼ 22.0 Hz), 114.8 (d, J ¼ 22.0 Hz), 83.1, 82.7, 47.6, 47.1, 46.2,
FT-IR, NMR and HRMS, being in good agreement with the 43.4, 42.7, 40.6; HRMS (ESI-TOF): m/z calcd for C29H26ClFN3O3
assigned structures.
[(M + H)+], 518.1641; found, 518.1645.
2-Benzyl-4-(2,4-dichlorophenyl)-9a-hydroxy-5-nitro-2,3,3a,4,6,
2-Benzyl-5-(4-uorobenzoyl)-9a-hydroxy-4-phenyl-2,3,3a,4,6,
7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-pyridin-1-one 7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one
(4a). White solid; Mp 289–290 ꢀC; IR (KBr): 3788, 3427, 1699, (4e). White solid; Mp 194–197 ꢀC; IR (KBr): 3324, 1701, 1596,
1638, 1253, 1168, 735, 657 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): 1515, 1214, 1008, 739 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d ¼
d ¼ 9.28 (br, 1H, NH), 7.57 (s, 1H, ArH), 7.32–7.41 (m, 2H, ArH), 9.57 (br, 1H, NH), 7.32–7.38 (m, J ¼ 6.8 Hz, 2H, ArH), 7.29–7.34
7.28–7.34 (m, 2H, ArH), 7.19 (d, J ¼ 7.1 Hz, 2H, ArH), 7.01 (d, J ¼ (m, 1H, ArH), 7.20 (d, J ¼ 6.8 Hz, 2H, ArH), 7.11–7.15 (m, 2H,
8.4 Hz, 1H, ArH), 6.90 (br, 1H, OH), 4.48 (d, J ¼ 15.0 Hz, 1H, CH), ArH), 7.01–7.06 (m, 1H, ArH), 7.00 (d, J ¼ 6.8 Hz, 2H, ArH), 6.86–
4.42 (AB, J ¼ 15.0 Hz, 2H, ArCH2), 3.73–3.84 (m, 2H, NCH2), 6.96 (m, 4H, ArH), 6.36 (br, 1H, OH), 4.43 (s, 2H, ArCH2), 3.72–
3.60–3.68 (m, 2H, NCH2), 3.38–3.48 (m, 1H, CH), 2.92–2.97 (m, 3.75 (m, 1H, CH), 3.67–3.74 (m, 2H, NCH2), 3.57–3.61 (m, 1H,
1H, NCH2), 2.70–2.76 (m, 1H, NCH2); 13C NMR (100 MHz, NCH2), 3.48–3.52 (m, 1H, NCH2), 3.05 (t, J ¼ 9.3 Hz, 1H, NCH2),
DMSO-d6): d ¼ 169.1, 155.8, 139.2, 136.5, 133.9, 132.1, 129.9, 2.78–2.83 (m, 1H, NCH2); 13C NMR (100 MHz, DMSO-d6): d ¼
129.3, 128.0, 127.8, 127.4, 102.2, 82.5, 46.7, 46.3, 44.9, 44.1, 43.2, 187.9, 170.1, 161.5 (d, J ¼ 232.0 Hz); 160.0, 146.4, 139.7, 136.8,
36.2; HRMS (ESI-TOF): m/z calcd for C22H21Cl2N4O4 [(M + H)+], 129.2, 128.6, 128.5, 128.3; 128.1, 128.0; 126.0; 114.8 (d, J ¼ 21.0
475.0934; found, 475.0941.
Hz); 114.6 (d, J ¼ 21.0 Hz), 83.4, 82.8, 47.6, 47.2, 46.2, 43.4, 42.6,
2-Benzyl-4-(4-chlorophenyl)-9a-hydroxy-5-nitro-2,3,3a,4,6,7, 39.3; HRMS (ESI-TOF): m/z calcd for C29H27FN3O3 [(M + Na)+],
8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one (4b). 506.1850; found, 506.1859.
ꢀ
White solid; Mp 250–253 C; IR (KBr): 3788, 3427, 1699, 1638,
2-Benzyl-5-(4-uorobenzoyl)-9a-hydroxy-4-(4-methoxy-phenyl)-
1253, 1168, 735, 657 cmꢁ1; H NMR (400 MHz, DMSO-d6): d ¼ 2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo-[3,4-e]-
1
ꢀ
9.24 (br, 1H, NH), 7.35–7.39 (m, 2H, ArH), 7.26–7.32 (m, 3H, pyridin-1-one (4f). White solid; Mp 215–218 C; IR (KBr): 3462,
ArH), 7.18–7.28 (m, 4H, ArH), 6.85 (br, 1H, OH), 4.41 (AB, J ¼ 1696, 1599, 1511, 1240, 751, 649 cmꢁ1
;
1H NMR (400 MHz,
14.9 Hz, 2H, ArCH2), 4.24–4.28 (m, 1H, CH), 3.74–3.85 (m, 2H, DMSO-d6): d ¼ 9.59 (br, 1H, NH), 7.37–7.42 (m, 2H, ArH),
NCH2), 3.55–3.68 (m, 2H, NCH2), 3.32–3.34 (m, 1H, CH), 2.82– 7.30–7.34 (m, 1H, ArH), 7.22 (d, J ¼ 7.4 Hz, 2H, ArH), 6.92–
2.90 (m, 2H, NCH2); 13C NMR (100 MHz, DMSO-d6): d ¼ 169.3, 7.00 (m, 6H, ArH), 6.74 (d, J ¼ 8.3 Hz, 2H, ArH), 6.34 (br, 1H,
155.5, 142.3, 136.6, 131.0, 130.0, 129.2, 128.2, 128.0; 128.0; OH), 4.43 (s, 2H, ArCH2), 3.76–3.78 (m, 1H, CH), 3.70–3.76
103.5, 82.7, 47.0, 46.8, 46.2, 44.1, 43.1, 38.6; HRMS (ESI-TOF): m/ (m, 2H, CH2), 3.66 (s, 3H, OCH3), 3.60–3.63 (m, 1H, CH),
z calcd for C22H22ClN4O4 [(M + H)+], 441.1324; found, 441.1320. 3.50–3.54 (m, 1H, NCH2), 3.03–3.06 (m, 1H, NCH2), 2.78–2.83
2-Benzyl-4-(2,4-dichlorophenyl)-5-(4-uorobenzoyl)-9a-hydroxy- (m, 1H, NCH2); 13C NMR (100 MHz, DMSO-d6): d ¼ 187.8,
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]-pyrrolo[3,4-e]- 170.1, 160.5 (d, J ¼ 234.0 Hz); 159.9, 157.6, 139.7, 138.2,
pyridin-1-one (4c). White solid; Mp 225–227 ꢀC; IR (KBr): 3329, 136.8, 129.2, 129.2, 128.6; 128.0; 114.8 (d, J ¼ 21.0 Hz), 114.6
1703, 1599, 1512, 1142, 843, 536 cmꢁ1
;
1H NMR (400 MHz, (d, J ¼ 21.0 Hz); 113.5; 83.6, 82.7, 55.3, 47.8, 47.1, 46.2, 43.3,
DMSO-d6): d ¼ 9.48 (br, 1H, NH), 7.27–7.38 (m, 5H, ArH), 7.12– 42.6, 39.0; HRMS (ESI-TOF): m/z calcd for C30H29FN3O4 [(M +
7.17 (m, 3H, ArH), 6.91–6.96 (m, 2H, ArH), 6.78–6.82 (m, 2H, H)+], 514.2137; found, 514.2142.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 9926–9934 | 9929

View Article Online
RSC Advances
Paper
131.6, 129.3, 128.5, 128.1, 128.1, 128.0, 127.8, 127.3, 82.4, 82.2,
2-Benzyl-4-(2,4-dichlorophenyl)-5-(2-uorobenzoyl)-9a-hydroxy-
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-
pyridin-1-one (4g). White solid; Mp 251–254 ꢀC; IR (KBr): 3333,
46.7, 46.2, 45.2, 43.4, 42.8, 36.2; HRMS (ESI-TOF): m/z calcd for
C
29H25Cl3N3O3 [(M + H)+], 568.0956; found, 568.0949.
1703, 1602, 1516, 1018, 755, 541 cmꢁ1 1H NMR (400 MHz,
;
2-Benzyl-5-(4-chlorobenzoyl)-4-(4-chlorophenyl)-9a-hydroxy-
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-
pyridin-1-one (4k). White solid; Mp 230–233 ꢀC; IR (KBr): 3319,
DMSO-d6): d ¼ 9.34 (br, 1H, NH), 7.34–7.40 (m, 2H, ArH), 7.24–
7.32 (m, 3H, ArH), 7.15–7.23 (m, 3H, ArH), 6.86–6.98 (m, 2H,
ArH), 6.54–6.58 (m, 1H, ArH), 6.53 (br, 1H, OH), 4.47–4.53 (m,
1H, ArCH2), 4.31–4.37 (m, 1H, ArCH2), 3.84–3.88 (m, 1H, CH),
3.70–3.76 (m, 2H, CH2), 3.59–3.63 (m, 1H, CH), 3.31–3.38 (m,
2H, NCH2), 3.00–3.08 (m, 1H, NCH2), 2.54–2.62 (m, 1H, NCH2);
13C NMR (100 MHz, DMSO-d6): d ¼ 184.4, 169.7, 159.4, 141.7,
136.7, 133.0, 132.4, 131.4; 129.9, 128.0, 127.0, 124.4, 115.7 (d, J ¼
22.0 Hz), 115.5 (d, J ¼ 22.0 Hz), 82.3, 82.4, 46.6, 46.2, 45.1, 43.3,
42.8, 35.6; HRMS (ESI-TOF): m/z calcd for C29H25Cl2FN3O3 [(M +
H)+], 552.1252; found, 552.1250.
1703, 1599, 1513, 1281, 827, 546 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d ¼ 9.54 (br, 1H, NH), 7.35–7.40 (m, 2H, ArH), 7.28–
7.32 (m, 1H, ArH), 7.17–7.23 (m, 6H, ArH), 7.03 (d, J ¼ 7.9 Hz,
2H, ArH), 6.86 (d, J ¼ 7.8 Hz, 2H, ArH), 6.43 (br, 1H, OH), 4.41
(AB, J ¼ 15.1 Hz, 2H, ArCH2), 3.72–3.74 (m, 1H, CH), 3.69–3.72
(m, 2H, CH2), 3.59–3.62 (m, 1H, CH2), 3.47–3.50 (m, 1H, NCH2),
3.04 (t, J ¼ 9.5 Hz, 1H, NCH), 2.74–2.80 (m, 1H, NCH2); 13C NMR
(100 MHz, DMSO-d6): d ¼ 187.6, 170.0, 159.9, 145.3, 141.9,
136.8, 132.6, 130.5, 130.1, 129.2, 128.2; 128.2, 128.1, 128.0, 82.9,
82.6, 47.5, 46.9, 46.2, 43.4, 42.7, 39.0; HRMS (ESI-TOF): m/z
calcd for C29H26Cl2N3O3 [(M + H)+], 534.1346; found, 534.1348.
2-Benzyl-5-(4-chlorobenzoyl)-9a-hydroxy-4-phenyl-2,3,3a,4,
6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one
(4l). White solid; Mp 200–202 ꢀC; IR (KBr): 3325, 1703, 1596,
1515, 1278, 1013, 751 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d ¼
9.57 (br, 1H, NH), 7.35–7.39 (m, 2H, ArH), 7.26–7.32 (m, 1H,
ArH), 7.13–7.22 (m, 6H, ArH), 7.05–7.09 (m, 1H, ArH), 6.99–7.04
(m, 2H, ArH), 6.85 (d, J ¼ 7.7 Hz, 2H, ArH), 6.37 (br, 1H, OH),
4.42 (AB, J ¼ 15.4 Hz, 2H, ArCH2), 3.74–3.77 (m, 1H, CH), 3.64–
3.72 (m, 2H, CH2), 3.57–3.62 (m, 1H, NCH2), 3.49–3.53 (m, 1H,
NCH2), 3.05 (t, J ¼ 9.4 Hz, 1H, NCH2), 2.78–2.83 (m, 1H, NCH2);
13C NMR (100 MHz, DMSO-d6): d ¼ 187.7, 170.1, 160.1, 146.4,
142.1, 136.9, 132.6, 129.3, 128.4, 128.2, 128.2, 128.0, 126.1, 83.4,
82.7, 47.7, 47.2, 46.2, 43.4, 42.7, 40.4; HRMS (ESI-TOF): m/z
calcd for C29H27ClN3O3 [(M + H)+], 500.1735; found, 500.1743.
2-Benzyl-5-(4-chlorobenzoyl)-9a-hydroxy-4-(4-methoxyphenyl)-
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-
pyridin-1-one (4m). White solid; Mp 237–239 ꢀC; IR (KBr): 3328,
2-Benzyl-5-(2-uorobenzoyl)-9a-hydroxy-4-phenyl-2,3,3a,4,6,
7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one
ꢀ
(4h). White solid; Mp 216–219 C; IR (KBr): 3430, 1701, 1599,
1
1517, 1135, 748, 551 cmꢁ1; H NMR (400 MHz, DMSO-d6): d ¼
9.40 (br, 1H, NH), 7.36–7.41 (m, 2H, ArH), 7.28–7.33 (m, 1H,
ArH), 7.16–7.24 (m, 3H, ArH), 6.95–7.08 (m, 4H, ArH), 6.84–6.91
(m, 3H, ArH), 6.58–6.64 (m, 1H, ArH), 6.43 (br, 1H, OH), 4.43
(AB, J ¼ 15.0 Hz, 2H, ArCH2), 3.71–3.77 (m, 2H, NCH2), 3.60–
3.63 (m, 1H, CH), 3.47–3.53 (m, 2H, NCH2), 3.38–3.42 (m, 1H,
CH), 3.06 (t, J ¼ 9.5 Hz, 1H, NCH2), 2.74–2.79 (m, 1H, NCH2); 13
C
NMR (100 MHz, DMSO-d6): d ¼ 184.3, 170.0, 159.4; 145.9, 136.8,
130.9, 129.7, 129.2, 128.6, 128.2, 128.0; 127.8, 125.9; 124.1;
115.6; 115.4, 84.7, 82.6, 47.3, 47.0, 46.2, 43.3, 42.7, 39.3; HRMS
(ESI-TOF): m/z calcd for C29H27FN3O3 [(M + H)+], 484.2031;
found, 484.2031.
2-Benzyl-5-(2-uorobenzoyl)-9a-hydroxy-4-(4-methoxyphenyl)-
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo-[3,4-e]-
ꢀ
pyridin-1-one (4i). White solid; Mp 221–224 C; IR (KBr): 3435,
1700, 1599, 1513, 1244, 749, 547 cmꢁ1 1H NMR (400 MHz,
;
1699, 1597, 1511, 1246, 1019, 833 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d ¼ 9.39 (br, 1H, NH), 7.36–7.40 (m, 2H, ArH), 7.30–
7.33 (m, 1H, ArH), 7.17–7.27 (m, 3H, ArH), 6.96–7.02 (m, 1H,
ArH), 6.87–6.93 (m, 1H, ArH), 6.80 (d, J ¼ 6.7 Hz, 2H, ArH), 6.60–
6.68 (m, 3H, ArH), 6.40 (br, 1H, OH), 4.43 (s, 2H, ArCH2), 3.70–
3.74 (m, 1H, CH), 3.64–3.68 (m, 2H, CH2), 3.63 (s, 3H, OCH3),
3.45–3.51 (m, 1H, CH), 3.36–3.46 (m, 2H, NCH2), 3.01–3.08 (m,
1H, NCH2), 2.62–2.68 (m, 1H, NCH2); 13C NMR (100 MHz,
DMSO-d6): d ¼ 184.3, 170.1, 159.3; 157.5, 137.9, 136.8, 129.6,
129.2, 129.1, 128.6, 128.0; 124.1; 115.5, 113.2; 84.9, 82.7, 55.3,
47.4, 47.0, 46.2, 43.3, 42.7, 38.7; HRMS (ESI-TOF): m/z calcd for
DMSO-d6): d ¼ 9.55 (br, 1H, NH), 7.35–7.38 (m, 2H, ArH), 7.29–
7.32 (m, 1H, ArH), 7.16–7.21 (m, 4H, ArH), 6.92 (d, J ¼ 7.8 Hz,
2H, ArH), 6.87 (d, J ¼ 7.8 Hz, 2H, ArH), 6.72 (d, J ¼ 7.8 Hz, 2H,
ArH), 6.32 (br, 1H, OH), 4.43 (AB, J ¼ 15.0 Hz, 2H, ArCH2), 3.68–
3.72 (m, 1H, CH), 3.68 (s, 3H, OCH3), 3.58–3.64 (m, 2H, CH2),
3.50 (d, J ¼ 7.6 Hz, 1H, CH), 3.02 (t, J ¼ 9.3 Hz, 1H, NCH2), 2.75–
2.80 (m, 1H, NCH2); 13C NMR (100 MHz, DMSO-d6): d ¼ 187.5,
170.1, 160.7; 157.6, 142.0, 138.2, 136.8, 132.6, 129.2, 129.2,
128.3, 128.0; 128.0, 113.5, 83.6, 82.7, 55.3, 47.8, 47.1, 46.2, 43.3,
42.6, 38.8; HRMS (ESI-TOF): m/z calcd for C30H29ClN3O4 [(M +
H)+], 530.1841; found, 530.1846.
C
30H29FN3O4 [(M + H)+], 514.2137; found, 514.2142.
2-Benzyl-5-(4-chlorobenzoyl)-4-(2,4-dichlorophenyl)-9a-hydroxy-
5-Benzoyl-2-benzyl-4-(2,4-dichlorophenyl)-9a-hydroxy-2,3,3a,
4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-
one (4n). White solid; Mp 222–225 ꢀC; IR (KBr): 3283, 1703,
1602, 1513, 1208, 701, 600 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d ¼ 9.53 (br, 1H, NH), 7.26–7.40 (m, 5H, ArH), 7.10–7.21 (m, 6H,
ArH), 6.77 (d, J ¼ 7.4 Hz, 2H, ArH), 6.52 (br, 1H, OH), 4.42 (AB,
J ¼ 15.0 Hz, 1H, ArCH2), 3.98–4.02 (m, 1H, CH), 3.73–7.77 (m,
2H, CH2), 3.59–3.63 (m, 1H, CH2), 3.45–3.49 (m, 1H, NCH2), 3.30
(t, J ¼ 8.9 Hz, 1H, NCH2), 3.06 (t, J ¼ 9.8 Hz, 1H, CH), 2.64 (t, J ¼
8.9 Hz, 1H, NCH2); 13C NMR (100 MHz, DMSO-d6): d ¼ 189.3,
169.7, 160.0, 142.9, 142.2, 136.7, 133.1, 132.4, 131.5, 129.2,
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-
ꢀ
pyridin-1-one (4j). White solid; Mp 223–226 C; IR (KBr): 3424,
1701, 1601, 1511, 1204, 841, 543 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d ¼ 9.50 (br, 1H, NH), 7.31–7.40 (m, 5H, ArH), 7.17–
7.25 (m, 5H, ArH), 6.80 (d, J ¼ 7.1 Hz, 2H, ArH), 6.53 (br, 1H,
OH), 4.42 (AB, J ¼ 14.8 Hz, 2H, ArCH2), 3.96–3.99 (m, 1H, CH),
3.70–3.78 (m, 2H, NCH2), 3.59–3.63 (m, 1H, CH2), 3.45–3.51 (m,
1H, NCH2), 3.29–3.33 (m, 1H, CH), 3.04–3.09 (m, 1H, NCH2),
2.63–2.67 (m, 1H, NCH2); 13C NMR (100 MHz, DMSO-d6): d ¼
188.0, 169.7, 159.9, 142.0, 141.6, 136.7, 133.0, 132.6, 132.4;
9930 | RSC Adv., 2014, 4, 9926–9934
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
128.8, 128.4, 128.0, 127.8, 127.4, 127.2, 125.8, 82.4, 82.1, 46.7, DMSO-d6): d ¼ 189.1, 169.8, 160.0, 142.2, 140.1, 137.4, 136.7,
46.2, 45.2, 43.4, 42.8, 36.3; HRMS (ESI-TOF): m/z calcd for 133.1, 132.4, 131.5, 129.2, 128.5, 128.0, 127.2, 125.9, 82.4, 82.0,
C
29H26Cl2N3O3 [(M + H)+], 534.1346; found, 534.1351.
46.7, 46.2, 45.2, 43.4, 42.7, 36.4, 21.2; HRMS (ESI-TOF): m/z
5-Benzoyl-2-benzyl-4-(4-chlorophenyl)-9a-hydroxy-2,3,3a,4,6, calcd for C30H28Cl2N3O3 [(M + H)+], 548.1502; found, 548.1500.
2-Benzyl-4-(4-chlorophenyl)-9a-hydroxy-5-(4-methylbenzoyl)-
7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one
(4o). White solid; Mp 216–219 ꢀC; IR (KBr): 3432, 1704, 1598, 2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-
1511, 1281, 1012, 694 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d ¼ pyridin-1-one (4s). White solid; Mp 228–230 ꢀC; IR (KBr): 3312,
9.56 (br, 1H, NH), 7.35–7.38 (m, 2H, ArH), 7.29–7.33 (m, 1H, 1703, 1595, 1512, 1215, 837, 580 cmꢁ1 1H NMR (400 MHz,
;
ArH), 7.10–7.24 (m, 7H, ArH), 7.00–7.04 (m, 2H, ArH), 6.83–6.87 DMSO-d6): d ¼ 9.58 (br, 1H, NH), 7.35–7.39 (m, 2H, ArH), 7.28–
(m, 2H, ArH), 6.41 (br, 1H, OH), 4.41 (AB, J ¼ 14.8 Hz, 2H, 7.32 (m, 1H, ArH), 7.18–7.24 (m, 4H, ArH), 7.05 (d, J ¼ 7.9 Hz,
ArCH2), 3.72–3.74 (m, 1H, CH), 3.68–3.72 (m, 2H, CH2), 3.59– 2H, ArH), 6.95 (d, J ¼ 7.4 Hz, 2H, ArH), 6.77 (d, J ¼ 7.4 Hz, 2H,
3.63 (m, 1H, CH2), 3.46–3.50 (m, 1H, NCH2), 3.05 (t, J ¼ 8.7 Hz, ArH), 6.37 (br, 1H, OH), 4.41 (AB, J ¼ 15.3 Hz, 2H, ArCH2), 3.74–
1H, NCH2), 2.75–2.83 (m, 1H, NCH2); 13C NMR (100 MHz, 3.78 (m, 1H, CH), 3.65–3.71 (m, 2H, CH2), 3.56–3.60 (m, 1H,
DMSO-d6): d ¼ 189.1, 170.0, 159.8, 145.5, 143.1, 136.8, 130.4, CH2), 3.46–3.50 (m, 1H, NCH2), 3.35–3.39 (m, 1H, CH), 3.03 (t,
130.1, 129.2, 128.0, 128.0, 128.0, 126.3, 82.9, 82.7, 47.5, 47.0, J ¼ 9.5 Hz, 1H, NCH2), 2.78–2.83 (m, 1H, NCH2), 2.21 (s, 3H,
46.2, 43.4, 42.6, 39.1; HRMS (ESI-TOF): m/z calcd for CH3); 13C NMR (100 MHz, DMSO-d6): d ¼ 189.1, 170.0, 159.9,
C
29H27ClN3O3 [(M + H)+], 500.1735; found, 500.1735.
145.5, 140.3, 137.4, 136.8, 130.4, 130.1, 129.2, 128.5, 128.0,
5-Benzoyl-2-benzyl-9a-hydroxy-4-phenyl-2,3,3a,4,6,7,8,9a- 128.0, 126.4, 82.8, 82.7, 47.6, 47.0, 46.1, 43.4, 42.6, 39.1, 21.2;
octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one (4p). White HRMS (ESI-TOF): m/z calcd for C30H29ClN3O3 [(M + H)+],
solid; Mp 202–205 ꢀC; IR (KBr): 3324, 1702, 1597, 1513, 1277, 1009, 514.1892; found, 514.1890.
1
698 cmꢁ1; H NMR (500 MHz, DMSO-d6): d ¼ 9.60 (br, 1H, NH),
2-Benzyl-9a-hydroxy-5-(4-methylbenzoyl)-4-phenyl-2,3,3a,4,
7.36–7.40 (m, 2H, ArH), 7.29–7.34 (m, 2H, ArH), 7.22–7.26 (m, 2H, 6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one
ArH), 7.10–7.20 (m, 5H, ArH), 7.04–7.09 (m, 1H, ArH), 7.01 (d, J ¼ (4t). White solid; Mp 213–216 ꢀC; IR (KBr): 3335, 1704, 1597,
7.5 Hz, 2H, ArH), 6.85 (d, J ¼ 7.5 Hz, 2H, ArH), 6.36 (br, 1H, OH), 1514, 1279, 907, 698 cmꢁ1; H NMR (400 MHz, DMSO-d6): d ¼
1
4.42 (AB, J ¼ 12.1 Hz, 2H, ArCH2), 3.73–3.77 (m, 1H, CH), 3.68–3.74 9.61 (br, 1H, NH), 7.35–7.40 (m, 2H, ArH), 7.25–7.29 (m, 1H,
(m, 2H, CH2), 3.58–3.65 (m, 1H, CH2), 3.38–3.53 (m, 1H, NCH2), ArH), 7.10–7.25 (m, 4H, ArH), 7.02–7.08 (m, 3H, ArH), 6.92 (d,
3.32–3.36 (m, 1H, CH), 3.07 (t, J ¼ 9.6 Hz, 1H, NCH2), 2.81–2.85 (m, J ¼ 7.6 Hz, 2H, ArH), 6.76 (d, J ¼ 7.6 Hz, 2H, ArH), 6.30 (br, 1H,
1H, NCH2); 13C NMR (125 MHz, DMSO-d6): d ¼ 189.5, 170.5, 160.4; OH), 4.41 (s, 2H, ArCH2), 3.73–3.77 (m, 1H, CH), 3.62–3.68 (m,
146.8, 143.7, 137.2, 129.6, 129.2, 128.7, 128.4, 128.4, 128.3; 126.8, 2H, CH2), 3.57–3.61 (m, 1H, CH), 3.48–3.52 (m, 1H, NCH2), 3.04
126.3, 83.7, 83.1, 48.0, 47.6, 46.6, 43.8, 43.1, 40.4; HRMS (ESI-TOF): (t, J ¼ 9.5 Hz, 1H, NCH2), 2.82–2.88 (m, 1H, NCH2), 2.20 (s, 3H,
m/z calcd for C29H28N3O3 [(M + H)+], 466.2125; found,466.2132.
CH3); 13C NMR (100 MHz, DMSO-d6): d ¼ 189.0, 170.1, 160.0;
5-Benzoyl-2-benzyl-9a-hydroxy-4-(4-methoxyphenyl)-2,3,3a,4, 146.5, 140.4, 137.3, 136.8, 129.2, 128.8, 128.4, 128.3; 128.1,
6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one 128.0; 127.8; 126.5; 126.0, 83.2, 82.7, 47.7, 47.1, 46.1, 43.4, 42.6,
ꢀ
(4q). White solid; Mp 217–220 C; IR (KBr): 3431, 1698, 1598, 39.3, 21.2; HRMS (ESI-TOF): m/z calcd for C30H30N3O3 [(M +
1511, 1245, 1021, 702 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d ¼ H)+], 480.2287; found, 480.2287.
9.59 (br, 1H, NH), 7.35–3.40 (m, 2H, ArH), 7.28–7.32 (m, 1H,
2-Benzyl-9a-hydroxy-4-(4-methoxyphenyl)-5-(4-methylbenzoyl)-
ArH), 7.16–7.22 (m, 3H, ArH), 7.11–7.15 (m, 2H, ArH), 6.92 (d, 2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]-
J ¼ 8.4 Hz, 2H, ArH), 6.86 (d, J ¼ 7.2 Hz, 2H, ArH), 6.71 (d, J ¼ 8.4 pyridin-1-one (4u). White solid; Mp 222–225 ꢀC; IR (KBr): 3416,
Hz, 2H, ArH), 6.32 (br, 1H, OH), 4.41 (s, 2H, ArCH2), 3.75 (d, J ¼ 1700, 1598, 1510, 1246, 1022, 758 cmꢁ1
;
1H NMR (400 MHz,
8.8 Hz, 1H, CH), 3.69–3.74 (m, 2H, CH2), 3.66 (s, 3H, OCH3), DMSO-d6): d ¼ 9.60 (br, 1H, NH), 7.35–7.40 (m, 2H, ArH), 7.29–
3.57–3.61 (m, 1H, CH), 3.51 (t, J ¼ 6.9 Hz, 1H, CH2), 3.04 (t, J ¼ 7.33 (m, 1H, ArH), 7.20 (d, J ¼ 7.1 Hz, 2H, ArH), 6.91–6.97 (m,
9.6 Hz, 1H, NCH2), 2.77–2.83 (m, 1H, NCH2); 13C NMR (100 4H, ArH), 6.79 (d, J ¼ 7.9 Hz, 2H, ArH), 6.73 (d, J ¼ 8.6 Hz, 2H,
MHz, DMSO-d6): d ¼ 189.0, 170.1, 160.7; 157.5, 143.3, 138.3, ArH), 6.26 (br, 1H, OH), 4.40 (s, 2H, ArCH2), 3.65–3.69 (m, 1H,
136.8, 129.2, 129.2, 128.0, 127.9, 126.4, 113.4; 83.6, 82.8, 55.3, CH), 3.61–3.67 (m, 2H, CH2), 3.63 (s, 3H, OCH3), 3.57–3.61 (m,
47.8, 47.1, 46.2, 43.4, 42.6, 38.9; HRMS (ESI-TOF): m/z calcd for 1H, CH), 3.48–3.52 (m, 1H, CH2), 3.02 (t, J ¼ 9.5 Hz, 1H, NCH2),
C
30H30N3O4 [(M + H)+], 496.2231; found, 496.2239.
2.80–2.84 (m, 1H, NCH2), 2.21 (s, 3H, CH3); 13C NMR (100 MHz,
2-Benzyl-4-(2,4-dichlorophenyl)-9a-hydroxy-5-(4-methylbenzoyl)- DMSO-d6): d ¼ 189.0, 170.2, 160.7, 157.5, 140.5, 138.3, 137.3,
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]- 136.8, 129.2, 129.2, 128.4, 128.0, 126.5, 113.5, 83.5, 82.8, 55.3,
ꢀ
pyridin-1-one (4r). White solid; Mp 234–237 C; IR (KBr): 3788, 47.8, 47.1, 46.1, 43.4, 42.6, 38.9, 21.2; HRMS (ESI-TOF): m/z
3427, 1699, 1638, 1253, 1168, 735, 657 cmꢁ1; 1H NMR (400 MHz, calcd for C31H32N3O4 [(M + H)+], 510.2387; found, 510.2398.
DMSO-d6): d ¼ 9.58 (br, 1H, NH), 7.43 (s, 1H, ArH), 7.32–7.39 (m,
2-Benzyl-4-(2,4-dichlorophenyl)-9a-hydroxy-5-(4-methoxy-
4H, ArH), 7.20–7.25 (m, 3H, ArH), 6.96 (d, J ¼ 7.0 Hz, 2H, ArH), benzoyl)-2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo-
6.70 (d, J ¼ 7.0 Hz, 2H, ArH), 6.50 (br, 1H, OH), 4.51 (AB, J ¼ 14.7 [3,4-e]pyridin-1-one (4v). White solid; Mp 229–231 ꢀC; IR (KBr):
Hz, 2H, ArCH2), 4.03–4.07 (m, 1H, CH), 3.70–3.78 (m, 2H, CH2), 3419, 1703, 1598, 1509, 1250, 838, 749 cmꢁ1; 1H NMR (400 MHz,
3.62 (d, J ¼ 7.5 Hz, 1H, CH), 3.48 (d, J ¼ 5.4 Hz, 1H, NCH2), 3.31 DMSO-d6): d ¼ 9.54 (br, 1H, NH), 8.29 (br, 1H, OH), 7.41 (s, 1H,
(d, J ¼ 7.9 Hz, 1H, NCH2), 3.05 (t, J ¼ 9.4 Hz, 1H, NCH2), 2.68– ArH), 7.26–7.37 (m, 4H, ArH), 7.15–7.18 (m, 3H, ArH), 6.76
3.73 (m, 1H, NCH2), 2.23 (s, 3H, CH3); 13C NMR (100 MHz, (d, J ¼ 8.6 Hz, 2H, ArH), 6.66 (d, J ¼ 8.6 Hz, 2H, ArH), 4.44 (AB,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 9926–9934 | 9931

View Article Online
RSC Advances
Paper
J ¼ 15.0 Hz, 1H, ArCH2), 4.05–4.09 (m, 1H, CH), 3.67–3.71 (m, 1703, 1595, 1545, 1237, 841, 541 cmꢁ1
;
1H NMR (400 MHz,
2H, CH2), 3.64 (s, 3H, OCH3), 3.55–3.59 (m, 1H, CH), 3.43–3.47 DMSO-d6): d ¼ 12.55 (br, 1H, NH), 7.17–7.40 (m, 8H, ArH), 6.90–
(m, 1H, NCH2), 3.26–3.30 (m, 1H, NCH2), 2.98–3.02 (m, 1H, 6.96 (m, 2H, ArH), 6.68–6.74 (m, 2H, ArH), 6.46 (br, 1H, OH),
NCH2), 2.64–2.68 (m, 1H, NCH2); 13C NMR (100 MHz, DMSO- 4.47 (d, J ¼ 14.7 Hz, 1H, ArCH2), 4.33 (d, J ¼ 14.7 Hz, 1H, ArCH2),
d6): d ¼ 188.6, 169.8, 160.1, 159.3, 142.2, 136.7, 135.3, 133.1, 3.79–3.83 (m, 1H, CH), 3.41–3.54 (m, 2H, CH2), 3.24–3.28 (m,
132.3, 131.5, 129.2, 128.6, 128.6, 128.0, 127.6, 127.3, 113.3, 82.4, 1H, CH), 3.12–3.18 (m, 1H, NCH2), 2.64–2.72 (m, 1H, NCH2),
82.0, 55.5, 46.7, 46.2, 45.3, 43.4, 42.7, 36.5; HRMS (ESI-TOF): m/z 1.79–1.99 (m, 2H, NCH2); 13C NMR (100 MHz, DMSO-d6): d ¼
calcd for C30H28Cl2N3O4 [(M + Na)+], 586.1271; found, 586.1270. 185.8, 169.8, 157.5, 141.8, 139.8, 136.7, 133.0, 132.7, 131.5,
2-Benzyl-4-(4-chlorophenyl)-9a-hydroxy-5-(4-methoxybenzoyl)- 129.2, 128.8, 128.5, 128.0, 127.8, 127.4, 115.1 (d, J ¼ 22.0 Hz),
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo-[3,4-e]- 114.9 (d, J ¼ 22.0 Hz), 83.9, 83.2, 46.5, 46.3, 44.4, 40.6, 40.4, 38.5,
pyridin-1-one (4w). White solid; Mp 230–232 ꢀC; IR (KBr): 3420, 36.4, 20.7; HRMS (ESI-TOF): m/z calcd for C30H27Cl2FN3O3 [(M +
1705, 1597, 1510, 1249, 1017, 649 cmꢁ1 1H NMR (400 MHz, H)+], 566.1408; found, 566.1412.
;
DMSO-d6): d ¼ 9.59 (br, 1H, NH), 7.35–7.40 (m, 2H, ArH), 7.28–
2-Benzyl-5-(4-chlorobenzoyl)-4-(2,4-dichlorophenyl)-10a-hydroxy-
7.33 (m, 1H, ArH), 7.19–7.24 (m, 4H, ArH), 7.08 (d, J ¼ 8.1 Hz, 2,3,3a,4,6,7,8,9-octahydropyrrolo[30,40:5,6]pyrido-[1,2-a]pyrimidin-
ꢀ
2H, ArH), 6.86 (d, J ¼ 8.2 Hz, 2H, ArH), 6.69 (d, J ¼ 8.2 Hz, 2H, 1(10aH)-one (5b). White solid; Mp 193–196 C; IR (KBr): 3402,
ArH), 6.36 (br, 1H, OH), 4.41 (AB, J ¼ 15.1 Hz, 2H, ArCH2), 3.81– 1703, 1593, 1547, 1244, 842, 517 cmꢁ1
;
1H NMR (400 MHz,
3.84 (m, 1H, CH), 3.72 (s, 3H, OCH3), 3.67–3.71 (m, 2H, CH2), CDCl3-d6): d ¼ 12.61 (br, 1H, NH), 7.25–7.29 (m, 3H, ArH),
3.56–3.60 (m, 1H, CH), 3.46–3.50 (m, 1H, NCH2), 3.03 (t, J ¼ 4.8 7.17–7.21 (m, 1H, ArH), 7.12–7.16 (m, 2H, ArH), 7.05–7.11 (m,
Hz, 1H, NCH2), 2.79–2.84 (m, 1H, NCH2); 13C NMR (100 MHz, 2H, ArH), 7.03 (d, J ¼ 8.1 Hz, 2H, ArH), 6.65 (d, J ¼ 8.1 Hz,
DMSO-d6): d ¼ 188.5, 170.0, 159.9, 159.3, 145.5, 136.8, 135.5, 2H, ArH), 4.35 (s, 2H, ArCH2), 4.09 (s, 1H, CH), 3.82 (br, 1H,
130.4, 130.1, 129.2, 128.1, 128.0, 128.1, 113.2, 82.8, 82.7, 55.4, OH), 3.31–3.44 (m, 4H, CH2), 3.09–3.18 (m, 2H, CH2), 2.78 (t,
47.6, 47.0, 46.1, 43.4, 42.6, 39.1; HRMS (ESI-TOF): m/z calcd for J ¼ 8.4 Hz, 1H, CH), 1.79–1.92 (m, 2H, NCH2); 13C NMR (100
C
30H29ClN3O4 [(M + H)+], 530.1841; found, 530.1840.
2-Benzyl-9a-hydroxy-5-(4-methoxybenzoyl)-4-phenyl-2,3,3a,4, 133.6, 133.3, 132.8, 131.1, 129.1, 128.3, 128.1, 127.9, 127.1,
MHz, CDCl3-d6): d ¼ 186.6, 169.7, 157.5, 140.6, 140.3, 134.9,
6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-1-one 127.0, 84.3, 82.9, 47.2, 46.7, 44.7, 39.8, 38.6, 36.1, 20.7; HRMS
(4x). White solid; Mp 192–194 ꢀC; IR (KBr): 3328, 1705, 1594, (ESI-TOF): m/z calcd for C30H27Cl3N3O3 [(M + H)+], 582.1113;
1
1247, 1023 694, 576 cmꢁ1; H NMR (400 MHz, DMSO-d6): d ¼ found, 582.1112.
9.62 (br, 1H, NH), 7.35–3.40 (m, 2H, ArH), 7.28–7.32 (m, 1H,
5-Benzoyl-2-benzyl-4-(2,4-dichlorophenyl)-10a-hydroxy-2,3,
ArH), 7.15–7.22 (m, 4H, ArH), 7.05–7.08 (m, 3H, ArH), 6.86 (d, 3a,4,6,7,8,9-octahydropyrrolo[30,40:5,6]pyrido[1,2-a]pyrimidin-
ꢀ
J ¼ 8.1 Hz, 2H, ArH), 6.67 (d, J ¼ 8.1 Hz, 2H, ArH), 6.28 (br, 1H, 1(10aH)-one (5c). White solid; Mp 188–190 C; IR (KBr): 3456,
OH), 4.41 (s, 2H, ArCH2), 3.80–3.84 (m, 1H, CH), 3.69–3.75 (m, 1703, 1598, 1544, 1049, 700, 459 cmꢁ1 1H NMR (400 MHz,
;
2H, CH2), 3.67 (s, 3H, OCH3), 3.56–3.60 (m, 1H, CH), 3.49–3.53 DMSO-d6): d ¼ 12.61 (br, 1H, NH), 7.33–7.41 (m, 5H, ArH), 7.09–
(m, 1H, NCH2), 3.43–3.47 (m, 1H, NCH2), 3.05 (t, J ¼ 9.4 Hz, 1H, 7.31 (m, 6H, ArH), 6.65–6.61 (m, 2H, ArH), 6.44 (br, 1H, OH),
NCH2), 2.84–2.89 (m, 1H, NCH2); 13C NMR (100 MHz, DMSO- 4.48 (d, J ¼ 14.9 Hz, 1H, ArCH2), 4.34 (AB, J ¼ 15.0 Hz, 2H,
d6): d ¼ 188.5, 170.1, 160.1; 159.3, 146.5, 136.8, 135.6, 129.2, ArCH2), 3.55–3.61 (m, 2H, CH2), 3.44–3.51 (m, 2H, CH2), 3.25–
128.3, 128.2, 128.2, 128.0, 126.0, 113.1, 83.2, 82.7, 55.4, 47.7, 3.29 (m, 1H, CH), 3.14–3.18 (m, 1H, NCH2), 2.70–2.76 (m, 1H,
47.2, 46.1, 43.4, 42.6, 39.4; HRMS (ESI-TOF): m/z calcd for NCH2), 1.90–1.96 (m, 2H, NCH2); 13C NMR (100 MHz, DMSO-
C
30H30N3O4 [(M + H)+], 496.2231; found, 496.2239.
2-Benzyl-9a-hydroxy-5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)- 131.4; 129.2, 128.4, 128.1, 128.0, 127.6, 127.3, 125.6, 83.8, 83.3,
d6): d ¼ 186.9, 169.9, 157.6, 143.3, 141.9, 136.7, 133.1, 132.6,
2,3,3a,4,6,7,8,9a-octahydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]- 46.5, 46.3, 44.5, 40.6, 38.5, 36.5, 20.8; HRMS (ESI-TOF): m/z
pyridin-1-one (4y). White solid; Mp 216–219 ꢀC; IR (KBr): 3431, calcd for C30H28Cl2N3O3 [(M + H)+], 548.1502; found, 548.1501.
1698, 1599, 1510, 1246, 833, 408 cmꢁ1
;
1H NMR (400 MHz,
2-Benzyl-4-(2,4-dichlorophenyl)-10a-hydroxy-5-(4-methyl-
DMSO-d6): d ¼ 9.62 (br, 1H, NH), 7.35–7.40 (m, 2H, ArH), 7.28– benzoyl)-2,3,3a,4,6,7,8,9-octahydropyrrolo[30,40:5,6]pyrido-[1,2-a]-
7.32 (m, 1H, ArH), 7.20 (d, J ¼ 7.4 Hz, 2H, ArH), 6.97 (d, J ¼ 8.4 pyrimidin-1(10aH)-one (5d). White solid; Mp 195–197 ꢀC; IR
Hz, 2H, ArH), 6.88 (d, J ¼ 8.4 Hz, 2H, ArH), 6.74 (d, J ¼ 8.4 Hz, (KBr): 3422, 1702, 1545, 1247, 1123, 761, 703 cmꢁ1
;
1H NMR
2H, ArH), 6.68 (d, J ¼ 8.4 Hz, 2H, ArH), 6.25 (br, 1H, OH), 4.40 (s, (400 MHz, DMSO-d6): d ¼ 12.72 (br, 1H, NH), 7.39–7.45 (m, 4H,
2H, ArCH2), 3.74–3.78 (m, 1H, CH), 3.69 (s, 3H, OCH3), 3.65– ArH), 7.35–7.39 (m, 1H, ArH), 7.31–7.35 (m, 1H, ArH), 7.22–
3.69 (m, 2H, CH2), 3.66 (s, 3H, OCH3), 3.61–3.65 (m, 1H, CH), 7.28 (m, 2H, ArH), 6.95 (d, J ¼ 7.8 Hz, 2H, ArH), 6.62 (d, J ¼ 7.8
3.55–3.59 (m, 1H, CH2), 3.48–3.52 (m, 1H, CH2), 3.02 (t, J ¼ 9.5 Hz, 2H, ArH), 4.43 (AB, J ¼ 15.0 Hz, 2H, ArCH2), 3.88–3.92 (m,
Hz, 1H, NCH2), 2.81–2.86 (m, 1H, NCH2); 13C NMR (100 MHz, 1H, CH), 3.82 (br, 1H, OH), 3.59–3.64 (m, 4H, CH2), 3.27–3.31
DMSO-d6): d ¼ 188.4, 170.2, 160.0, 159.3, 157.5, 138.4, 136.8, (m, 1H, CH), 3.13–3.17 (m, 1H, CH2), 2.76 (t, J ¼ 8.8 Hz, 1H,
135.6, 129.2, 128.2, 128.0, 113.5, 113.1, 83.5, 82.8, 55.4, 55.3, CH2), 1.22 (s, 3H, CH3), 1.83–1.93 (m, 2H, NCH2); 13C NMR
47.9, 47.1, 46.1, 43.4, 42.6, 39.0; HRMS (ESI-TOF): m/z calcd for (100 MHz, DMSO-d6): d ¼ 186.9, 169.9, 157.6, 142.0, 140.5,
C
31H32N3O5 [(M + H)+], 526.2336; found, 526.2344.
136.8, 136.7, 133.1, 132.6, 131.4, 129.2, 128.6, 128.0, 127.3,
2-Benzyl-4-(2,4-dichlorophenyl)-5-(4-uorobenzoyl)-10a-hydroxy- 125.6, 83.8, 83.3, 46.5, 46.3, 44.5, 39.3, 38.5, 36.6, 21.2, 20.8;
2,3,3a,4,6,7,8,9-octahydropyrrolo[30,40:5,6]pyrido-[1,2-a]pyrimidin- HRMS (ESI-TOF): m/z calcd for C31H30Cl2N3O3 [(M + H)+],
ꢀ
1(10aH)-one (5a). White solid; Mp 187–190 C; IR (KBr): 3403, 562.1659; found, 561.1663.
9932 | RSC Adv., 2014, 4, 9926–9934
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
13 K. Mizushige, T. Ueda, K. Yukiiri and H. Suzuki, Cardiovasc.
Drug Rev., 2002, 20, 163.
2-Benzyl-4-(2,4-dichlorophenyl)-10a-hydroxy-5-(4-methoxy-
benzoyl)-2,3,3a,4,6,7,8,9-octahydropyrrolo[30,40:5,6]pyrido[1,2-a]-
pyrimidin-1(10aH)-one (5e). White solid; Mp 179–182 ꢀC; IR
14 Y. Abe, H. Kayakiri, S. Satoh, T. Inoue, Y. Sawada,
N. Inamura, M. Asano, I. Aramori, C. Hatori, H. Sawai,
T. Oku and H. Tanaka, J. Med. Chem., 1998, 41, 4587.
15 R. J. Boerner and H. J. Moller, Psychopharmakotherapie, 1997,
4, 145.
16 R.-L. Yan, H. Yan, C. Ma, Z.-Y. Ren, X.-A. Gao, G.-S. Huang
and Y.-M. Liang, J. Org. Chem., 2012, 77, 2024.
17 H. Kakeya, I. Takahashi, G. Okada and H. J. Osada,
J. Antibiot., 1995, 48, 733.
18 T. Agatsuma, T. Akama, S. Nara, S. Matsumiya, R. Nakai,
H. Ogawa, S. Otaki, S. I. Ikeda, Y. Saitoh and Y. Kanda,
Org. Lett., 2002, 4, 4387.
19 (a) J. G. Greger, S. J. P. Yoon-Miller, N. R. Bechtold,
S. A. Flewelling, J. P. Macdonald, C. R. Downey,
E. A. Cohen and E. T. Pelkey, J. Org. Chem., 2011, 76, 8203;
(b) S. E. Boiadjiev and D. A. Lightner, J. Org. Chem., 1998,
63, 6220; (c) M. Hosseini, H. Kringelum, A. Murray and
J. E. Tønder, Org. Lett., 2006, 8, 2103.
1
(KBr): 3408, 1700, 1596, 1544, 1244, 1041, 702 cmꢁ1; H NMR
(400 MHz, DMSO-d6): d ¼ 12.75 (br, 1H, NH), 7.43 (s, 1H, ArH),
7.35–7.40 (m, 2H, ArH), 7.31–7.34 (m, 1H, ArH), 7.29–7.33 (m,
1H, ArH), 7.21–7.25 (m, 2H, ArH), 6.67–6.73 (m, 4H, ArH), 6.62
(br, 1H, OH), 4.34 (AB, J ¼ 14.9 Hz, 2H, ArCH2), 3.92–3.95 (m,
1H, CH), 3.64 (s, 3H, OCH3), 3.42–3.49 (m, 2H, CH2), 3.26–3.30
(m, 1H, CH), 3.10–3.19 (m, 1H, CH2), 2.76 (t, J ¼ 8.8 Hz, 1H,
CH2), 1.80–1.90 (m, 2H, NCH2), 1.83–1.93 (m, 2H, CH2); 13C
NMR (100 MHz, DMSO-d6): d ¼ 186.2, 169.6, 158.5, 157.4, 141.7,
136.4, 135.5, 132.8, 132.3, 131.1; 128.9, 128.2, 127.7, 127.0,
126.9, 113.1, 83.5, 82.9, 55.1, 46.2, 46.0, 44.2, 40.2, 38.2, 36.4,
20.5; HRMS (ESI-TOF): m/z calcd for C31H30Cl2N3O4 [(M + H)+],
578.1608; found, 578.1615.
Acknowledgements
We gratefully acknowledge the nancial support from the
Natural Science Foundation of China (no. 81160384, 21162037,
21262042, U1202221 and 21362042) and the Talent Found in
Yunnan Province (2012HB001).
20 Z.-Q. Feng, F.-M. Chu, Z.-R. Guo and P.-Y. Sun, Bioorg. Med.
Chem. Lett., 2009, 19, 2270.
´
21 J. Bosch, T. Roca, J. L. Catena, O. Liorens, J. J. Perez,
´
´
C. Lagunas, A. G. Fernandez, I. Miquel, A. Fernandez-
Serratc and C. Farrerons, Bioorg. Med. Chem. Lett., 2000,
10, 1745.
Notes and references
¨
1 (a) E. N. Smirnova, T. V. Onschenskaya, V. P. Zvolinskii and 22 C. Peifer, R. Selig, K. Kinkel, D. Ott, F. Totzke, C. Schachtele,
¨
D. L. Nende, Fiz. Khim. Poverkhn., 1988, 65; (b) J. S. Bae,
D. W. Lee, D. H. Lee and D.-S. Jeong, WO 2007011163A1,
2007, Chem. Abstr., 2007, 146, 193485.
R. Heidenreich, M. Rocken, D. Schollmeyer and S. Laufer,
J. Med. Chem., 2008, 51, 3814.
23 G. Martiny-Baron, M. G. Kazanietz, H. Mischak,
´
2 W.-W. Zhang, Y.-B. Chen, W.-D. Chen, Z.-W. Liu and Z. Li,
J. Agric. Food Chem., 2010, 58, 6296.
P. M. Blumberg, G. Kochs, H. Hug, D. Marme and
C. Schachtele, J. Biol. Chem., 1993, 268, 9194.
3 G. C. Mroski, L. D. Markley, P. H. Hipskind, H. Boshoff, 24 J. Paeshuyes, J. M. Chezl, M. Froeyen, P. Leyssen,
S. Cho, S. G. Frabzblau and M. J. Millr, ACS Med. Chem.
Lett., 2011, 2, 466.
4 K. S. Gudmundsson, J. D. Williams, J. C. Drach and
L. B. Townsend, J. Med. Chem., 2003, 46, 1449.
H. Dutartre, R. Vrancken, B. Canard, C. Letellier, T. Li,
H. Mittendorfer, F. Koenen, P. Kerkhofs, E. Declercq,
P. Herdewijn, G. Puerstinger, A. Gueiffier, O. Chavignon,
J. C. Teulade and J. Neyts, J. Virol., 2007, 81, 11046.
5 M. A. Ismail, R. Brun, T. Wenzler, F. A. Tanious, W. D. Wilson 25 (a) J. Kempson, J.-Q. Guo, J. Das, R. V. Moquin, S. H. Spergel,
and D. W. Boykin, J. Med. Chem., 2004, 47, 3658.
6 Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull., 1992,
40, 1170.
7 J. J. Kaminsky and A. M. Doweyko, J. Med. Chem., 1997, 40,
427.
8 K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth,
D. E. Cavender, G. C. Olini, B. Fahmy and J. J. Siekierka,
Bioorg. Med. Chem. Lett., 2003, 13, 347.
S. H. Watterson, C. M. Langevine, A. J. Dyckman, M. Pattoli,
J. R. Burke, X.-X. Yang, K. M. Gillooly, K. W. McIntyre,
L. Chen, J. H. Dodd, M. McKinnon, J. C. Barrish and
W. J. Pitts, Bioorg. Med. Chem. Lett., 2009, 19, 2646; (b)
S. H. Watterson, C. M. Langevine, K. V. Kirk, J. Kempson,
J.-Q. Guo, S. H. Spergel, J. Das, R. V. Moquin,
A. J. Dyckman, D. Nirschl, K. Gregor, M. A. Pattoli,
X.-X. Yang, K. W. McIntyre, G.-C. Yang, M. A. Galella,
H. Booth-Lute, L. Chen, Z. Yang, D. Wang-Iverson,
M. McKinnon, J. H. Dodd, J. C. Barrish, J. R. Burke and
W. J. Pitts, Bioorg. Med. Chem. Lett., 2011, 21, 7006.
¨
9 Z.-P. Zhang, M.-P. Kung, A. Wilson, C. W. Lee, K. Plossl,
C. Hou, D. M. Holtzman and H. F. Kung, J. Med. Chem.,
2003, 46, 237.
10 C. Hamdouchi, B. Zhong, J. Mendoza, E. Collins, 26 J. J. Kulagowski, W. Blair, R. J. Bull, C. Chang, G. Deshmukh,
C. Jaramillo, J. E. De Diego, D. Robertson, C. D. Spencer,
B. D. Anderson, S. A. Watkins, F. Zhanga and H. B. Brooks,
Bioorg. Med. Chem. Lett., 2005, 15, 1943.
H. J. Dyke, C. Eigenbrot, N. Ghilardi, P. Gibbons,
T. K. Harrison, P. R. Hewitt, M. Liimatta, C. A. Hurley,
A. Johnson, T. Johnson, J. R. Kenny, P. B. Kohli,
R. J. Maxey, R. Mendonca, K. Mortara, J. Murray,
R. Narukulla, S. Shia, M. Steffek, S. Ubhayakar, M. Ultsch,
A. V. Abbema, S. I. Ward, B. Waszkowycz and M. Zak,
J. Med. Chem., 2012, 55, 5901.
11 Y. Abe, H. Kayakiri, S. Satoh, T. Inoue, Y. Sawada, K. Imai,
N. Inamura, M. Asano, C. Hatori, A. Katayama, T. Oku and
H. J. Tanaka, J. Med. Chem., 1998, 41, 564.
12 T. S. Harrison and G. M. Keating, CNS Drugs, 2005, 19, 65.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 9926–9934 | 9933

View Article Online
RSC Advances
Paper
27 (a) V. Gaumet, E. Moreau, A. Taleb, F. Leal, J. Neyts, 32 M. M. Abdelhalim, M. M. T. El-Saidi, S. T. Rabie and
J. Paeshuyse, C. Lartigue, O. Chavignon, A. Gueiffier, G. A. Elmegeed, Steroids, 2007, 72, 459.
J. C. Teulade, J. Metin and J. M. Chezal, Tetrahedron Lett., 33 (a) F.-C. Yu, S.-J. Yan, L. Hu, Y.-C. Wang and J. Lin, Org. Lett.,
´
2010, 51, 6082; (b) J. M. Chezal, E. Moreau, G. Delmas,
A. Gueiffier, Y. Blache, G. Grassy, C. Lartigue,
O. Chavignon and J. C. Teulade, J. Org. Chem., 2001, 66, 6576.
28 (a) C. Huang, S.-J. Yan, X.-H. Zeng, X.-Y. Dai, Y. Zhang,
2011, 13, 4782; (b) S.-J. Yan, Y.-L. Chen, L. Liu, N.-Q. He and
J. Lin, Green Chem., 2010, 12, 2043; (c) S.-J. Yan, Y.-L. Chen,
L. Liu, Y.-J. Tang and J. Lin, Tetrahedron Lett., 2011, 52, 465; (d)
S.-J. Yan, Y.-F. Niu, R. Huang and J. Lin, Synlett, 2009, 17, 2821.
C. Qing and J. Lin, Eur. J. Med. Chem., 2011, 46, 1172; (b) 34 (a) L.-R. Wen, Z.-R. Li, M. Li and H. Cao, Green Chem., 2012,
S.-J. Yan, Y.-J. Liu, Y.-L. Chen, L. Liu and J. Lin, Bioorg.
Med. Chem. Lett., 2010, 20, 5225.
29 (a) C. H. Tieman and W. D. Kollmeyer, US Pat. 3,948,934,
14, 707; (b) L.-R. Wen, C.-Y. Jiang, M. Li and L.-J. Wang,
Tetrahedron, 2011, 67, 293; (c) F.-C. Yu, R. Huang, H.-C. Ni,
J. Fan, S.-J. Yan and J. Lin, Green Chem., 2013, 15, 453.
1976, Chem. Abstr., 1976, 85, 46680; (b) P. E. Porter and 35 ESI.†
W. D. Kollmeyer, US Pat. 4,053,623, 1977, Chem. Abstr., 36 J.-H. Zhang, M.-X. Wang and Z.-T. Huang, J. Chem. Soc.,
1978, 88, 37796.
Perkin Trans. 1, 1999, 2087.
30 B. E. Maryanoff, W. Ho, D. F. McComsey, A. B. Reitz, 37 (a) Z.-T. Huang and M.-X. Wang, Synthesis, 1992, 1273; (b)
P. P. Grow, S. O. Nortey, R. P. Shank, B. Dubinsky,
R. J. Taylor and J. F. Gardocki, J. Med. Chem., 1995, 38, 16.
31 S. N. Suryawanshi, S. Pandey, B. A. Bhatt and S. Gupta, Eur. J.
Med. Chem., 2007, 42, 511.
Z.-J. Li and D. Charles, Synth. Commun., 2001, 31, 527; (c)
X.-B. Chen, X.-M. Liu, R. Huang, S.-J. Yan and J. Lin, Eur. J.
Org. Chem., 2013, 4607.
38 P. L. Southwick and E. F. Barnas, J. Org. Chem., 1962, 27, 98.
9934 | RSC Adv., 2014, 4, 9926–9934
This journal is © The Royal Society of Chemistry 2014