Synthesis and biological evaluation of XB-1 analogues as novel histamine H3 receptor antagonists and neuroprotective agents

Article abstract of DOI:10.1039/c3ra46392c

A novel class of H₃ receptor antagonists, XB-1 analogues based on benzophenone or oxydibenzene scaffolds were synthesized, and their biological activities were evaluated to determine their in vitro neuroprotective effects against Aβ_25-35-induced damage in primary cortical neurons and against glutamate-induced neuronal injury in primary cerebellar granule neurons. The results indicated that all of the tested analogues displayed neuroprotective activity at 0.1 μM or 1 μM. These findings may provide new insights into the development of novel promising H₃ receptor antagonists with potential neuroprotective activity.

Full text of DOI:10.1039/c3ra46392c

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Synthesis and biological evaluation of XB-1
analogues as novel histamine H3 receptor
Cite this: RSC Adv., 2014, 4, 6761
antagonists and neuroprotective agents†
a
Xiaofeng Bao, Yanyan Jin,a Xiaolu Liu,a Hong Liao,bc Luyong Zhangbc
*
bc
*
and Tao Pang
A novel class of H3 receptor antagonists, XB-1 analogues based on benzophenone or oxydibenzene
scaffolds were synthesized, and their biological activities were evaluated to determine their in vitro
neuroprotective effects against Ab25–35-induced damage in primary cortical neurons and against
glutamate-induced neuronal injury in primary cerebellar granule neurons. The results indicated that all of
the tested analogues displayed neuroprotective activity at 0.1 mM or 1 mM. These findings may provide
new insights into the development of novel promising H3 receptor antagonists with potential
neuroprotective activity.
Received 4th November 2013
Accepted 19th December 2013
DOI: 10.1039/c3ra46392c
www.rsc.org/advances
of AD have shown that treatment with an H3 receptor antagonist
attenuates learning and memory decits.12,14,18 Therefore, the H3
Introduction
receptor is expected to be a promising therapeutic target for the
treatment of AD. Several H3 receptor antagonists have been
demonstrated to have promising neuroprotective activity. For
example, the H3 antagonist clobenpropit was shown to have
signicant neuroprotective activity against Ab-induced neuro-
toxicity in PC12 cells,19 and the H3 antagonist thioperamide was
indicated to exert a neuroprotective effect.20
Interest in the development of H3 antagonists as drugs for the
treatment of a variety of CNS disorders has recently grown
dramatically. Several H3 receptor antagonists, such as thioper-
amide,21 ciproxifan,22 GT-2331,23 FUB-181,24 iodoproxyfan,25 and
SCH-79876,26 have been reported (Fig. 1), but almost all of these
compounds contain an imidazole ring in their structures and
have been found to exhibit some disadvantages, such as signi-
cantly binding discrepancies across species27 and undesired
affinity for cytochrome P450.28 To avoid these drawbacks, scien-
tists are now focusing on exploring new classes of
non-imidazole H3 receptor antagonists. Several new classes of
non-imidazole H3 receptor antagonists, such as BF-2.649,29 ABT-
239,30 A-349821 (ref. 32) and JNJ-5207852 (ref. 34) (Fig. 2), have
Alzheimer's disease (AD) is
a chronic neurodegenerative
disorder characterized by the accumulation of b-amyloid peptide
(Ab) in brain areas associated with learning and memory func-
tions.1,2 Ab is the major component of senile plaques, and
extensive Ab deposition in AD brain plays a critical role in the
development and pathogenesis of AD.3 The neurotoxicity of Ab
appears to depend on its ability to aggregate, and the active
portion of the Ab molecule appears to be the fragment of amino
acids 25 to 35.4,5 Many lines of evidence have conrmed that Ab
exhibits neurotoxicity and induces apoptosis.6,7 Glutamate-
induced excitotoxicity has also been implicated in Alzheimer's
disease.8–10 H3 receptor antagonists are currently being evaluated
for their potential use in a number of central nervous system
disorders, including AD.11–15 Histamine subtype 3 (H3) receptor,
one of the four G-protein coupled receptors of the histamine
receptor family, is mainly located presynaptically on histamin-
ergic neurons in the central nervous system (CNS), where it
regulates histamine biosynthesis and the release of histamin-
ergic neurons.16 The knowledge of histamine H3 receptors
suggests the potential therapeutic applications of histamine H3
receptor antagonists for several CNS diseases, such as Alz-
heimer's disease.17 Several studies using genetic mouse models
aDepartment of Biochemical Engineering, Nanjing University of Science and
Technology, Chemical Engineering Building B308, 200 Xiaolinwei, Nanjing, P. R.
China. E-mail: baoxiaofeng@mail.njust.edu.cn; Tel: +86-2584315945
bNew Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, P. R.
China. E-mail: tyne_pang@hotmail.com; Tel: +86-2583271042
cState Key Laboratory of Natural Medicines, China Pharmaceutical University,
Nanjing, 210009, P. R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46392c
Fig. 1 Imidazole-based H3 receptor antagonists.
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Results and discussion
Synthesis of cyclized benzophenone XB-1 analogues 5a–d
The preparation of the targeted cyclized benzophenone H3
receptor antagonists required several distinct synthetic routes,
which are depicted in Scheme 1. (R)-2-Methylpyrrolidine was
alkylated with 3-butynnyl p-toluenesulfonate to yield (R)-1-(3-
butynyl)-2-methylpyrrolidine. For the preparation of the target
analogues 5a–d, compounds 1b–d were converted to 2b–d
through Friedel–Cras acylation with anisole at yields of 33%,
81%, and 95%, respectively. The selective demethylation of 2b–d
to 3b–d was readily achieved with the use of the non-nucleo-
philic Brønsted acid HBr in AcOH; these compounds were
obtained at yields of 51%, 92%, and 80%, respectively. The
treatment of 3a–d with 0.5 eq. of iodine and potassium iodine
selectively produced 4a–d, which contain iodine in the ortho
position to the hydroxyl group, at yields of 94%, 35%, 70%, and
49%, respectively. The use of a substoichiometric amount of
iodine reduced the unwanted diiodination that we observed with
the use of a stoichiometric amount of iodine. The Pd-catalyzed
reaction of 4a–d with (R)-1-(3-butynyl)-2-methyl pyrrolidine
solution in CH3CN (0.1 M) gave the target products 5a–d at
isolated yields of 19%, 16%, 21%, and 18%, respectively.
Fig. 2 Non-imidazole-based H3 receptor antagonists.
been reported to show promising results in animal experiments.
To date, however, few molecules are successfully progressing
through to advanced stage trials because of poor drug-like prop-
erties, such as poor selectivity and poor brain permeability.32,34,39
Recently, several new non-imidazole-based compounds,
such as CEP-26401 and its analogues,33 have been described in
the literature as excellent H3R antagonists with high affinity for
both hH3Rs (Ki ¼ 2.0 nM) and rH3Rs (Ki ¼ 7.2 nM) (Fig. 3).
Reports showed that substitution of N-pyridazin-3-one nitrogen
with methyl, ethyl, isopropyl, benzyl, and phenyl group could
not affect its binding affinity and had essentially equivalent
binding affinity for both hH3R and rH3R compared to CEP-
26401.33 On the other hand, incorporating an alcohol on the
(R)-2-methyl pyrrolidine or substituting it with piperidine side
chain signicantly reduced its binding affinity in 7-fold and
15-fold respectively.33 GlaxoSmithKline has also reported a
compound (GSK189254,31 Fig. 3) as a novel H3R antagonist with
high binding affinity for human H3R (Ki ¼ 0.26 nM). We
previously reported the successful preparation of two new non-
imidazole H3 receptor antagonists:35,36 XB-1 and its nitro
analogue 2 (Fig. 3). Both XB-1 and 2 were found to have high
affinity and selectivity to the human H3 receptor (Ki ¼ 1.9 nM
and 0.4 nM respectively), and 2 was further developed as a PET
radioligand, denoted [18F]XB-1, for the imaging of brain H3
receptors. Inspired by these encouraging results, in this study,
we aimed to synthesize a novel class of H3 receptor antagonists,
XB-1 analogues, based on benzophenone or oxydibenzene
scaffolds. We hypothesize that these analogues of XB-1 might
also behave as promising H3 receptor antagonists with potential
neuroprotective activity.
Synthesis of noncyclized benzophenone XB-1 analogues 7a–f
and 7a0–f0
A different synthetic route was used to produce the targeted
noncyclized benzophenone XB-1 analogues 7a–f and 7a0–f0, as
shown in Scheme 2. Compounds 6a–f and 6a0–f0 were obtained
at high yield through the alkylation of 3a–f with 1-bromo-3-
chloropropane or 1-bromo-2-chloromethane in the presence of
K2CO3 in CH3CN. Lower yields of 6a,b and 6a0,b0 were achieved
through the alkylation of 3a,b with 1,3-dibromopropane or 1,2-
dibromopropane. The coupling of 6a–f and 6a0–f0 with (R)-2-
methyl pyrrolidine in the presence of KI and K2CO3 in CH3CN
yielded the targeted compounds 7a–f and 7a0–f0, respectively.
The detailed experimental procedures and the characterization
of the new compounds are described in the experimental
section.
Scheme 1 Synthesis of 5a–d. Reagents and conditions: (i) 3-butynyl
p-toluenesulfonate, K2CO3, CH3CN, 50 ꢀC, 24 h; (ii) AlC13, CH2Cl2, rt, 4
h; (iii) HBr, AcOH, reflux, 24 h; (iv) NH4OH, I2, KI, rt, 18 h; (v) (a):
Pd(OAc)2, (p-tol)3P, CuI, CH3CN, (R)-1-(3-butyny1)-2-methyl-
pyrrolidine, rt, 10 min; (b): iPr2NH, 60 ꢀC, 20 h. 3a was purchased from
Sigma Aldrich (China).
Fig. 3 Chemical structures of H3R antagonists.
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Scheme 2 Synthesis of 7a–f, 7a0–f. Reagents and conditions: (vi) 1-
bromo-3-chloropropane/1-bromo-2-chloroethane, K2CO3, CH3CN,
reflux, 24 h; (vii) (R)-2-methyl pyrrolidine, KI, K2CO3, CH3CN, reflux, 24 h.
Scheme 4 Synthesis of 7B, 7E, 7F, 7B0, 7E0 and 7F0. Reagents and
conditions:
(xii)
1-bromo-3-chloropropane/1-bromo-2-chloro-
ethane, K2CO3, CH3CN; (xiii) (R)-2-methylpyrrolidine, KI, K2CO3,
CH3CN.
Synthesis of cyclized oxydibenzene XB-1 analogues 5B–5F
Preliminary evaluation of biological activity
The preparation of the targeted cyclized oxydibenzene XB-1
analogues 5B–5F required different synthetic routes from 5a–d,
which are depicted in Scheme 3. Compounds 1B–F were con-
verted to 2B–F through their coupling with 4-methoxyphenol in
the presence of KOH, CuI, n-Bu4NBr, and K3PO3 in DMF at
yields of 84.9%, 31.6%, and 77.8%, respectively, followed by
procedures analogous to those used to prepare 5a–d. The
detailed experimental procedures and characterization of the
new compounds are described in the ESI.†
Primary cortical neurons cultures were obtained from fetal
Sprague Dawley rats at embryonic day 18 (E18).37 Cerebellar
granule neuronal cells (CGCs) were isolated from 8-day-old
Sprague Dawley rat pups, as described previously.38 The cortical
neurons and CGCs were cultured in complete Neurobasal
culture medium supplemented with 2% B27 and 0.5 mM
GlutaMax, and the cultures were incubated in a humidied
atmosphere of 5% CO2 and 95% air at 37 ꢀC. The cortical
neurons cultured at DIV4 were pretreated with the compounds
for 24 h and then incubated with 5 mM Ab25–35 for an additional
24 h. The CGCs cultured at DIV6 were pretreated with the
compounds for 24 h and then incubated with 100 mM glutamate
for an additional 24 h. The cell viability was evaluated by
incubating with 0.5 mg mLꢁ1 3-[4,5-dimethylthiazol-2-yl]-2,5-
diphenyltetrazolium bromide (MTT) for 4 h under 5% CO2/95%
air at 37 ꢀC. The media were replaced with 100 mL of DMSO, and
the absorbance was read at 570 nM. The data are expressed as
the means ꢂ SD.
Synthesis of noncyclized oxydibenzene XB-1 analogues 7B–F
and 7B0–F0
The syntheses of the targeted noncyclized oxydibenzene XB-1
analogues 7B, 7E, 7F, 7B0, 7E0, and 7F0 are shown in Scheme 4.
The synthetic procedures are analogues to those used to prepare
7a–f. Compounds 6B–F, 6B0 and, 6E0–F0 were obtained at high
yield through the alkylation of 3B–F with 1-bromo-3-chlor-
opropane or 1-bromo-2-chloromethane in the presence of
K2CO3 in CH3CN. The coupling of 6B–F and 6B0–F0 with (R)-2-
methyl pyrrolidine in the presence of KI and K2CO3 in CH3CN
formed the target compounds 7B–F and 7B0–F0 at high yields.
Details of the reaction procedures and the characterization of
the new compounds are described in the ESI.†
H3 antagonists have been shown to exhibit neuroprotective
roles in Alzheimer's disease. To determine their biological
activities, all of the compounds were evaluated for their in vitro
neuroprotective effects against Ab25–35 (the toxic fragment of
Ab)-induced damage in primary cortical neurons and gluta-
mate-induced neuronal injury in primary cerebellar granule
neurons. The results are shown in Table 1 and 2. Compared
with the parent compound 2, all of the compounds displayed
neuroprotective activity at 0.1 mM or 1 mM. Notably, compound
7B at 0.1 mM exhibited a somewhat better protective effect
compared to parent compound 2 against glutamate-induced
neuronal injury. The SAR trend showed that the oxydibenzene
moiety series exhibited
a little better protective effects
compared to benzophenone moiety series at 0.1 mM against
glutamate-induced neuronal injury. Decreasing the rigidity by
substitution of noncyclized oxydibenzene moiety with cyclized
oxydibenzene moiety had no signicant affect on the neuro-
protective activity against glutamate-induced neuronal injury at
0.1 mM or 1 mM. Pallas soware was also used to predict the
lipophilicity for these compounds and their computed cLogP
values are calculated to be between 3.0 and 5.0. Particularly,
Scheme 3 Synthesis of 5B, 5E,and 5F. Reagents and conditions: (viii)
4-methoxyphenol, KOH/CuI, n-Bu4NBr, K3PO4, DMF; (ix) HBr,
CH3CCOOH; (x) MeNH2, I2, KI; (xi) Pb(OAC)2, (p-to1)3P, CuI, iPr2NH,
(R)-1-(but-3-yn-1-yI)-2-methylpyrrolidine, CH3CN.
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Table 1 Neuroprotective effects of all of the compounds against
Ab25–35-induced neurotoxicity in primary rat cortical neurons
compound 7B has low computed cLogP value of 3.16 ꢂ 0.44. It
has been reported that the cLogP value for parent compound 2
is 4.34 ꢂ 0.34 and it can penetrate into the brain to show good
PET imaging in the specic brain area.36 So these analogues
may have the penetration ability of blood–brain barrier to show
biological activity. These data indicate that these compounds
may have the potential as H3 receptor antagonists for the
treatment of Alzheimer's disease.
Cell viabilitya (%)
No.
Compound
0.1 mM
1 mM
1
2
3
4
5
6
7
8
2
57.7 ꢂ 3.6
73.0 ꢂ 4.1
58.2 ꢂ 4.0
66.6 ꢂ 5.1
74.7 ꢂ 7.2
69.5 ꢂ 6.8
62.1 ꢂ 2.1
66.9 ꢂ 4.9
68.1 ꢂ 5.1
70.3 ꢂ 6.1
60.3 ꢂ 1.5
62.4 ꢂ 4.2
59.7 ꢂ 2.8
59.5 ꢂ 2.8
57.7 ꢂ 1.0
58.9 ꢂ 1.8
57.9 ꢂ 2.5
60.8 ꢂ 1.5
N.T.b
80.8 ꢂ 7.2
62.2 ꢂ 3.6
77.7 ꢂ 6.4
69.3 ꢂ 1.8
73.0 ꢂ 2.4
72.7 ꢂ 3.8
80.6 ꢂ 2.0
78.1 ꢂ 4.1
76.4 ꢂ 3.5
72.5 ꢂ 3.4
73.6 ꢂ 1.3
76.8 ꢂ 1.0
75.0 ꢂ 1.0
76.2 ꢂ 1.7
76.1 ꢂ 1.1
75.1 ꢂ 1.6
76.9 ꢂ 2.9
74.1 ꢂ 1.6
67.3 ꢂ 3.0
7a0
7b
7b0
7c
7d
Experimental section
7e
All of the reagents and organic solvents were ACS grade or
higher and used without further purication. Unless otherwise
noted, all of the chemicals were purchased from J&K Scientic
(China) and Sigma Aldrich (China). The reactions were per-
formed under an argon atmosphere with standard Schlenk
techniques. Thin-layer chromatography was performed on a
HAIYANG silica gel F254 plate, and the compounds were visu-
alized under UV light (l ¼ 254 nm). Column chromatography
was conducted using HAIYANG silica gel (type: 200–300 mesh
7e0
9
7f
10
11
12
13
14
15
16
17
18
19
7f0
5B
5E
5F
7B
7B0
7E
7F
7F0
1
ZCX-2). The H (500 MHz), 13C NMR (126 MHz), and 19F NMR
Thioperamide
(470 MHz) spectra were recorded on an Avance 500 spectrom-
eter (Bruker; Billerica, MA, USA). The chemical shis are
reported in d units (ppm) downeld relative to the chemical
shi for tetramethylsilane. The GC-MS spectra were obtained on
a Trace DSQ GC-MS instrument (Thermo Fisher Scientic Corp.,
Waltham, MA, USA), and the ESI-MS were obtained on a TSQ
Quantum ESI-MS (Thermo Fisher Scientic Corp., Waltham,
MA, USA).
a
The neuroprotective effects of these compounds against Ab25–35
-
induced neurotoxicity in cortical neurons. The cell viability obtained
with the control was considered 100%, and the average cell viability
aer Ab25–35 exposure was 54.6% ꢂ 4.0. The positive control is
thioperamide. b N.T. means not tested.
Table 2 Neuroprotective effects of all of the compounds against
glutamate-induced neurotoxicity in primary rat cerebellar granule
neuronal cells (CGCs)
(2-Fluorophenyl)(4-hydroxy-3-iodophenyl)methanone (4a)
A solution of 1.0 g (4.6 mmol) of 3a in 60 mL of NH4OH (25–
ꢀ
28%) was stirred at 25 C for 15 min and then treated with a
Cell viabilitya (%)
solution of KI (3.74 g, 22.5 mmol) and I2 (1.17 g, 4.62 mmol) in
10 mL of H2O. Aer stirring at 25 ꢀC for 18 h, the reaction
mixture was adjusted to pH 7, extracted with EtOAc, washed
with H2O and brine, dried with MgSO4, and ltered. The ltrate
was concentrated under vacuum. The residue was puried by
ash chromatography and eluted with 98% CH2Cl2/2% MeOH
No.
Compound
0.1 mM
1 mM
1
2
3
4
5
6
7
8
2
76.7 ꢂ 4.3
75.5 ꢂ 5.2
76.6 ꢂ 4.7
73.4 ꢂ 4.0
75.2 ꢂ 4.3
74.8 ꢂ 9.3
72.2 ꢂ 4.8
77.3 ꢂ 6.5
73.5 ꢂ 2.2
76.1 ꢂ 1.5
79.2 ꢂ 7.4
83.8 ꢂ 7.2
79.5 ꢂ 2.2
92.7 ꢂ 3.5
78.0 ꢂ 2.8
79.0 ꢂ 4.7
82.2 ꢂ 2.2
75.0 ꢂ 5.5
N.T.b
86.6 ꢂ 4.5
84.9 ꢂ 4.7
75.9 ꢂ 2.9
79.1 ꢂ 4.4
75.3 ꢂ 7.9
75.6 ꢂ 7.6
75.9 ꢂ 5.2
71.5 ꢂ 7.1
82.7 ꢂ 7.7
85.9 ꢂ 9.5
77.7 ꢂ 4.4
79.7 ꢂ 7.4
7a0
7b
7b0
1
to give 4a (1.5 g, 94.3%). H NMR (DMSO-d6): d 11.56 (s, 1H),
7c
7d
8.06 (d, 1H, J ¼ 3.6 Hz), 7.63 (m, 2H), 7.52 (m, 1H), 7.35 (m, 2H),
7.01 (m, 1H). 13C NMR (DMSO-d6): d 189.30, 161.32, 159.32,
157.35, 140.19, 132.66, 131.53, 129.53, 126.03, 124.25, 115.71,
114.18, 84.38.
7e
7e0
9
7f
10
11
12
13
14
15
16
17
18
19
7f0
5B
5E
5F
(R)-(2-Fluorophenyl)(2-(2-(2-methylpyrrolidin-1-yl)ethyl)-
71.7 ꢂ 3.4 benzofuran-5-yl)methanone (5a)
7B
79.9 ꢂ 4.6
(R)-1-(3-Butynyl)-2-methylpyrrolidine (52 mL of 0.1 M solution
in CH3CN, 5.2 mmol) and compound 4a (1.5 g, 4.38 mmol) were
7B0
75.7 ꢂ 3.4
75.0 ꢂ 2.4
7E
7F
72.9 ꢂ 3.8 mixed in a 100 mL round bottom ask. Pd(OAc)2 (30 mg, 0.12
7F0
69.4 ꢂ 6.0
mmol), tri(4-methylpenyl)phosphine (80 mg, 0.25 mmol), and
CuI (125.3 mg, 0.66 mmol) were then added to the reaction
Thioperamide
92.8 ꢂ 5.7
a
The neuroprotective effects of these compounds against glutamate- mixture. Aer stirring at 25 ꢀC for 10 min, the reaction mixture
induced neurotoxicity in cerebellar granule neurons. The cell viability
was treated with i-Pr2NH (6.3 mL, 44.25 mmol) and then
obtained with the control was considered 100%, and the average
heated at 60 ꢀC under N2 for 16 h. The reaction mixture was
allowed to cool and ltered through celite, and the ltrate was
cell viability aer glutamate exposure was 63.3%. The positive control
is thioperamide. b N.T. means not tested.
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concentrated under reduced pressure. The residue was puried
(R)-(2-(2-(2-Methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(2-
on silica gel and eluted with 98% CH2Cl2/2% MeOH to yield 5a
(290 mg, 19%). H NMR (CDCl3): d 7.94 (s, 1H), 7.75 (m, 1H),
nitrophenyl)methanone (5b)
1
(R)-1-(3-Butynyl)-2-methylpyrrolidine (51 mL of 0.1 M solution
in CH3CN, 5.1 mmol) and compound 4b (1.5 g, 4.08 mmol) were
mixed in a 100 mL round bottom ask. Pd(OAc)2 (27 mg, 0.12
mmol), tri(4-methylpenyl) phosphine (73 mg, 0.24 mmol), and
CuI (231 mg, 1.6 mmol) were then added to the reaction
mixture. Aer stirring at 25 ꢀC for 10 min, the reaction mixture
was treated with i-Pr2NH (5.7 mL, 80.3 mmol) and then heated
at 60 ꢀC under N2 for 16 h. The reaction mixture was allowed to
cool and ltered through celite, and the ltrate was concen-
trated under reduced pressure. The residue was puried on
silica gel and eluted with 98% CH2Cl2/2% MeOH to provide 5b
(246 mg, 16%). 1H NMR (CDCl3): d 8.25 (d, 1H, J ¼ 8.0 Hz), 7.87
(d, 1H, J ¼ 1.2 Hz), 7.78 (m, 1H), 7.70 (m, 2H), 7.52 (m, 1H), 7.46
(d, 1H, J ¼ 8.4 Hz), 6.48 (s, 1H), 3.20 (m, 2H), 3.0 (m, 2H), 2.50
(m, 1H), 2.40 (m, 1H), 2.22 (m, 1H), 1.93 (m, 1H), 1.72 (m, 2H),
1.44 (m, 1H), 1.14 (d, 1H, J ¼ 6.0 Hz); 13C NMR (CDCl3): d 194.55,
158.99, 156.63, 148.03, 144.36, 137.70, 135.87, 133.34, 130.96,
130.31, 127.10, 126.02, 124.83, 112.89, 106.68, 66.24, 54.74,
51.65, 32.80, 26.52, 22.81, 17.12. ESI-MS (M+ + 1): found 379.02;
calculated for C22H22N2O4, 379.16.
7.59 (m, 1H), 7.51 (m, 2H), 7.32 (td, 1H, J1 ¼ 0.8 Hz, J2 ¼ 7.5 Hz),
7.24 (m, 1H), 6.63 (s, 1H), 3.23 (m, 2H), 3.02 (m, 2H), 2.46 (m,
2H), 2.25 (m, 1H), 1.98 (m, 1H), 1.76 (m, 2H), 1.43 (m, 1H), 1.13
(d, 3H, J ¼ 6.2 Hz); 13C NMR (CDCl3): d 194.81, 160.85, 160.28,
159.16, 134.29, 133.92, 131.59, 130.61, 126.86, 125.64, 124.72,
117.40, 117.22, 112.04, 104.47, 61.64, 54.73, 52.91, 33.64, 28.49,
22.48, 18.71; 19F NMR (CDCl3): d ꢁ114.13. ESI-MS (M+ + 1):
found 352.95; calculated for C21H24FNO2, 352.17.
(4-Methoxyphenyl)(2-nitrophenyl)methanone (2b)
2-Nitrobenzoyl chloride (4 g, 21.56 mmol) and 3.45 g of anhy-
drous aluminum chloride were suspended in 160 mL of toluene.
Anisole (2.331 g, 21.56 mmol) was gradually added to the
ꢀ
mixture. The reaction mixture was slowly heated to 40 C, stir-
red for 24 h, cooled to room temperature, and extracted with
EtOAc and H2O. The organic layer was collected and dried with
MgSO4. Aer the removal of the organic solvent under vacuum,
the residue was puried through column chromatography and
eluted with 20% EtOAc/hexane to provide 2b (1.885 g, 33%) as a
yellow powder. 1H NMR (CDCl3): d 8.23 (dd, 1H, J1 ¼ 0.80 Hz, J2
¼ 8.2 Hz), 7.76 (td, 1H, J1 ¼ 1.1 Hz, J2 ¼ 7.5 Hz), 7.73 (d, 2H, J ¼
8.8 Hz), 7.66 (m, 1H), 7.48 (dd, 1H, J1 ¼ 1.3 Hz, J2 ¼ 7.5 Hz), 6.93
(d, 2H, J ¼ 8.9 Hz), 3.87 (s, 3H).
(3-Fluorophenyl)(4-methoxyphenyl)methanone (2c)
3-Fluorobenzoyl chloride (5 g, 31.5 mmol) and 5.04 g of anhy-
drous aluminum chloride were suspended in 25 mL of
dichloromethane. Anisole (3.41 g, 31.5 mmol) was gradually
added to the mixture. The mixture was then slowly heated to 40
ꢀC, stirred for 24 h, cooled to room temperature, and extracted
with EtOAc and H2O. The organic layer was collected and dried
with MgSO4. Aer removal of the organic solvent under vacuum,
the residue was puried with column chromatography and
eluted with 80% hexane/20% EtOAc to provide 2c (5.6 g, 81%) as
a white solid. 1H NMR (CDCl3): d 7.84 (m, 2H), 7.52 (m, 1H), 7.46
(m, 2H), 7.28 (m, 1H), 6.99 (m, 2H), 3.90 (s, 3H).
(4-Hydroxyphenyl)(2-nitrophenyl)methanone (3b)
(4-Methoxyphenyl) (2-nitrophenyl)methanone (1.885 g, 7.33
mmol) was suspended in hydrobromic acid (75 mL, 40%) and
acetic acid (63 mL, 99.7%). The reaction mixture was reuxed
for 24 h, concentrated under vacuum, and then extracted with
EtOAc and H2O. The organic layer was collected and dried with
MgSO4. Aer removal of the organic solvent under vacuum, the
residue was puried with ash chromatography and eluted with
80% hexane/20% EtOAc to yield 3b (909 mg, 51%) as a grey
1
ꢀ
solid; mp: 122 C. H NMR (CDCl3): d 8.24 (d, 2H, J ¼ 8.2 Hz),
7.77 (m, 2H), 7.68 (m, 3H), 7.48 (dd, 2H, J1 ¼ 1.1 Hz, J2 ¼ 7.5 Hz),
6.87 (d, 2H, J ¼ 8.8 Hz).
(3-Fluorophenyl)(4-hydroxyphenyl)methanone (3c)
(3-Fluorophenyl)(4-methyloxyphenyl)methanone (4.84 g, 21
mmol) was suspended in hydrobromic acid (160 mL, 40%) and
acetic acid (133 mL, 99.7%). The reaction mixture was reuxed
for 24 h, concentrated under vacuum, and then extracted with
EtOAc and H2O. The organic layer was collected and dried with
MgSO4. Aer removal of the organic solvent under vacuum, the
residue was puried with ash chromatography and eluted with
80% hexane/20% EtOAc to yield 3c (4.18 g, 92%) as a white
(4-Hydroxy-3-iodophenyl)(2-nitrophenyl)methanone (4b)
A solution of 3.0 g (12 mmol) of 3b in 180 mL of NH4OH (25–
ꢀ
28%) was stirred at 25 C for 15 min and then treated with a
solution of KI (10.1 g) and I2 (1.4 g) in 10 mL of H2O. Aer
ꢀ
stirring at 25 C for 48 h, the reaction mixture was adjusted to
pH 7, extracted with EtOAc, washed with H2O and brine, dried,
and ltered, and the ltrate was concentrated under vacuum.
The residue was puried by ash chromatography and eluted
1
solid. H NMR (CDCl3): d 7.93 (m, 2H), 7.68 (m, 1H), 7.62 (m,
1H), 7.60 (m, 1H), 7.44 (m, 1H), 7.11 (m, 2H).
1
with 98% CH2Cl2/2% MeOH to give 4b (1.6 g, 35.2%). H NMR
(3-Fluorophenyl)(4-hydroxy-3-iodophenyl)methanone (4c)
(DMSO-d6): d 8.25 (dd, 1H, J1 ¼ 8.2 Hz, J2 ¼ 0.8 Hz), 8.16 (d, 1H, J
¼ 2.0 Hz), 7.79 (t, 1H, J1 ¼ 7.5 Hz, J2 ¼ 1.1 Hz), 7.70 (m, 1H), 7.59 A solution of 1.0 g (2.31 mmol) of 3c in 39 mL of NH4OH (25–
ꢀ
(dd, 1H, J1 ¼ 8.5 Hz, J2 ¼ 2.0 Hz), 7.46 (dd, 1H, J1 ¼ 7.5 Hz, J2 ¼ 28%) was stirred at 25 C for 15 min and then treated with a
1.3 Hz), 7.01 (d, 1H, J ¼ 8.5 Hz), 5.88 (s, 1H); 13C NMR (DMSO- solution of KI (3.74 g, 22.5 mmol) and I2 (1.17 g, 4.62 mmol) in
d6): d 189.82, 161.46, 145.79, 139.67, 134.49, 134.24, 131.23, 10 mL of H2O. The reaction mixture was stirred at 25 ꢀC for 18 h.
130.67, 128.36, 128.27, 124.21, 114.30, 84.78. ESI-MS (Mꢁ + 1): The reaction mixture was adjusted to pH 7, extracted with
found 367.79; calculated for C21H24FNO2, 367.94.
EtOAc, washed with H2O and brine, dried, and ltered, and the
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ltrate was concentrated under vacuum. The residue was puri- chromatography and eluted with 80% hexane/20% EtOAc to
ed by ash chromatography and eluted with 98% CH2Cl2/2% yield 3d (4.57 g, 80%) as a white power. 1H NMR (CDCl3/DMSO-
MeOH to give 4c (1.1 g, 70%). 1H NMR (CD3OD): d 8.17 (d, 1H, J d6): d 10.36 (s, 1H), 7.92 (m, 2H), 7.62 (m, 3H), 7.29 (m, 1H), 6.88
¼ 2.1 Hz), 7.67 (dd, 1H, J1 ¼ 2.2 Hz, J2 ¼ 6.4 Hz), 7.54 (m, 1H), (d, 2H, J ¼ 8.6 Hz); 13C NMR (CDCl3/DMSO-d6): d 192.10, 161.77,
7.49 (m, 1H), 7.41 (m, 1H), 7.36 (m, 1H), 6.92 (d, 2H, J ¼ 8.5 Hz). 139.68, 139.52, 136.70, 131.89, 129.66, 127.78, 126.78, 114.73,
93.87. ESI-MS (Mꢁ
22H22FNO2, 322.96.
+ 1): found 322.85; calculated for
(R)-(3-Fluorophenyl)(2-(2-(2-methylpyrrolidin-1-yl)ethyl)-
benzofuran-5-yl)methanone (5c)
C
(4-Hydroxy-3-iodophenyl)(3-iodophenyl)methanone (4d)
(R)-1-(3-butynyl)-2-methylpyrrolidine (30 mL of 0.1 M solution
in CH3CN, 3 mmol) and compound 4c (1 g, 3.08 mmol) were A solution of 3.68 g (11.36 mmol) of 3d in 137 mL of NH4OH
mixed in a 100 mL round bottom ask. Pd(OAc)2 (21 mg, (25–28%) was stirred at 25 ꢀC for 15 min and then treated with a
0.09 mmol), tri(4-methylpenyl)phosphine (56 mg, 0.19 mmol), solution of KI (9.42 g, 56.8 mmol) and I2 (1.447 g, 5.7 mmol) in
and CuI (88 mg, 0.5 mmol) were then added to the reaction 15 mL of H2O. The reaction mixture was stirred at 25 ꢀC for 14 h.
mixture. Aer stirring at 25 ꢀC for 10 min, the reaction mixture The reaction mixture was adjusted to pH 7, extracted with
was treated with i-Pr2NH (4.6 mL, 32.3 mmol) and then heated EtOAc, washed with H2O and brine, dried, and ltered, and the
at 60 ꢀC under N2 for 16 h. The reaction mixture was allowed to ltrate was concentrated under vacuum. The residue was puri-
cool and was ltered through celite, and the ltrate was ed by ash chromatography and eluted with 98% CH2Cl2/2%
concentrated under reduced pressure. The residue was puried MeOH to give 4d (2.15 g, 49%) as a yellow solid; mp: 210–212 ꢀC.
on silica gel and eluted with 98% CH2Cl2/2% MeOH to yield 5c 1H NMR (DMSO-d6): d 11.45 (s, 1H), 8.07 (d, 1H, J ¼ 2.1 Hz), 7.99
(224 mg, 21%). 1H NMR (CDCl3): d 7.95 (s, 1H), 7.74 (dd, 1H, J1 ¼ (m, 1H), 7.96 (m, 1H), 7.63 (m, 2H), 7.34 (m, 1H), 7.01 (d, 1H, J ¼
1.0 Hz, J2 ¼ 8.6 Hz), 7.57 (d, 1H, J ¼ 7.6 Hz), 7.49 (m, 2H), 7.45 8.5 Hz); 13C-NMR (DMSO-d6): d 191.12, 160.76, 140.52, 139.97,
(m, 1H), 7.28 (m, 1H), 6.53 (s, 1H), 3.22 (m, 2H), 3.02 (m, 2H), 139.06, 136.71, 131.87, 129.98, 128.70, 127.94, 113.95, 94.36,
2.49 (m, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 1.94 (m, 1H), 1.81 (m, 84.41; ESI-MS (Mꢁ
+ 1): found 448.68; calculated for
1H), 1.72 (m, 1H), 1.45 (m, 1H), 1.14 (d, 3H, J ¼ 6.1 Hz); 13C NMR
C22H22N2O4, 448.85.
(CDCl3): d 195.21, 163.49, 161.52, 159.94, 157.23, 140. 57,
133.99, 132.01, 129.96, 129.01, 125.99, 123.54, 119.13, 118.96, (R)-(3-Iodophenyl)(2-(2-(2-methylpyrrolidin-1-yl)ethyl)-
116.85, 116.67, 110.84, 103.02, 60.04, 53.91, 51.85, 32.81, 28.25, benzofuran-5-yl)methanone (5d)
21.81, 19.09; 19F NMR (CDCl3): d ꢁ112.11. ESI-MS (M+ + 1):
(R)-1-(but-3-yn-1-yl)-2-methylpyrrolidine (20 mL of 0.1 M solu-
tion in CH3CN, 2 mmol) and compound 4d (612 mg, 1.36 mmol)
found 352.10; calculated for C22H22FNO2, 352.17.
were mixed in a 100 mL round bottom ask. Pd(OAc)2 (9 mg,
0.04 mmol), tri(4-methylpenyl)phosphine (24 mg, 0.08 mmol),
(3-Iodophenyl)(4-methoxyphenyl)methanone (2d)
Dichloromethane (178 mL) was cooled in an ice bath and and CuI (77 mg, 0.4 mmol) were then added to the reaction
treated portionwise with AlCl3 (2.52 g, 18.9 mmol). 3-Iodo- mixture. Aer stirring at 25 ꢀC for 10 min, the reaction mixture
benzoyl chloride 1d (4.7 g, 17.64 mmol) in dichloromethane was was treated with i-Pr2NH (1.9 mL, 13.55 mmol) and then heated
then added to the mixture while ensuring that the temperature at 60 ꢀC under N2 for 20 h. The reaction mixture was allowed to
did not exceed 10 ꢀC. The reaction mixture was stirred at 0 ꢀC for cool and ltered through celite, and the ltrate was concen-
10 min, and anisole (1.78 g, 16.48 mmol) wasꢀadded dropwise trated under reduced pressure. The residue was puried on
such that the temperature did not exceed 10 C. The solution silica gel and eluted with 98% CH2Cl2/2% MeOH to provide 5d
was allowed to warm to room temperature overnight. The (112 mg, 18%). 1H NMR (CDCl3): d 8.12 (t, 1H, J ¼ 1.5 Hz), 7.94
mixture was concentrated under vacuum and then extracted (d, 1H, J ¼ 1.6 Hz), 7.91 (m, 1H), 7.73 (m, 2H), 7.50 (d, 1H, J ¼ 8.6
with EtOAc and H2O. The organic layer was collected and dried Hz), 7.23 (t, 1H, J ¼ 7.8 Hz), 6.55 (s, 1H), 3.27 (m, 2H), 3.06 (t, 2H,
with MgSO4. Aer removal of the organic solvent under vacuum, J ¼ 7.8 Hz), 2.55 (m, 1H), 2.47 (m, 1H), 2.28 (m, 1H), 1.97 (m,
the residue was puried with column chromatography and 1H), 1.85 (m, 1H), 1.75 (m, 1H), 1.50 (m, 1H), 1.19 (d, 3H, J ¼ 6.1
eluted with 90% hexane/10% EtOAc to obtain 2d (5.66 g, 95%) Hz); 13C NMR (CDCl3): 196.45, 160.90, 158.70, 142.28, 141.84,
1
as a white powder. H NMR (CDCl3): d 8.08 (s, 1H), 7.9 (d, 1H, 140.00, 133.41, 131.36, 130.50, 130.40, 127.50, 125.02, 112.32,
J ¼ 7.8 Hz), 7.81 (d, 2H, J ¼ 8.2 Hz), 7.70 (d, 1H, J ¼ 7.6 Hz), 7.21 104.69, 95.45, 61.87, 55.22, 53.16, 34.08, 31.18, 23.19, 20.11. ESI-
(t, 1H, J ¼ 7.7 Hz), 6.98 (d, 2H, J ¼ 5 Hz), 3.90 (s, 3H).
MS (M+ + 1): found 459.92; calculated for C12H22INO2, 460.08.
(4-Hydroxyphenyl)(3-iodophenyl)methanone (3d)
(4-(3-Chloropropoxy)phenyl)(2-uorophenyl)methanone (6a)
Compound 2d (5.95 g, 17.61 mmol) was suspended in hydro- (2-Fluorophenyl)(4-hydroxyphenyl)methanone (865 mg,
4
bromic acid (164 mL, 40%) and acetic acid (136 mL, 99.7%). The mmol) and 1-bromo-3-chloropropane (1.26 g, 8 mmol) were
reaction mixture was reuxed for 24 h. The reaction mixture was suspended in 10 mL of acetonitrile. Anhydrous potassium
allowed to cool and then extracted with EtOAc/brine, EtOAc/ carbonate (1.66 g, 12 mmol) was then added to the reaction
aqueous NaHCO3, and EtOAc/H2O. The organic layer was mixture. The reaction mixture was reuxed for 24 h, concen-
collected and dried with MgSO4. Aer removal of the organic trated under vacuum, and extracted with EtOAc and H2O. The
solvent under vacuum, the residue was puried with ash organic layer was collected and dried with MgSO4. Aer removal
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of the organic solvent under vacuum, the residue was puried through celite, and the ltrate was concentrated under reduced
with ash chromatography and eluted with 80% hexane/20% pressure. The residue was puried with ash chromatography
EtOAc to provide compound 6a (1.02 g, 87.1%) as a white wax; and eluted with 99% MeOH/1% CH2Cl2 to give compound 7a0
mp: 61–63 ꢀC. 1H NMR (CDCl3): d 7.84 (d, 2H, J ¼ 8.0 Hz), 7.51 (452 mg, 69.0%) as a yellow oil. 1H NMR (CDCl3): d 7.83 (d, 2H, J
(m, 2H), 7.25 (m, 1H), 7.15 (m, 1H), 6.96 (d, 2H, J ¼ 8.8 Hz), 4.19 ¼ 7.80 Hz), 7.50 (m, 2H), 7.25 (t, 1H, J ¼ 7.50 Hz), 7.15 (t, 1H, J ¼
(t, 2H, J ¼ 5.8 Hz), 3.75 (d, 2H, J ¼ 6.2 Hz), 2.26 (q, 2H, J1 ¼ 6.0 8.90 Hz), 6.96 (d, 2H, J ¼ 8.90 Hz), 4.19 (m, 2H), 3.25 (m, 2H),
Hz, J2 ¼ 6.0 Hz); 13C NMR (CDCl3): d 192.02, 163.20, 160.87, 2.60 (m, 1H, J1 ¼ 6.05 Hz, J2 ¼ 6.55 Hz), 2.50 (m, 1H), 2.33 (m,
158.87, 132.77, 132.45, 130.58, 127.63, 124.41, 116.38, 114.34, 1H), 1.95 (m, 1H), 1.83 (m, 1H), 1.75 (m, 1H), 1.46 (m, 1H), 1.16
64.68, 41.41, 32.14 ppm. GC-MS (M+): found 292.01; calculated (d, 3H, J ¼ 6.10 Hz). 13CNMR (CDCl3): d 193.43, 164.69, 163.97,
for C16H14ClFO2, 292.07.
162.24, 160.24, 148.58, 133.79, 132.39, 132.32, 131.93, 128.79,
125.70, 117.89, 117.72, 117.55, 116.17, 115.78, 115.38, 68.92,
61.97, 56.31, 54.05, 33.89, 23.40, 20.46 ppm. 19F NMR (CDCl3): d
(R)-(2-Fluorophenyl)(4-(3-(2-methylpyrrolidin-1-yl)propoxy)-
phenyl)methanone (7a)
ꢁ111.99 ppm. ESI-MS (M+
+ 1): 328.02; calculated for
C
20H23FNO2, 328.16.
Compound 6a (522 mg, 1.78 mmol), (R)-2-methylprrodine
(303.13 mg, 3.56 mmol), potassium iodide (295.48 mg,
1.78 mmol), anhydrous potassium carbonate (738 mg, 5.34
mmol), and acetonitrile (99.0%, 15 mL) were added to a round-
bottom ask. The mixture was heated at reux for 24 h. The
mixture was then cooled to room temperature and concen-
trated, and the product was puried by column chromatog-
raphy and eluted with 98% CH2Cl2/2% MeOH to give 7a (505
mg, 83.2%) as a yellow oil. 1H NMR (CDCl3): d 7.74 (d, 2H, J ¼ 7.7
Hz), 7.45 (m, 2H), 7.20 (t, 1H, J ¼ 7.5), 7.09 (t, 1H, J ¼ 8.6 Hz),
6.88 (d, 2H, J ¼ 7.6 Hz), 4.12 (t, 2H, J ¼ 5.4 Hz), 3.79 (m, 1H), 3.62
(m, 1H), 3.49 (m, 1H), 3.23 (m, 1H), 3.13 (m, 1H), 2.58 (m, 1H),
2.29 (m, 2H), 2.17 (m, 1H), 2.08 (m, 1H), 1.94 (m, 1H), 1.58
(s, 3H); 13C NMR (CDCl3): d 192.02, 162.65, 160.79, 158.79,
132.90, 132.85, 132.37, 130.65, 130.47, 127.37, 127.25, 124.44,
116.38, 116.38, 114.41, 114.15, 65.34, 53.36, 50.41, 31.57, 29.73,
25.38, 21.39, 15.61 ppm. ESI-MS (M+ + 1): found 342.04; calcu-
lated for C21H24FNO2, 342.19.
(4-(3-Chloropropoxy)phenyl)(2-nitrophenyl)methanone (6b)
(4-Hydroxy phenyl)(2-nitrophenyl)methanone (848 mg, 3.48
mmol) and 1-bromo-3-chloro propane (1.096 g, 6.96 mmol)
were suspended in 10 mL of acetonitrile (99.0%). Anhydrous
potassium carbonate (1.443 g, 10.44 mmol) was then added in
the reaction mixture. The reaction mixture was reuxed for 24
h, concentrated under vacuum, and then extracted with EtOAc
and H2O. The organic layer was collected and dried with
MgSO4. Aer removal of the organic solvent under vacuum,
the residue was puried with ash chromatography and eluted
with 80% hexane/20% EtOAc to provide 7b (1.369 g, 78.3%) as
a pale yellow solid; mp: 99–102 ꢀC. 1H NMR (CDCl3): d 8.17 (d,
1H, J ¼ 8.20 Hz), 7.73 (t, 1H, J ¼ 7.5 Hz), 7.70 (d, 2H, J ¼ 8.85
Hz), 7.62 (m, 1H, J1 ¼ 1.2 Hz, J2 ¼ 7.25 Hz), 7.44 (m, 1H, J1 ¼
1.05 Hz, J2 ¼ 7.5 Hz), 6.91 (d, 2H, 8.85 Hz), 4.14 (t, 2H, J ¼ 5.85
Hz), 3.70 (d, 2H, J¼ 6.30 Hz), 2.21 (m, 2H, J1 ¼ 6.00 Hz, J2 ¼
6.10 Hz); 13C NMR (CDCl3): d 192.24, 163.40, 146.78, 136.47,
134.29, 131.85, 130.55, 129.20, 128.97, 124.61, 114.66, 64.76,
41.44, 32.06. GC-MS (M+): found 318.99; calculated for
(4-(2-Chloroethoxy)phenyl)(2-uorophenyl)methanone (6a0)
(2-Fluorophenyl)(4-hydroxyphenyl)methanone (1.000 g, 4.6
mmol) and 1-bromo-2-chloroethane (0.766 mL, 9.2 mmol) were
suspended in 20 mL of acetonitrile. Anhydrous potassium
C
16H14ClNO4, 319.06.
carbonate (1.908 g, 13.8 mmol) was then added to the mixture. (R)-(4-(3-(2-Methylpyrrolidin-1-yl)propoxy)phenyl)(2-
The reaction mixture was reuxed for 24 h, concentrated under nitrophenyl)methanone (7b)
vacuum, and extracted with EtOAc and H2O. The organic layer
(4-(3-Chloropropoxy)phenyl)(2-nitrophenyl)methanone (639
was collected and dried over MgSO4. Aer removal of the
mg, 2 mmol), (R)-2-methylprrodine (340.6 mg, 4 mmol),
organic solvent under vacuum, the residue was puried with
potassium iodide (332 mg, 2 mmol), potassium carbonate
ash chromatography and eluted with 90% hexane/10% EtOAc
anhydrous (829 mg, 3 mmol), and acetonitrile (99.0%, 20 mL)
1
to provide compound 6a0 (660 mg, 51.5%) as a yellow oil. H
were added to a round-bottom ask. The mixture was heated at
NMR (CDCl3): d 7.81 (d, 2H, J ¼ 7.9 Hz), 7.47 (m, 2H), 7.23 (t, 1H,
reux for 24 h, cooled to room temperature, and concentrated,
J ¼ 7.5 Hz), 7.12 (t, 1H, J ¼ 9.0 Hz), 6.94 (d, 2H, J ¼ 9.0 Hz), 4.26
and the product was puried by column chromatography and
(t, 2H, J ¼ 5.7 Hz), 3.81 (t, 2H, J ¼ 5.8 Hz); 13CNMR (CDCl3): d
eluted with 5% MeOH/CH2Cl2 to give 7b (634 mg, 86.1%) as a
191.93, 162.59, 160.83, 158.84, 132.85, 132.40, 130.79, 127.45,
124.41, 116.35, 114.43, 68.22, 41.87 ppm. GC-MS (M+): found
277.93; calculated for C15H12ClFO2, 278.05.
1
pale yellow oil. H NMR (CDCl3): d 8.23 (d, 1H, J ¼ 8.25 Hz),
7.83 (m, 1H), 7.73 (m, 1H), 7.69 (d, 2H, J ¼ 8.75 Hz), 7.50
(m, 1H), 6.99 (d, 2H, J ¼ 8.80 Hz), 4.10 (t, 2H, J ¼ 5.75 Hz), 3.18
(m, 1H, J1 ¼ 3.80 Hz, J2 ¼ 6.60 Hz), 3.05 (m, 1H), 2.40 (dd, 1H, J1
¼ 6.95 Hz, J2 ¼ 7.70 Hz), 2.23 (m, 2H), 2.01 (m, 3H), 1.75 (m,
2H), 1.42 (m, 1H), 1.12 (d, 3H, J ¼ 6.15 Hz); 13C NMR (CDCl3): d
(R)-(2-Fluorophenyl)(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)-
phenyl)methanone (7a0)
A mixture of compound 6a0 (560 mg, 2 mmol), K2CO3 (829 mg, 192.83, 163.91, 146.97, 136.15, 134.11, 131.65, 130.62, 128.92,
6 mmol), KI (332 mg, 2 mmol), and (R)-2-methylpyrrolidine 128.80, 124.33, 114.40, 66.53, 60.67, 53.54, 50.60, 32.14, 27.68,
(242 mL, 2.4 mmol) in acetonitrile (25 mL) was heated at 85 C 21.03, 17.22. ESI-MS (M+ + 1): found 368.99; calculated for
ꢀ
for 24 h. The reaction mixture was allowed to cool and ltered
C11H24N2O4 369.18.
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(4-(2-Chloroethoxy)phenyl)(2-nitrophenyl)methanone (6b0)
(R)-(3-Fluorophenyl)(4-(3-(2-methylpyrrolidin-1-yl)propoxy)-
phenyl)methanone (7c)
(4-Hydroxyphen yl)(2-nitrophenyl)methanone (500 mg, 2.06
mmol) and 1-bromo-2-chloroethane (341 mL, 4.12 mmol) were (4-(3-Chloropropoxy)phenyl)(3-uorophenyl)methanone 6c (250
suspended in 30 mL of acetonitrile. Anhydrous potassium mg, 0.85 mmol), (R)-2-methylprrodine (103 mL, 1.02 mmol), KI
carbonate (854 mg, 6.18 mmol) was then added to the mixture. (141 mg, 0.85 mmol), anhydrous potassium carbonate (235 mg,
The reaction mixture was reuxed for 24 h, concentrated under 1.7 mmol), and acetonitrile (25 mL) were added to a round-
vacuum, and extracted with EtOAc and H2O. The organic layer bottom ask. The mixture was heated at reux for 30 h, cooled
was collected and dried over MgSO4. Aer removal of the organic to room temperature, and concentrated, and the product was
solvent under vacuum, the residue was puried with ash chro- puried by column chromatography and eluted with 98%
matography and eluted with 90% hexane/10% EtOAc to yield CH2Cl2/2% MeOH to yield compound 7c (229 mg, 78.9%) as a
compound 6b0 (460 mg, 72.8%) as a brown oil. 1H NMR (CDCl3): d primrose yellow transparent oil. 1H NMR (CDCl3): d 7.80
8.23 (d, 1H, J ¼ 7.30 Hz), 7.77 (t, 1H, J ¼ 6.40 Hz), 7.73 (d, 2H, J ¼ (m, 2H), 7.51 (d, 1H, J ¼ 7.7 Hz), 7.43 (m, 2H), 7.24 (m, 1H), 6.96
8.90 Hz), 7.67 (t, 1H, J ¼ 6.95 Hz), 7.48 (d, 1H, J ¼ 6.15 Hz), 6.95 (d, 2H, J ¼ 8.8 Hz), 4.11 (m, 2H), 3.19 (m, 1H), 3.00 (m, 1H), 2.35
(d, 2H, J ¼ 8.95 Hz), 4.30 (t, 2H, J ¼ 5.75 Hz), 3.83 (t, 2H, J ¼ 4.70 (m, 1H), 2.24 (m, 1H), 2.16 (m, 1H), 2.03 (m, 2H), 1.93 (m, 1H),
Hz); 13CNMR (CDCl3): d 192.28, 162.80, 146.75, 136.36, 134.27, 1.78 (m, 1H), 1.69 (m, 1H), 1.44 (m, 1H), 1.11 (d, 3H, J ¼ 6.0 Hz);
131.84, 130.55, 129.56, 128.94, 124.60, 114.72, 68.25, 41.77 ppm. 13C NMR (CDCl3): d 194.04, 163.47, 163.08, 161.50, 140.52,
GC-MS (M+): found 305.03; calculated for C15H12ClNO4, 305.04.
132.58, 129.95, 129.90, 129.50, 125.48, 118.94, 118.77, 116.60,
116.42, 114.27, 66.72, 60.57, 53.99, 50.64, 32.69, 28.26, 21.73,
18.80; 19F NMR (CDCl3): d ꢁ112.17. ESI-MS (M+ + 1): found
342.3, calculated for C20H23N2O4, 342.19.
(R)-(4-(2-(2-Methylpyrrolidin-1-yl)ethoxy)phenyl)(2-
nitrophenyl)methanone (7b0)
A mixture of compound 6b0 (450 mg, 1.5 mmol), K2CO3 (622 mg,
(4-(3-Chloropropoxy)phenyl)(3-iodophenyl)methanone (6d)
4.5 mmol), KI (249 mg, 1.5 mmol), and (R)-2-methylpyrrolidine
ꢀ
(182 mL, 1.8 mmol) in acetonitrile (25 mL) was heated at 85 C (4-Hydroxyphenyl)(3-iodophenyl)methanone 3d (450 mg,
for 48 h. The reaction mixture was allowed to cool and ltered 1.4 mmol) and 1-bromo-3-chloropropane (277 mL, 2.8 mmol)
through celite, and the ltrate was concentrated under reduced were suspended in 25 mL of acetonitrile. Anhydrous potassium
pressure. The residue was puried with ash chromatography carbonate (580 mg, 4.2 mmol) was then added to the reaction
and eluted with 98% CH2Cl2/2% MeOH to give compound 7b0 mixture. The reaction mixture was reuxed for 15 h, concen-
(438 mg, 82.6%) as a brown oil. 1H NMR (CDCl3): d 8.20 (d, 1H, J trated under vacuum, and then extracted with EtOAc and H2O.
¼ 8.25 Hz), 7.74 (t, 1H, J ¼ 7.45 Hz), 7.70 (d, 2H, J ¼ 8.75 Hz), The organic layer was collected and dried with MgSO4. Aer
7.64 (t, 1H, J ¼ 7.60 Hz), 7.46 (d, 1H, J ¼ 7.30 Hz), 6.92 (d, 2H, J ¼ removal of the organic solvent under vacuum, the residue was
8.8 Hz), 4.19 (t, 2H, J ¼ 6.00 Hz), 3.25 (m, 2H), 2.63 (m, 1H, J1 ¼ puried with ash chromatography and eluted with 90%
5.95 Hz, J2 ¼ 6.50 Hz), 2.54 (m, 1H), 2.36 (q, 1H, J ¼ 8.90 Hz), hexane/10% EtOAc to provide compound 6d (538 mg, 95.9%) as
1.95 (m, 1H), 1.83 (m, 1H), 1.75 (m, 1H), 1.48 (m, 1H), 1.17 (d, a white solid. 1H NMR (CDCl3): d 8.08 (m, 1H), 7.89 (d, 1H, J ¼
3H, J ¼ 6.10 Hz); 13C NMR (CDCl3): d 192.21, 163.42, 146.88, 7.9 Hz), 7.79 (m, 1H), 7.69 (m, 1H), 7.21 (t, 1H, J ¼ 7.8 Hz), 6.98
136.62, 134.18, 131.83, 130.44, 129.19, 129.04, 124.61, 114.76, (d, J ¼ 8.8 Hz, 2H), 4.22 (t, 2H, J ¼ 5.8 Hz), 3.77 (t, 2H, J ¼ 6.3
67.30, 60.96, 54.90, 52.57, 32.45, 22.02, 18.86 ppm. ESI-MS (M+ + Hz), 2.29 (q, 2H, J ¼ 6.0 Hz); 13C NMR (CDCl3): d 193.77, 162.73,
1): found 355.01, calculated for C20H23N2O4, 355.16.
140.75, 140.28, 138.40, 132.66, 130.01, 129.73, 128.88 (s),
114.33, 94.14, 64.69, 41.40, 32.14.
(4-(3-Chloropropoxy)phenyl)(3-uorophenyl)methanone (6c)
(R)-(3-Iodophenyl)(4-(3-(2-methylpyrrolidin-1-yl)propoxy)-
phenyl)methanone (7d)
(3-Fluorophenyl) (4-hydroxyphenyl)methanone 3c (500 mg, 2.3
mmol) and 1-bromo-3-chloropropane (455 mL, 4.6 mmol) were
suspended in 25 mL of acetonitrile. Anhydrous potassium Compound 6d (350 mg, 0.87 mmol), (R)-2-methylprrodine
carbonate (954 mg, 6.9 mmol) was then added to the reaction (106 mL, 1.04 mmol), KI (144 mg, 0.87 mmol), anhydrous
mixture. The reaction mixture was reuxed for 19 h, concen- potassium carbonate (361 mg, 2.61 mmol), and acetonitrile (30
trated under vacuum, and then extracted with EtOAc and H2O. mL) were added to a round-bottom ask. The mixture was
The organic layer was collected and dried with MgSO4. Aer heated at reux for 24 h, cooled to room temperature, and
removal of the organic solvent under vacuum, the residue was concentrated, and the product was puried by column chro-
puried with ash chromatography and eluted with 90% matography and eluted with 98% CH2Cl2/2% MeOH to provide
1
hexane/10% EtOAc to yield compound 6c (663 mg, 98.5%) as a compound 7d (244 mg, 62.1%) as a primrose yellow solid. H
chromatic transparent oil. 1H NMR (CDCl3): d 7.81 (m, 2H), 7.51 NMR (CDCl3): d 8.06 (m, 1H), 7.88 (d, 1H, J ¼ 7.9 Hz), 7.78 (d,
(m, 1H), 7.44 (m, 2H), 7.25 (m, 1H), 6.97 (dd, 2H, J1 ¼ 6.8 Hz, J2 2H, J ¼ 8.8 Hz), 7.68 (d, 1H, J ¼ 7.7 Hz), 7.20 (t, 1H, J ¼ 7.8 Hz),
¼ 2.0 Hz), 4.20 (t, 2H, J¼ 5.85 Hz), 3.76 (t, 2H, J ¼ 6.3 Hz), 2.27 6.96 (d, 2H, J ¼ 8.8 Hz), 4.12 (m, 2H), 3.28 (m, 1H), 3.06 (m, 1H),
(q, 2H, J1 ¼ 6.0 Hz, J2 ¼ 12.1 Hz); 13C NMR (CDCl3): d 193.91, 2.49 (m, 1H), 2.36 (m, 1H), 2.28 (m, 1H), 2.09 (m, 2H), 1.99 (m,
163.48, 162.70, 161.51, 140.43, 132.60, 130.02, 125.53, 119.01, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.52 (m, 1H), 1.17 (d, 3H, J ¼ 6.2
116.58, 114.27, 64.68, 41.37, 32.10.
Hz); 13C NMR (CDCl3): d 193.85, 163.02, 140.69, 140.34, 138.36,
6768 | RSC Adv., 2014, 4, 6761–6775
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132.63, 129.97, 129.49, 128.83, 114.31, 94.06, 66.61, 61.00, 129.64, 114.48, 113.24, 67.11, 40.67. GC-MS (M+): found 278.03;
53.90, 50.66, 32.56, 27.97, 21.70, 18.44. ESI-MS (M+ + 1): found calculated for C15H12ClFO2, 278.05.
450.2, calculated for C20H24INO2, 450.09.
(R)-(4-Fluorophenyl)(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)-
phenyl)methanone (7e0)
(4-(3-Chloropropoxy)phenyl)(4-uorophenyl)methanone (6e)
A mixture of compound 6e0 (279 mg, 1 mmol), K2CO3 (484 mg,
3.5 mmol), KI (100 mg, 0.6 mmol), and (R)-2-methylpyrrolidine
(200 mL, 2 mmol) in acetonitrile (15 mL) was heated at 85 ꢀC for
(4-Fluorophenyl)(4-hydroxyphenyl)methanone (1.08 g, 5 mmol)
and 1-bromo-3-chloropropane (1.57 g, 10 mmol) were sus-
pended in 10 mL of acetonitrile (99.0%). Anhydrous potassium
carbonate (2.07 g, 15 mmol) was then added to the reaction
24 h. The reaction mixture was allowed to cool and ltered
through celite, and the ltrate was concentrated under reduced
mixture. The reaction mixture was reuxed for 24 h, concen-
pressure. The residue was puried with ash chromatography
trated under vacuum, and then extracted with EtOAc and H2O.
and eluted with 98% CH2Cl2/2% MeOH to give compound 7e0
The organic layer was collected and dried with MgSO4. Aer
(173 mg, 53.0%) as a yellow oil. 1H NMR (CDCl3): d 7.79 (m, 4H),
removal of the organic solvent under vacuum, the residue was
7.15 (t, 2H, J ¼ 8.6 Hs), 6.98 (d, 2H, J ¼ 8.8 Hs), 4.19 (m, 2H), 3.25
puried with ash chromatography and eluted with 20% EtOAc/
(m, 2H), 2.58 (m, 1H, J1 ¼ 6.0 Hz, J2 ¼ 6.4 Hz), 2.44 (m, 1H), 2.30
hexane to provide 1 (789 mg, 54.6%) as a white wax; mp: 47–48
(q, 1H, J ¼ 8.8 Hz), 1.94 (m, 1H), 1.82 (m, 1H), 1.73 (m, 1H), 1.45
(m, 1H), 1.15 (d, 3H, J ¼ 6.1 Hz); 13C NMR (CDCl3): d 194.20,
166.16, 164.14, 162.66, 134.56, 132.42, 132.36, 130.08, 115.51,
115.34, 114.30, 67.58, 60.58, 55.01, 52.75, 32.52, 22.03, 19.17;
19FNMR (CDCl3): d ꢁ106.95. ESI-MS (M+ + 1): 328.01; calculated
for C20H23FNO2, 328.16.
ꢀC. 1H NMR (CDCl3): d 7.82 (m, 4H), 7.17 (t, 2H, J ¼ 8.6 Hz), 7.00
(d, 2H, J ¼ 8.8 Hz), 4.22 (t, 2H, J ¼ 5.8 Hz), 3.79 (t, 2H, J ¼ 6.2
Hz), 2.30 (q, 2H, J1 ¼ 6.0 Hz, J2 ¼ 12 Hz); 13C NMR (CDCl3): d
194.02, 166.06, 164.05, 162.34, 134.38, 132.23, 130.20, 115.22,
114.08, 64.49, 41.24, 32.02. GC-MS (M+): found 291.93; calcu-
lated for C16H14ClFO2, 292.07.
(4-(3-Chloropropoxy)phenyl)(4-nitrophenyl)methanone (6f)
(R)-(4-Fluorophenyl)(4-(3-(2-methylpyrrolidin-1-yl)propoxy)-
phenyl)methanone (7e)
(4-Hydroxyphenyl)(4-nitrophenyl)methanone (1.332 g, 5.48
mmol) and 1-bromo-3-chloropropane (3.451 g, 10.96 mmol)
were suspended in 20 mL of acetonitrile (99.0%). Anhydrous
potassium carbonate (2.272 g, 16.44 mmol) was then added to
the reaction mixture. The reaction mixture was reuxed for 24 h,
concentrated under vacuum, and then extracted with EtOAc and
H2O. The organic layer was collected and dried with MgSO4.
Aer removal of the organic solvent under vacuum, the residue
was puried with ash chromatography and eluted with 80%
EtOAc/20% hexane to provide 1 (1.369 g, 78.3%) as a pale yellow
Compound 6e (292 mg, 1 mmol), (R)-2-methylprrodine (170.3
mg, 2 mmol), potassium iodide (166 mg, 1 mmol), anhydrous
potassium carbonate (415 mg, 3 mmol), and acetonitrile
(99.0%, 10 mL) were added to a round-bottom ask. The
mixture was heated at reux for 24 h, cooled to room temper-
ature, and concentrated, and the product was puried by
column chromatography and eluted with 98% CH2Cl2/2%
MeOH to give 7e (212 mg, 62%) as a light brown solid; mp: 127–
129 ꢀC. 1H NMR (CDCl3): d 7.79 (m, 4H), 7.15 (t, 2H, J ¼ 8.2 Hz),
6.97 (d, 2H, J ¼ 8.2 Hz), 4.19 (m, 2H), 3.74 (s, 1H), 3.43 (m, 2H),
3.07 (m, 2H), 2.5 (m, 1H), 2.28 (m, 2H), 2.16 (m, 1H), 2.07 (m,
1H), 1.92 (m, 1H), 1.57 (d, 3H, J ¼ 6.1 Hz); 13CNMR (CDCl3): d
193.95, 166.12, 164.11, 161.72, 134.19, 132.39, 132.31, 133.24,
130.62, 115.46, 115.29, 114.05, 65.22, 53.17, 50.55, 31.48, 29.65,
25.39, 21.25, 15.51. ESI-MS (M+ + 1): found 342.04; calculated for
1
ꢀ
solid; mp: 110–112 C. H NMR (CDCl3): d 8.36 (d, 2H, J ¼ 8.6
Hz), 7.91 (d, 2H, J ¼ 8.6 Hz), 7.83 (d, 2H, J ¼ 8.8 Hz), 7.02 (d, 2H,
J ¼ 8.8 Hz), 4.24 (t, 2H, J ¼ 5.8 Hz), 3.79 (t, 2H, J ¼ 6.2 Hz), 2.31
(q, 2H, J1 ¼ 6.0 Hz, J2 ¼ 6.0 Hz); 13C NMR (CDCl3): d 193.42,
163.14, 149.57, 143.76, 132.67, 130.34, 129.14, 123.50, 114.45,
64.66, 41.20, 32.00. GC-MS (M+): found 319.01; calculated for
C
16H14ClNO4, 319.06.
C
14H24FNO2, 342.19.
(R)-(4-(3-(2-Methylpyrrolidin-1-yl)propoxy)phenyl)(4-
nitrophenyl)methanone (7f)
(4-(2-Chloroethoxy)phenyl)(4-uorophenyl)methanone (6e0)
(4-Fluorophenyl)(4-hydroxyphenyl)methanone (1.000 g, 4.6 Compound 6f (319 mg, 1 mmol), (R)-2-methylprrodine (170.3
mmol) and 1-bromo-2-chloroethane (0.766 mL, 9.2 mmol) were mg, 2 mmol), potassium iodide (166 mg, 1 mmol), anhydrous
suspended in 20 mL of acetonitrile. Anhydrous potassium potassium carbonate (415 mg, 3 mmol), and acetonitrile
carbonate (1.908 g, 13.8 mmol) was then added to the mixture. (99.0%, 10 mL) were added to a round-bottom ask. The
The reaction mixture was reuxed for 24 h, concentrated under mixture was heated at reux for 24 h, cooled to room temper-
vacuum, and extracted with EtOAc and H2O. The organic layer ature, and concentrated, and the product was puried by
was collected and dried over MgSO4. Aer removal of the column chromatography and eluted with 95% CH2Cl2/5%
organic solvent under vacuum, the residue was puried with MeOH to give 6 (288 mg, 78.2%) as a yellow oil; mp: 167–169 ꢀC.
ash chromatography and eluted with 90% hexane/10% EtOAc 1H NMR (CDCl3): d 8.33 (d, 2H, J ¼ 8.4 Hz), 7.88 (d, 2H, J ¼ 8.4
1
to provide compound 6e0 (700 mg, 54.6%) as a white wax. H Hz), 7.80 (d, 2H, J ¼ 8.6 Hz), 7.00 (d, 2H, J ¼ 8.6 Hz), 4.23 (t, 2H,
NMR (CDCl3): d 7.80 (m, 4H), 7.15 (t, 2H, J ¼ 8.6 Hz), 6.99 (d, 2H, J¼ 5.4 Hz), 3.88 (m, 1H), 3.57 (m, 2H), 3.24 (m, 2H), 2.67 (m, 1H),
J ¼ 8.7 Hz), 4.31 (t, 2H, J ¼ 5.8 Hz), 3.85 (t, 2H, J ¼ 5.8 Hz); 13
C
2.38 (m, 2H), 2.26 (m, 1H), 2.16 (m, 1H), 2.05 (m, 1H), 1.66
NMR (CDCl3): d 193.01, 165.13, 163.12, 160.79, 133.28, 131.43, (s, 3H); 13C NMR (CDCl3): d 192.35, 161.54, 148.52, 142.55,
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131.64, 129.35, 128.40, 122.50, 113.47, 64.35, 52.21, 49.34,
30.44, 28.65, 24.30, 20.32, 14.47. ESI-MS (M+ + 1): found 369.02;
calculated for C21H24N2O4, 369.18.
4-(2-Nitrophenoxy)phenol (3B)
Compound 2B (3.724 g, 15.2 mmol) was suspended in hydro-
bromic acid (155 mL, 40%) and acetic acid (125 mL, 99.7%). The
reaction mixture was reuxed for 16 h and extracted with
CH2Cl2 and H2O. The organic layer was collected and dried over
MgSO4. Aer removal of the organic solvent under vacuum, the
residue was puried with ash chromatography and eluted with
EtOAc/hexane (20 : 80, v/v) to provide compound 3B (3.299 g,
93.9%) as a yellow solid. 1H NMR (DMSO-d6): d 9.50 (s, 1H), 7.98
(dd, 1H, J1 ¼ 1.55 Hz, J2 ¼ 8.10 Hz), 7.58 (m, 1H), 7.22 (m, 1H),
6.93 (m, 3H), 6.80 (m, 2H) ppm.
(4-(2-Chloroethoxy)phenyl)(4-nitrophenyl)methanone (6f0)
(4-Hydroxylphenyl)(4-nitrophenyl)methanone (1.483 g, 6.1 mmol)
and 1-bromo-2-chloroethane (1.015 mL, 12.2 mmol) were sus-
pended in 50 mL of acetonitrile. Anhydrous potassium carbonate
(2.529 g, 12.2 mmol) was then added to the mixture. The reaction
mixture was reuxed for 24 h, concentrated under vacuum, and
extracted with EtOAc and H2O. The organic layer was collected
and dried over MgSO4. Aer removal of the organic solvent under
vacuum, the residue was puried with ash chromatography and
eluted with 90% hexane/10% EtOAc to obtain compound 6f0
(1.120 g, 60.7%) as a white wax. 1H NMR (CDCl3): d 8.35 (d, 2H,
J ¼ 8.7 Hz), 7.90 (d, 2H, J ¼ 8.8 Hz), 7.83 (d, 2H, J ¼ 8.8 Hz), 7.02
(d, 2H, J ¼ 8.8 Hz), 4.34 (t, 2H, J ¼ 5.8 Hz), 3.87 (t, 2H, J ¼ 5.8 Hz);
13C NMR (CDCl3): d 193.51, 162.65, 149.67, 143.70, 132.80,
130.48, 129.62, 123.63, 114.66, 68.33, 41.77 ppm. GC-MS (M+):
found 305.02; calculated for C15H12ClNO4, 305.04.
2-Iodo-4-(2-nitrophenoxy)phenol (4B)
At 0 ꢀC, 40% aqueous MeNH2 (14.8 mL) and then a solution of
KI (5.93 g, 35.7 mmol) and I2 (2.40 g, 9.45 mmol) in H2O
(18.5 mL) were added to a solution of 4-(4-nitrophenoxy)phenol
(1.46 g, 6.30 mmol) in EtOH (148 mL). The reaction mixture was
ꢀ
stirred at 0 C for 1 h, quenched with H2O, and extracted with
EtOAc. The organic layer was dried over MgSO4, ltered, and
concentrated under reduced pressure. The residue was puried
by column chromatography on silica gel and eluted with CH2Cl2
to give 4B (1.086 g, 48.3%). 1H NMR (DMSO-d6): d 10.38 (s, 1H),
8.00 (dd, 1H, J1 ¼ 1.6 Hz, J2 ¼ 8.1 Hz), 7.61 (m, 1H), 7.43 (d, 1H,
J ¼ 2.9 Hz), 7.26 (m, 1H), 7.00 (m, 2H), 6.91 (d, 1H, J ¼ 8.8 Hz);
13C NMR (DMSO-d6): d 154.73, 151.05, 147.97, 140.88, 135.44,
130.11, 126.07, 123.79, 121.44, 119.72, 115.94, 85.18 ppm.
(R)-(4-(2-(2-Methylpyrrolidin-1-yl)ethoxy)phenyl)(4-
nitrophenyl)methanone (7f0)
A mixture of compound 6f0 (611 mg, 2 mmol), K2CO3 (829 mg,
6 mmol), KI (332 mg, 2 mmol), and (R)-2-methylpyrrolidine
ꢀ
(240 mL, 2.4 mmol) in acetonitrile (25 mL) was heated at 85 C
for 24 h. The reaction mixture was allowed to cool and ltered
through celite, and the ltrate was concentrated under reduced
pressure. The residue was puried through ash chromatog-
raphy and eluted with 98% CH2Cl2/2% MeOH to yield
compound 7f0 (590 mg, 83.0%) as a yellow oil. 1H NMR (CDCl3):
d 8.34 (d, 2H, J ¼ 8.8 Hz), 7.89 (d, 2H, J ¼ 8.8 Hz), 7.81 (d, 2H, J ¼
8.8 Hz), 7.00 (d, 2H, J ¼ 9.0 Hz), 4.20 (m, 2H), 3.26 (m, 2H), 2.59
(m, 1H, J1 ¼ 6.1 Hz, J2 ¼ 6.4 Hz), 2.47 (m, 1H), 2.31 (q, 1H, J ¼ 8.8
Hz), 1.95 (m, 1H), 1.83 (m, 1H), 1.74 (m, 1H), 1.45 (m, 1H), 1.15
(d, 3H, J ¼ 6.1 Hz); 13C NMR (CDCl3): d 193.45, 163.39, 149.52,
143.88, 132.71, 130.40, 128.90, 123.53, 114.59, 67.78, 60.49,
55.01, 52.69, 32.52, 22.02, 19.22 ppm. ESI-MS (M+ + 1): found
355.04, calculated for C20H23N2O4, 355.16.
(R)-2-Methyl-1-(2-(5-(2-nitrophenoxy)benzofuran-2-yl)ethyl)-
pyrrolidine (5B)
(R)-1-(But-3-yn-1-yl)-2-methylpyrrolidine (20 mL of 0.1 M solu-
tion in CH3CN, 2.0 mmol) and compound 4B (500 mg,
1.40 mmol) were mixed in a 100 mL round-bottom ask.
Pd(OAc)2 (9 mg, 0.041 mmol), tri(4-methylpenyl)phosphine
(25 mg, 0.082 mmol), and CuI (78 mg, 0.41 mmol) were then
added to the reaction mixture. Aer stirring at 25 ꢀC for 10 min,
the reaction mixture was treated with i-Pr2NH (1.96 mL, 13.94
mmol) and then heated at 60 ꢀC under N2 for 16 h. The reaction
mixture was allowed to cool and ltered through celite, and the
ltrate was concentrated under reduced pressure. The residue
was puried on silica gel and eluted with 98% CH2Cl2/2%
1
MeOH to provide 5B (145 mg, 28.2%). H NMR (CDCl3): d 7.95
1-(4-Methoxyphenoxy)-2-nitrobenzene (2B)
(dd, 1H, J1 ¼ 1.6 Hz, J2 ¼ 8.2 Hz), 7.48 (m, 1H), 7.40 (d, 1H, J ¼
8.8 Hz), 7.18 (m, 2H), 6.97 (m, 2H), 6.62 (s, 1H), 3.80 (m, 1H),
3.65 (m, 3H), 3.48 (m, 1H), 3.35 (m, 1H), 3.04 (m, 1H), 2.31
(m, 1H), 2.22 (m, 1H), 2.09 (m, 1H), 2.00 (m, 1H), 1.66 (d, 3H, J ¼
5.5 Hz); 13C NMR (CDCl3): d 154.50, 151.84, 141.00, 134.32,
129.55, 125.79, 122.86, 119.77, 116.65, 112.14, 111.51, 105.25,
65.04, 53.27, 50.76, 31.40, 25.18, 21.41, 15.55. ESI-MS: found [M
+ H]+ 367.12; calculated for C21H22N2O4, [M+ + H], 367.16.
A mixture of 4-methoxyphenol (4.0 g, 32.2 mmol) and anhy-
drous potassium hydroxide (2.0 g, 35.6 mmol) was heated at
150 ꢀC and stirred for 10 min. Aer the mixture melted, 1-
chloro-2-nitrobenzene (4.0 g, 25.4 mmol) was added, and the
mixture was stirred at 170 ꢀC for 2 h (TLC monitor). The reaction
mixture was poured into 80 mL of 3% potassium hydroxide
aqueous solution, stirred at room temperature for approxi-
mately 2 h, and then cooled to 4 ꢀC. The solid was ltered with
suction and washed with water. The crude product was then
dissolved in CH2Cl2, introduced onto a silica gel column, and
1-Fluoro-4-(4-methoxyphenoxy)benzene (2E)
eluted with 10% EtOAc/90% hexane to obtain compound 2B 1-Fluoro-4-iodobenzene (444 mg, 2 mmol), CuI (38 mg, 0.2
(5.29 g, 84.9%) as a yellow solid. 1H NMR (DMSO-d6): d 8.02 (dd, mmol), n-Bu4NBr (64 mg, 0.2 mmol), and K3PO4 (849 mg, 4
1H, J1 ¼ 1.65 Hz, J2 ¼ 8.15 Hz), 7.62 (m, 1H), 7.27 (m, 1H), 7.08 mmol) were added to a round-bottom ask containing 4-
(m, 2H), 6.99 (m, 3H), 3.76 (s, 3H) ppm.
methoxyphenol (248 mg, 2 mmol) under a N2 atmosphere; DMF
6770 | RSC Adv., 2014, 4, 6761–6775
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(2 mL) was then added to the mixture. The reaction mixture was 119.65, 119.59, 116.37, 116.28, 116.19, 111.82, 110.56, 105.22,
vigorously reuxed for 22 h. Aer cooling to room temperature, 65.12, 53.28, 50.65, 31.37, 25.13, 21.41, 15.50 ppm; 19F NMR
saturated NH4Cl (20 mL) was added, and the organic layer was (CDCl3): d 121.34 ppm. ESI-MS: found [M + H]+ 340.03; calcu-
extracted with EtOAc (3 ꢃ 20 mL). The combined organic layer lated for C21H22FNO2, [M+ + H], 340.16.
was then washed with brine (20 mL), dried over MgSO4, ltered,
and concentrated to dryness. The reside was puried using a
silica gel column with EtOAc/hexane (5 : 95, v/v) to obtain
compound 2E (138 mg, 31.6%) as a pale yellow oil. 1H NMR
(CDCl3): d 6.98 (t, 2H, J ¼ 9.05 Hz), 6.95 (d, 2H, J ¼ 9.1 Hz), 6.90
(m, 2H), 6.88 (d, 2H, J ¼ 9.05 Hz), 3.79 (s, 3H) ppm; 19FNMR
(CDCl3): d 121.34 ppm.
1-(4-Methoxyphenoxy)-4-nitrobenzene (2F)
A mixture of 4-methoxyphenol (2.0 g, 16.1 mmol) and anhydrous
potassium hydroxide (1.0 g, 17.8 mmol) were heated at 150 C
ꢀ
and stirred for 10 min. Aer the mixture melted, 1-chloro-4-
nitrobenzene (2.0 g, 12.7 mmol) was added, and the mixture was
stirred at 170 ꢀC for 2 h (TLC monitor). The reaction mixture was
poured into 50 mL of 3% potassium hydroxide aqueous solution,
stirred at room temperature for approximately 2 h, and then
4-(4-Fluorophenoxy)phenol (3E)
ꢀ
Compound 2E (1.472 g, 6.75 mmol) was suspended in hydro-
bromic acid (70 mL, 40%) and acetic acid (58 mL, 99.7%). The
reaction mixture was reuxed for 16 h and extracted with
CH2Cl2 and H2O. The organic layer was collected and dried over
MgSO4. Aer removal of the organic solvent under vacuum, the
residue was puried with ash chromatography and eluted with
CH2Cl2 (100%) to yield compound 3E (1.005 g, 72.9%) as a milky
white solid. 1H NMR (500 MHz, DMSO-d6): d 7.00 (t, 2H, J ¼ 8.75
Hz), 6.91 (m, 4H), 6.82 (d, 2H, J ¼ 8.85 Hz), 4.92 (s, 1H).
cooled to 4 C. The solid was ltered with suction and washed
with water. The crude product was dissolved in CH2Cl2, intro-
duced onto a silica gel column, and eluted with 10% EtOAc/90%
hexane to provide compound 2F (2.432 g, 77.8%) as a yellow
solid. 1H NMR (DMSO-d6): d 8.24 (d, 2H, J ¼ 9.25 Hz), 7.16 (d, 2H,
J ¼ 9.05 Hz), 7.05 (m, 4H), 3.79 (s, 3H).
4-(4-Nitrophenoxy)phenol (3F)
Compound 2F (1.80 g, 7.34 mmol) was suspended in hydro-
bromic acid (77 mL, 40%) and acetic acid (63 mL, 99.7%). The
reaction mixture was reuxed for 16 h and extracted with
CH2Cl2 and H2O. The organic layer was collected and dried over
Na2SO4. Aer removal of the organic solvent under vacuum, the
residue was puried with ash chromatography and eluted with
EtOAc/hexane (20 : 80, v/v) to provide compound 3F (1.65 g,
2-Iodo-4-(4-uorophenoxy)phenol (4E)
At 0 ꢀC, 40% aqueous MeNH2 (11.4 mL) and then a solution of
KI (4.55 g, 27.4 mmol) and I2 (1.65 g, 6.52 mmol) in H2O (15 mL)
were added to a solution of compound 3E (987 mg, 4.83 mmol)
in EtOH (114 mL). The reaction mixture was stirred at 0 ꢀC for 1
h, quenched with H2O, and extracted with EtOAc. The organic
layer was dried over MgSO4, ltered, and concentrated under
reduced pressure. The residue was puried by column chro-
matography on silica gel and eluted with CH2Cl2 to give 4E
(1.157 g, 72.6%). 1H NMR (CDCl3): d 7.29 (d, 1H, J ¼ 2.6 Hz), 7.00
(t, 2H, J ¼ 9.1 Hz), 6.94 (d, 1H, J ¼ 8.8 Hz), 6.91 (m, 3H), 5.18
(s, 1H) ppm; 13C NMR (CDCl3): d 159.70, 157.78, 153.63, 151.34,
128.32, 121.06, 119.67, 116.52, 115.43, 85.22 ppm.
1
96.8%) as a yellow powder. H NMR (DMSO-d6): d 9.57 (s, 1H),
8.21 (d, 2H, J ¼ 9.35 Hz), 7.02 (m, 4H), 6.85 (d, 2H, J ¼ 8.95 Hz).
2-Iodo-4-(4-nitrophenoxy)phenol (4F)
At 0 ꢀC, 40% aqueous MeNH2 (18 mL) and then a solution of KI
(7.32 g, 44.1 mmol) and I2 (2.66 g, 10.5 mmol) in H2O (10 mL)
were added to a solution of 4-(4-nitrophenoxy)phenol (1.80 g,
7.78ꢀmmol) in EtOH (183 mL). The reaction mixture was stirred
at 0 C for 1 h, quenched with H2O, and extracted with EtOAc.
The organic layer was dried over MgSO4, ltered, and concen-
trated under reduced pressure. The residue was puried by
column chromatography on silica gel and eluted with CH2Cl2 to
(R)-2-Methyl-1-(2-(5-(4-uorophenoxy)benzofuran-2-yl)ethyl)-
pyrrolidine (5E)
(R)-1-(But-3-yn-1-yl)-2-methylpyrrolidine (20 mL of 0.1 M solu-
tion in CH3CN, 2.0 mmol) and compound 4E (510 mg, 1.54
mmol) were mixed in a 100 mL round-bottom ask. Pd(OAc)2
(10 mg, 0.0454 mmol), tri(4-methylpenyl)phosphine (28 mg,
0.0909 mmol), and CuI (86 mg, 0.454 mmol) were then added to
the reaction mixture. Aer stirring at 25 ꢀC for 10 min, the
reaction mixture was treated with i-Pr2NH (2.17 mL, 15.4 mmol)
and then heated at 60 ꢀC under N2 for 16 h. The reaction
mixture was allowed to cool and ltered through celite, and the
1
give 4F (1.013 g, 36.5%). H NMR (DMSO-d6): d 10.46 (s, 1H),
8.22 (d, 1H, J ¼ 9.2 Hz), 7.52 (d, 1H, J ¼ 2.8 Hz), 7.07 (m, 3H),
6.97 (d, 1H, J ¼ 8.7 Hz); 13C NMR (DMSO-d6): d 164.19, 155.22,
146.97, 142.48, 131.30, 126.70, 122.57, 117.16, 116.04.
(R)-2-Methyl-1-(2-(5-(4-nitrophenoxy)benzofuran-2-yl)ethyl)-
pyrrolidine (5F)
ltrate was concentrated under reduced pressure. The residue (R)-1-(But-3-yn-1-yl)-2-methylpyrrolidine (20 mL of 0.1 M solu-
was puried on silica gel and eluted with 98% CH2Cl2/2% tion in CH3CN, 2.0 mmol) and compound 4F (500 mg,
1
MeOH to provide 5E (155 mg, 29.6%). H NMR (CDCl3): d 7.36 1.40 mmol) were mixed in a 100 mL round bottom ask.
(d, 1H, J ¼ 8.85 Hz), 7.08 (d, 1H, J ¼ 2.45 Hz), 7.01 (t, 2H, J ¼ 8.65 Pd(OAc)2 (9 mg, 0.041 mmol), tri(4-methylpenyl)phosphine
Hz), 6.94 (m, 3H), 6.60 (s, 1H), 4.16–3.92 (m, 1H), 3.82–3.63 (m, (25 mg, 0.082 mmol), and CuI (78 mg, 0.41 mmol) were then
2H), 3.61–3.45 (m, 2H), 3.41–3.30 (m, 1H), 3.04–2.80 (m, 1H), added to the reaction mixture. Aer stirring at 25 ꢀC for 10 min,
2.39–2.21 (m, 2H), 2.17–1.97 (m, 2H), 1.82–1.59 (m, 3H); 13C the reaction mixture was treated with i-Pr2NH (1.96 mL, 13.94
NMR (CDCl3): d 159.49, 157.57, 154.12, 153.30, 151.19, 129.29, mmol) and then heated at 60 ꢀC under N2 for 16 h. The reaction
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mixture was allowed to cool and ltered through celite, and the and H2O. The organic layer was collected and dried over MgSO4.
ltrate was concentrated under reduced pressure. The residue Aer removal of the organic solvent under vacuum, the residue
was puried on silica gel and eluted with 98% CH2Cl2/2% was puried with ash chromatography and eluted with EtOAc/
MeOH to provide 5F (145 mg, 28.2%). 1H NMR (DMSO-d6): d hexane (10 : 90, v/v) to provide compound 6B0 (555 mg, 43.8%)
8.19 (d, 2H, J ¼ 9.2 Hz), 7.45 (d, 1H, J ¼ 8.8 Hz), 7.24 (d, 1H, J ¼ as a jasmine solid. 1H NMR (CDCl3): d 7.92 (dd, 1H, J1 ¼ 1.60 Hz,
2.4 Hz), 6.99 (m, 3H), 6.66 (s, 1H), 3.79 (m, 1H), 3.65 (m, 2H), J2 ¼ 8.15 Hz), 7.45 (m, 1H), 7.13 (m, 1H), 7.02 (m, 2H), 6.92 (m,
3.48 (m, 2H), 3.26 (m, 1H), 2.94 (m, 1H), 2.26 (m, 2H), 2.04 (m, 3H), 4.22 (t, 2H, J ¼ 5.80 Hz), 3.82 (2H, t, J ¼ 5.85 Hz); 13C NMR
2H), 1.64 (d, 3H, J ¼ 5.7 Hz) ppm; 13C NMR (DMSO-d6): d 164.19, (CDCl3): d 155.44, 151.75, 149.31, 140.78, 134.29, 125.78, 122.62,
154.79, 152.21, 150.46, 142.53, 129.78, 126.03, 117.47, 116.69, 121.17, 119.25, 116.21, 68.67, 42.18 ppm.
112.84, 112.33, 105.25, 65.03, 53.25, 50.87, 31.45, 25.29, 21.42,
15.60. ESI-MS: found [M
C
+
H]+, 367.06; calculated for (R)-2-Methyl-1-(2-(4-(2-nitrophenoxy)phenoxy)ethyl)
21H22N2O4, [M+ + H], 367.16.
pyrrolidine (7B0)
A mixture of compound 6B0 (300 mg, 1.02 mmol), K2CO3
(846 mg, 6.12 mmol), KI (338 mg, 2.04 mmol), and (R)-2-meth-
1-(4-(3-Chloropropoxy)phenoxy)-2-nitrobenzene (6B)
Compound 3B (500 mg, 2.16 mmol) and 1-bromo-3-chlor- ylpyrrolidine (206 mL, 2.04 mmol) in acetonitrile (20 mL) was
opropane (427 mL, 4.32 mmol) were suspended in 25 mL heated at 85 ꢀC for 48 h. The reaction mixture was cooled to
acetonitrile. Anhydrous potassium carbonate (896 mg, 6.48 room temperature and ltered through diatomite, and the
mmol) was then added to the mixture. The reaction mixture was ltrate was concentrated under reduced pressure. The residue
reuxed for 38 h, concentrated under vacuum, and extracted was puried with ash chromatography and eluted with
with EtOAc and H2O. The organic layer was collected and dried MeOH/CH2Cl2 (3 : 97, v/v) to give compound 7B0 (253 mg,
over MgSO4. Aer removal of the organic solvent under vacuum, 72.5%) as a deep yellow wax. 1H NMR (CDCl3): d 7.92 (d, 1H, J ¼
the residue was puried with ash chromatography and eluted 8.10 Hz), 7.45 (m, 1H), 7.12 (t, 1H, J ¼ 7.90 Hz), 6.99 (m, 2H),
with EtOAc/hexane (10 : 90, v/v) to provide compound 6B (573 6.92 (t, 3H, J ¼ 7.95 Hz), 4.17 (t, 2H, J ¼ 4.95 Hz), 3.34 (m, 1H),
mg, 86.1%) as a yellow oil. 1H NMR (CDCl3): d 7.94 (dd, 1H, J1 ¼ 3.28 (m, 1H), 2.67 (m, 1H), 2.60 (m, 1H), 2.44 (m, 1H), 2.00 (m,
1.50 Hz, J2 ¼ 8.15 Hz), 7.46 (m, 1H), 7.14 (m, 1H), 7.03 (m, 2H), 1H), 1.88 (m, 1H), 1.78 (m, 1H), 1.53 (m, 1H), 1.23 (d, 3H, J ¼
6.93 (d, 3H, J ¼ 8.85 Hz), 4.12 (t, 2H, J ¼ 5.80 Hz), 3.77 (t, 2H, J ¼ 6.10 Hz); 13C NMR (CDCl3): d 155.89, 151.97, 148.80, 140.71,
6.30 Hz), 2.26 (m, 2H); 13C NMR (CDCl3): d 156.01, 151.91, 134.17, 125.75, 122.37, 121.19, 119.05, 115.93, 67.10, 61.17,
148.87, 140.75, 134.24, 125.74, 122.48, 121.18, 119.13, 115.90, 54.82, 52.71, 32.29, 21.89, 18.62 ppm. ESI-MS: found [M + H]+,
64.87, 41.64, 32.30 ppm.
343.08; calculated for C19H22N2O4, [M+ + H], 343.16.
(R)-2-Methyl-1-(3-(4-(2-nitrophenoxy)phenoxy)propyl)
pyrrolidine (7B)
1-(4-(3-Chloropropoxy)phenoxy)-4-uorobenzene (6E)
Compound 3E (408 mg, 2.0 mmol) and 1-bromo-3-chlor-
A mixture of compound 6B (450 mg, 1.46 mmol), K2CO3 (605 opropane (396 mL, 4.0 mmol) were suspended in 10 mL of
mg, 4.38 mmol), KI (242 mg, 1.46 mmol), and (R)-2-methyl- acetonitrile. Adding anhydrous potassium carbonate (829 mg,
pyrrolidine (177 mL, 1.75 mmol) in acetonitrile (25 mL) was 6.0 mmol) was then added to the mixture. The reaction mixture
heated at 85 ꢀC for 48 h. The reaction mixture was cooled to was reuxed for 43 h, concentrated under vacuum, and extrac-
room temperature and ltered through diatomite, and the ted with EtOAc and H2O. The organic layer was collected and
ltrate was concentrated under reduced pressure. The residue dried over MgSO4. Aer removal of the organic solvent under
was puried with ash chromatography and eluted with MeOH/ vacuum, the residue was puried with ash chromatography
CH2Cl2 (3 : 97, v/v) to obtain compound 7B (237 mg, 45.5%) as a and eluted with EtOAc/hexane (5 : 95, v/v) to provide compound
buff oil. 1H NMR (CDCl3): d 7.92 (dd, 1H, J1 ¼ 1.30 Hz, J1 ¼ 8.15 6E (547 mg, 97.5%) as a pale yellow oil. 1H NMR (CDCl3): d 7.03–
Hz), 7.44 (m, 1H), 7.12 (m, 1H), 7.01 (m, 2H), 6.92 (m, 3H), 4.03 6.99 (m, 2H), 6.98–6.89 (m, 6H), 4.11 (t, 2H, J ¼ 5.90 Hz), 3.78
(m, 2H), 3.20 (m, 1H), 3.01 (m, 1H), 2.35 (m, 1H), 2.23 (m, 1H), (t, 2H, J ¼ 6.35 Hz), 2.25 (m, 2H); 13C NMR (CDCl3): d 159.41,
2.16 (m, 1H), 2.04 (m, 2H), 1.92 (m, 1H), 1.80 (m, 1H), 1.71 (m, 157.50, 155.05, 150.96, 120.38, 119.34, 116.37, 115.70, 64.84,
1H), 1.45 (m, 1H), 1.12 (d, 3H, J ¼ 6.00 Hz); 13C NMR (CDCl3): d 41.66, 32.40 ppm; 19F NMR (CDCl3): d ꢁ121.20 ppm.
156.35, 152.06, 148.50, 140.66, 134.12, 125.71, 122.27, 121.18,
118.94, 115.85 67.00, 60.43, 54.06, 50.85, 32.76, 28.59, 21.73, (R)-1-(3-(4-(4-Fluorophenoxy)phenoxy)propyl)-2-
19.00 ppm. ESI-MS: found [M + H]+, 357.17; calculated for methylpyrrolidine (7E)
C19H22N2O4, [M+ + H], 357.19.
A mixture of compound 6E (500 mg, 1.785 mmol), K2CO3 (740
mg, 5.355 mmol), KI (296 mg, 1.785 mmol), and (R)-2-methyl-
pyrrolidine (244 mL, 2.412 mmol) in acetonitrile (20 mL) was
1-(4-(2-Chloroethoxy)phenoxy)-2-nitrobenzene (6B0)
Compound 3B (1 g, 4.32 mmol) and 1-bromo-2-chloroethane heated at 85 ꢀC for 48 h. The reaction mixture was cooled to
(716 mL, 8.64 mmol) were suspended in 30 mL of acetonitrile. room temperature and ltered through diatomite, and the
Anhydrous potassium carbonate (1.792 g, 12.96 mmol) was then ltrate was concentrated under reduced pressure. The residue
added to the mixture. The reaction mixture was reuxed for was puried with ash chromatography and eluted with MeOH/
33 h, concentrated under vacuum, and extracted with EtOAc CH2Cl2 (3 : 97, v/v) to give compound 7E (443 mg, 75.4%) as a
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pale yellow oil. 1H NMR (CDCl3): d 7.00–6.93 (m, 2H), 6.92–6.86 (d, 2H, J ¼ 9.25 Hz), 7.05 (d, 2H, J ¼ 9.05 Hz), 6.98 (m, 4H), 4.15
(m, 6H), 4.01 (m, 2H), 3.22 (m, 1H), 3.01 (m, 1H), 2.35 (m, 1H), (t, 2H, J ¼ 5.80 Hz), 3.79 (t, 2H, J ¼ 6.30 Hz), 2.28 (m, 2H); 13C
2.23 (m, 1H), 2.17 (m, 1H), 2.02 (m, 2H), 1.92 (m, 1H), 1.80 NMR (CDCl3): d 164.22, 156.40, 148.02, 142.35, 126.00, 122.00,
(m, 1H), 1.71 (m, 1H), 1.46 (m, 1H), 1.13 (d, 3H, J ¼ 6.1 5 Hz); 13
C
116.47, 116.00, 64.83, 41.62, 32.29 ppm.
NMR (CDCl3): d 159.32, 157.41, 155.34, 154.34, 150.62, 120.32,
119.19, 119.13, 116.26, 116.07, 115.65, 66.99, 60.55, 54.07, (R)-2-Methyl-1-(3-(4-(4-nitrophenoxy)phenoxy)propyl)
50.94, 32.74, 28.60, 21.72, 18.93 ppm; 19F NMR (CDCl3): d pyrrolidine (7F)
ꢁ121.41 ppm. ESI-MS: found [M + H]+, 330.07; calculated for
A mixture of compound 6F (450 mg, 1.46 mmol), K2CO3
C
20H24FNO2, [M+ + H], 330.18.
(605 mg, 4.38 mmol), KI (242 mg, 1.46 mmol), and (R)-2-meth-
ylpyrrolidine (177 mL, 1.75 mmol) in acetonitrile (25 mL) was
heated at 85 ꢀC for 34 h. The reaction mixture was cooled to
1-(4-(2-Chloroethoxy)phenoxy)-4-uorobenzene (6E0)
Compound 3E (530 mg, 2.6 mmol) and 1-bromo-2-chloroethane room temperature and ltered through diatomite, and the
(433 mL, 5.2 mmol) were suspended in 10 mL of acetonitrile. ltrate was concentrated under reduced pressure. The residue
Anhydrous potassium carbonate (1.078 g, 7.8 mmol) was then was puried with ash chromatography and eluted with MeOH/
added to the mixture. The reaction mixture was reuxed for 45 CH2Cl2 (3 : 97, v/v) to give compound 7F (182 mg, 34.9%) as a
1
h, concentrated under vacuum, and extracted with EtOAc and brown oil. H NMR (CDCl3): d 8.17 (d, 2H, J ¼ 9.20 Hz), 7.00
H2O. The organic layer was collected and dried over MgSO4. (d, 2H, J ¼ 9.05 Hz), 6.94 (m, 4H), 4.03 (m, 2H), 3.21 (m, 1H),
Aer removal of the organic solvent under vacuum, the residue 3.01 (m, 1H), 2.35 (m, 1H), 2.23 (m, 1H), 2.16 (m, 1H), 2.02
was puried with ash chromatography and eluted with EtOAc/ (m, 2H), 1.93 (m, 1H), 1.80 (m, 1H), 1.71 (m, 1H), 1.45 (m, 1H),
hexane (5 : 95, v/v) to provide compound 6E0 (330 mg, 47.7%) as 1.12 (d, 3H, J ¼ 6.10 Hz); 13C NMR (CDCl3): d 164.28, 156.71,
a pale yellow solid. 1H NMR (CDCl3): d 7.04–6.99 (m, 2H), 6.97– 147.70, 142.27, 125.95, 121.88, 116.38, 115.96, 66.99, 60.40,
6.90 (m, 6H), 4.22 (t, 2H, J ¼ 5.85 Hz), 3.82 (t, 2H, J ¼ 5.85 Hz); 54.07, 50.85, 32.77, 28.62, 21.73, 19.03 ppm. ESI-MS: found [M +
13C NMR (CDCl3): d 159.48, 157.56, 154.45, 151.44, 120.31, H]+, 357.17; calculated for C19H22N2O4, [M+ + H], 357.03.
119.49, 116.38, 116.06, 68.72, 42.12 ppm; 19F NMR (CDCl3): d
ꢁ120.89 ppm.
1-(4-(2-Chloroethoxy)phenoxy)-4-nitrobenzene (6F0)
Compound 3F0 (500 mg, 2.16 mmol) and 1-bromo-2-chloroethane
(0.358 mL, 4.32 mmol) were suspended in 25 mL of acetonitrile.
Anhydrous potassium carbonate (896 mg, 6.48 mmol) was then
(R)-1-(2-(4-(4-Fluorophenoxy)phenoxy)ethyl)-2-
methylpyrrolidine (7E0)
A mixture of compound 6E0 (320 mg, 1.2 mmol), K2CO3 (498 mg, added to the mixture. The reaction mixture was reuxed for 36 h,
3.6 mmol), KI (199 mg, 1.2 mmol), and (R)-2-methylpyrrolidine concentrated under vacuum, and extracted with EtOAc and H2O.
(146 mL, 1.44 mmol) in acetonitrile (20 mL) was heated at 85 ꢀC The organic layer was collected and dried over MgSO4. Aer
for 48 h. The reaction mixture was cooled to room temperature removal of the organic solvent under vacuum, the residue was
and ltered through diatomite, and the ltrate was concen- puried with ash chromatography and eluted with EtOAc/
trated under reduced pressure. The residue was puried with hexane (10 : 90, v/v) to provide compound 6F0 (377 mg, 59.3%) as
ash chromatography and eluted with MeOH/CH2Cl2 (3 : 97, a jasmine solid. 1H NMR (CDCl3): d 8.20 (d, 2H, J ¼ 9.25 Hz), 7.06
v/v) to give compound 7E0 (263 mg, 69.2%) as a pale orange oil. (d, 2H, J ¼ 9.05 Hz), 6.98 (m, 4H), 4.26 (t, 2H, J ¼ 5.80 Hz), 3.85 (t,
1H NMR (CDCl3): d 7.01–6.96 (m, 2H), 6.93–6.87 (m, 6H), 4.09 2H, J ¼ 5.80 Hz); 13C NMR (CDCl3): d 164.07, 155.85, 148.51,
(m, 2H), 3.24 (m, 2H), 2.53 (m, 1H), 2.43 (m, 1H), 2.29 (m, 1H), 142.46, 126.01, 122.03, 116.55, 116.34, 68.67, 42.03 ppm.
1.92 (m, 1H), 1.81 (m, 1H), 1.71 (m, 1H), 1.42 (m, 1H), 1.15 (d,
3H, J ¼ 6.10 Hz); 13C NMR (CDCl3): d 159.32, 157.44, 155.14, (R)-2-Methyl-1-(2-(4-(4-nitrophenoxy)phenoxy)ethyl)
154.29, 150.73, 120.27, 119.26, 119.20, 116.27, 116.08, 115.67, pyrrolidine (7F0)
67.69, 60.56, 54.07, 52.97, 32.51, 21.99, 19.18 ppm; 19F NMR
A mixture of compound 6F0 (300 mg, 1.02 mmol), K2CO3 (423 mg,
(CDCl3): d ꢁ121.33 ppm. ESI-MS: found [M + H]+, 316.06;
3.06 mmol), KI (169 mg, 1.02 mmol), and (R)-2-methylpyrrolidine
calculated for C19H22N2O4, [M+ + H], 316.16.
(123 mL, 1.22 mmol) in acetonitrile (20 mL) was heated at 85 ꢀC
for 37 h. The reaction mixture was cooled to room temperature
and ltered through diatomite, and the ltrate was concentrated
1-(4-(3-Chloropropoxy)phenoxy)-4-nitrobenzene (6F)
Compound 3F (500 mg, 2.16 mmol) and 1-bromo-3-chlor- under reduced pressure. The residue was puried with ash
opropane (0.427 mL, 4.32 mmol) were suspended in 25 mL of chromatography and eluted with MeOH/CH2Cl2 (2 : 98, v/v) to
1
acetonitrile. Anhydrous potassium carbonate (896 g, 6.48 give compound 7F0 (271 mg, 77.5%) as a brown wax. H NMR
mmol) was then added to the mixture. The reaction mixture was (CDCl3): d 8.18 (d, 2H, J ¼ 9.30 Hz), 7.02 (d, 2H, J ¼ 9.1 Hz), 6.96
reuxed for 24 h, concentrated under vacuum, and extracted (m, 4H), 4.23 (m, 2H), 3.35 (m, 2H), 2.75 (m, 2H), 2.52 (m, 1H),
with EtOAc and H2O. The organic layer was collected and dried 2.05 (m, 1H), 1.94 (m, 1H), 1.83 (m, 1H), 1.60 (m, 1H), 1.29 (d, 3H,
over MgSO4. Aer removal of the organic solvent under vacuum, J ¼ 6.00 Hz); 13C NMR (CDCl3): d 164.17, 156.03, 148.15, 142.36,
the residue was puried with ash chromatography and eluted 125.99, 121.96, 116.49, 116.12, 66.51, 61.85, 54.72, 52.56, 32.09,
with EtOAc/hexane (10 : 90, v/v) to provide compound 6F 21.83, 18.11 ppm. ESI-MS: found [M + H]+, 343.05; calculated for
(563 mg, 84.7%) as a light brown solid. 1H NMR (CDCl3): d 8.20 C19H22N2O4, [M+ + H], 343.16.
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Conclusions
In summary, a series of XB-1 analogues were synthesized and
evaluated at two low concentrations (0.1 mM and 1 mM) to
determine their neuroprotective effects in an in vitro neuronal
injury model in primary neurons. The biological results indi-
cated that all of the synthesized compounds displayed neuro-
protective effects against Ab25–35
- and glutamate-induced
neurotoxicity. Of the tested compounds, 7B exhibited a marked
protective effect at a very low concentration of 0.1 mM. Further
studies to improve the neuroprotective activity and clarify the
neuroprotective mechanism of these compounds are currently
in progress and will pave the way for the exploitation of these
compounds as novel potential PET radioligands.
Conflict of interests
The authors declare no competing nancial interest.
Acknowledgements
This research was supported by the NSF of China (81371616),
the Natural Science Foundation of Jiangsu Province (no.
BK2011704, BK20130653), the Fundamental Research Funds for
the Central Universities (30920130111024, JKZD2013006) and
the Research Fund for the Doctoral Program of Higher Educa-
tion of China (20133219120020). We are very grateful to Dr
Victor W. Pike and Dr Shuiyu Lu in NIH/NIMH for helpful
discussions in this project.
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