Synthesis and structure-activity relationship of cyclopentenone oximes as novel inhibitors of the production of tumor necrosis factor-α

Article abstract of DOI:10.1016/j.bmcl.2014.04.115

3-Alkyl-2-aryl-2-cyclopenten-1-one oxime derivatives (1) were studied as a novel class of inhibitors of tumor necrosis factor α (TNF-α) with regard to synthesis and in vitro SAR inhibition of TNF-α. The in vitro IC₅₀ values of these compounds i

Full text of DOI:10.1016/j.bmcl.2014.04.115

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationship of cyclopentenone
oximes as novel inhibitors of the production of tumor necrosis
factor-
a
a
a
a
Yeonjoon Kim a,b, Yong Deog Hong a, , Yung Hyup Joo , Byung Young Woo , Sun-Young Kim ,
⇑
Hyun Ju Koh a, Miyoung Park a, Kyoung Hee Byoun a, Song Seok Shin a,
⇑
a AmorePacific R&D Unit, 314-1 Bora-dong, Giheung-gu, Yongin-si, Gyeonggi-do 449-729, Republic of Korea
b Solvay Korea, Ewha-Solvay R&I Center 150, Bukahyun-ro, Seodaemun-gu, Seoul, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Alkyl-2-aryl-2-cyclopenten-1-one oxime derivatives (1) were studied as a novel class of inhibitors of
tumor necrosis factor (TNF- ) with regard to synthesis and in vitro SAR inhibition of TNF- . The
in vitro IC50 values of these compounds in rat and human peripheral blood mononuclear cells were at
Received 10 February 2014
Revised 21 April 2014
Accepted 29 April 2014
Available online xxxx
a
a
a
the sub-micromolar level.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
TNF-a
Cyclopentenone oximes
SAR
PBMCs
Tumor necrosis factor-
a
(TNF-a
), originally defined as an
effects, and narrow therapeutic margins. Therefore, an urgent need
endotoxin-induced serum factor that induced necrosis of tumors,1
is currently known as one of the most important cytokines in
exists for new TNF-
drawbacks.
a inhibitors that can overcome these
inflammation and immunology. Overexpression of TNF-
a
has been
We conducted an in vitro screen of in-house library compounds
in our drug discovery program (COX-2) and selected cyclopente-
observed in variety of immunological disorders including
a
rheumatoid arthritis, ankylosing spondylitis, psoriasis, inflamma-
tory bowel disease (IBD), sepsis, endotoxin shock, multiple sclerosis,
none compounds that displayed TNF-a inhibiting activity at
sub-micromolar concentrations. We identified a novel derivative,
2-cyclopenten-1-one oxime (1) (Fig. 2), with inhibitory activity
insulin resistance, and chronic hepatitis.2 Inhibition of TNF-
a
activity by TNF-
a
monoclonal antibodies or soluble receptors such
against the production of TNF-a induced by LPS in rat peripheral
blood mononuclear cells (PBMCs). Subsequently, we synthesized
more 2-cyclopenten-1-one oxime compounds with different
substituents and tested their TNF-a inhibitory activities.
as etanercept,3 infliximab,4 and adalimumab5 has been effective in
treating rheumatoid arthritis, ankylosing spondylitis, IBD, and
psoriatic arthritis.
Despite their success in treating many disorders, their
requirement of delivery via injections and associated high costs
have limited their use to very few people. Small molecule inhibi-
Among alkyl–alkyl, aryl–aryl, alkyl–aryl, and aryl–alkyl
combinations for R1 and R2, we found that alkyl–aryl substitutions
resulted in the best inhibition of TNF-
a in vitro. We further opti-
tors that inhibit either the action or production of TNF-
an alternative solution that carries low cost and allows oral or
other non-injection modes of administration of the drug. Current
a
provide
mized these compounds by varying the length or size of acyclic
or cyclic alkyl groups and phenyl ring substitutions (Fig. 3).
3-Alkyl-2-aryl-2-cyclopenten-1-one oxime derivatives (1) were
prepared as outlined in Scheme 1. 3-Alkyl-2-cyclopenten-1-one (2)
was synthesized from commercially available 2-cyclopenten-1-one
or 3-alkoxy-2-cyclopenten-1-one. The addition of alkyl metal
reagents (alkyllithium or alkylmagnesium chloride) to 2-cyclopen-
ten-1-one and the oxidative rearrangement of the resulting allylic
alcohol by PCC afforded 2.6 Alternatively, the addition of alkyl
metal reagents to 3-alkoxy-2-cyclopenten-1-one followed by
research on small molecule TNF-
a inhibitors (Fig. 1) has resulted
in few successes due to weak clinical potencies, unwanted side
⇑
Corresponding authors. Tel.: +82 31 280 5919; fax: +82 31 281 8391 (Y.D.H.);
tel.: +82 31 280 5915; fax: +82 31 281 8391 (S.S.S.).
E-mail addresses: hydhong@amorepacific.com (Y.D. Hong), ssshin@amorepacific.
com (S.S. Shin).
http://dx.doi.org/10.1016/j.bmcl.2014.04.115
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kim, Y.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.115

2
Y. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
OMe
NH
N
O
O
H
N
SO2Me
N
O
N
NH
O
O
F
O
SB-203580 (p38 inhibitor)
Rolipram (PDE4 inhibitor)
thalidomide
Figure 1. Examples of current small molecule TNF-
a
inhibitors.
R2
R1
NOH
1
Figure 2. 2-Cyclopenten-1-one oxime (1), a novel class of TNF-a inhibitors.
Figure 3. Binding mode between residues in the TNF-
a
binding pocket and result pose (A), rolipram (B), and 1ac (C).
acidification also afforded 2.7 Iodination of 2 with iodine/pyridine/
cyclopenten-1-one (4), which then condensed into the desired
3-alkyl-2-aryl-2-cyclopenten-1-one oximes (1)10 by treatment
with hydroxylamine hydrochloride in pyridine.
8
CCl4 produced 2-iodo-2-cyclopenten-1-one (3). Suzuki coupling9
of 3 with appropriate arylboronic acids afforded 3-alkyl-2-aryl-2-
When R1 was a bulky group such as cyclopentyl or cyclohexyl,
the yield of the first step, that is, reaction of the alkyl metal reagent
with 2-cyclopenten-1-one or 3-alkoxy-2-cyclopenten-1-one was
very low. This problem was overcome by using TMSCl-assisted
1,4-addition.11 For example, 1,4-addition of the cyclopentyl cup-
rate, which was generated with CuBrÁMeS and cyclopentylmagne-
sium chloride, to 3-methoxy-2-cyclopenten-1-one was facilitated
by trimethylsilyl chloride (TMSCl) in the presence of hexamethyl
phosphoramide (HMPA), and the resulting TMS enol ether was
converted to 2a by simple treatment with aqueous hydrochloric
acid as shown in Scheme 2.
R1
R1
I
X
a,b
d
or c
O
O
O
X=H or
X=OR (Me or Et)
2
3
R2
NOH
R2
R1
R1
e
f
O
4
1
These oxime compounds (1) were tested for inhibition of the
Scheme 1. Reagents and conditions: (a) R1MgCl or R1Li, THF, 1–2 h at 0 °C ? room
temp; (b) PCC/celite/CH2Cl2 for 2-cyclopenten-1-one; (c) R1MgCl or R1Li, THF, 1–2 h
at 0 °C ? room temp, and then aq HCl for 3-alkoxy-2-cyclopenten-1-one; (d) I2,
pyridine, CCl4; (e) R2B(OH)2, Pd(PPh3)4, 2 N Na2CO3, toluene–EtOH, reflux; (f)
NH2OHÁHCl, pyridine.
TNF-
a production stimulated by LPS in rat and human PBMCs
using the protocols reported in the literature.12 Table 1 summa-
rizes these results in rat PBMCs along with TNF-a/PDE4 inhibitor
rolipram as a positive control.
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Y. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Table 3
MeO
a
Docking score and polar interaction of the rolipram and 1ac with TNF-
a active site
Sufex-dock total scorea
Polar interaction
O
Compounds
O
Rolipram
1ac
7.3232
6.3302
1.2018
2.5228
2a
Scheme 2. Reagents and conditions: (a) c-C5H9MgCl, CuBrÁMe2S, HMPA, TMSCl,
THF, À78 °C ? room temp, and then aq HCl.
a
Represents the binding affinity expressed in units of ÀlogKd.
Table 1
In vitro TNF-
peripheral blood mononuclear cells (rPBMCs)
To understand the interaction between 1ac and TNF-
we performed molecular docking simulations between 1ac and
a
dimer,
a inhibitory activities of cyclopentenone oxime derivatives (1) in rat
the TNF-
a active site (X-ray crystal structure with protein data-
Compds
R1
R2
TNF-a IC50 (lM)
a
bank [PDB] code 2az5)13 with the Surflex-Dock v.2.7 SYBYL-X
2.1.1 software program (Tripos, L.P., St. Louis, MO, USA).
1aa
1ab
1ac
1ad
1ae
1af
1ba
1bb
1bc
1ca
1cb
1cc
1da
1db
1ea
1eb
1f
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Butyl
n-Butyl
n-Propyl
n-Propyl
Ethyl
Methyl
4-Fluorophenyl
3,4-Difluorophenyl
3-Nitrophenyl
3,4-Methylenedioxyphenyl
3-Hydroxyphenyl
3-Trifluoromethyphenyl
4-Fluorophenyl
3,4-Difluorophenyl
3-Chloro-4-fluorophenyl
4-Fluorophenyl
3,4-Difluorophenyl
3-Pyridinyl
4-Fluorophenyl
3,4-Methylenedioxyphenyl
4-Fluorophenyl
3,4-Difluorophenyl
3,4-Difluorophenyl
3,4-Difluorophenyl
0.46
0.13
0.07
0.35
6.22
3.07
1.24
0.34
0.42
3.83
3.65
14.12
7.88
2.52
2.66
0.72
4.56
48.7
0.27
Using SYBYL, we extracted the ligand from the protein complex
in the PDB file, and hydrogen atoms were added to the enzyme;
staged minimization was performed using the Tripos Force Field.
The partial atomic charges were calculated using the Gasteiger–
Hückel method. The docked conformations with the highest dock-
ing scores were selected for binding mode analysis.
From the results of the analysis of the protein and the ligands
rolipram and 1ac, we observed that the ligand orientation in the
binding site favored hydrophobic interaction. A partial H-bond
observed in the interaction of the ligands with the active site res-
idue tyr151 indicates
inhibition.
a possible explanation for the strong
The Surflex-Dock scores (total scores) are shown in Table 3. The
total score of 1ac (6.3302) was slightly lower than that of rolipram
(7.3232); however, the 1ac had a superior polar interaction value
of 2.5228 (rolipram, 1.2018). As a result of polar interaction, 1ac
showed stronger inhibitory activity (IC50 = 0.07) than rolipram
(IC50 = 0.27). Therefore, the in vitro values were in good agreement
with the results of docking simulations.
In summary, 2-cyclopenten-1-one oximes, a novel class of TNF-
inhibitors, has been successfully developed. Some of these com-
pounds have more potent in vitro inhibitory activities than roli-
pram. Further investigations to develop these compounds as
anti-inflammatory drugs are under way.
1g
Rolipram
a
Values are the mean of at least two experiments.
Cyclopentyl as an R1 alkyl group was the most potent inhibitor
with an IC50 of 0.07
M and 3-nitrophenyl as the R2 group. The
l
a
cyclohexyl group was less potent but was comparable to the
n-propyl group, which showed the best effect among the linear
alkyl chains. Inhibitory activity weakened as the chain length
increased. Furthermore, inhibitory activity weakened with chain
length shorter than that of n-propyl and with 3,4-difluorophenyl
as the R2 group, as seen in the IC50 values: n-pentyl < n-propyl >
References and notes
ethyl > > methyl (3.65, 0.72, 4.56, and 48.7 lM, respectively).
1. Carswell, E. A.; Old, L. J.; Kassel, R. L.; Green, S.; Fiore, N.; Williamson, B. Proc.
Natl. Acad. Sci. U.S.A. 1975, 72, 3666.
2. Reviews: (a) Newton, R. C.; Decicco, C. P. J. Med. Chem. 1999, 42, 2295; (b)
Taylor, P. C.; Williams, R. O.; Feldmann, M. Curr. Opin. Biotechnol. 2004, 15, 557.
3. Enbrel™ (etanercept) Prescribing Information. Immunex Corporation. July
2005.
4. Remicade™ (infliximab) Prescribing Information. Centocor Inc., September
2005.
5. Humira™ (adalimumab) Prescribing Information. Abbott Lab. October 2005.
6. Majetich, G.; Condon, S.; Hull, K.; Ahmad, S. Tetrahedron Lett. 1989, 30, 1033.
7. Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman, L. E. J. Am. Chem. Soc. 1988, 110,
4625.
Effects of various substituents on the phenyl ring of R2 were also
evaluated. With cyclopentyl as R1, the strongest to weakest
inhibition was as follows: 3-nitro > 3,4-difluoro > 4-fluoro ꢀ 3,
4-methylenedioxy > 3-CF3 > 3-OH (IC50 0.07, 0.13, 0.46, 0.35, 3.07,
and 6.22
3-nitro substituents, respectively, showed the most potent
activities with IC50 values of 0.13 and 0.07 M, both of which are
more potent than rolipram (IC50 0.2 M).
As shown in Table 2, these compounds were also highly potent
against human TNF- , with an IC50 range of 0.24–4.59 M, which
was comparable to or better than that for the positive control,
lM). The compounds 1ab and 1ac with 3,4-difluoro and
l
l
8. Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P.
M.; Uskokovi, M. R. Tetrahedron Lett. 1992, 33, 917.
9. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
a
l
rolipram (IC50 0.27
l
M).
10. Selected compounds were prepared as follows. 3-Cyclopentyl-2-cyclopenten-1-one
(2a): To a stirred suspension of 800 mg of copper bromide dimethylsulfide in
100 ml of THF equilibrated to À78 °C, were added in series 24 ml of 2.0 M
cyclopentylmagnesium chloride in diethyl ether and 8 ml of HMPA under inert
atmosphere. To the mixture was added a solution of 5.4 ml of TMSCl and 4.3 g
of 3-methoxy-2-cyclopenten-1-one in 20 ml of THF. The reaction mixture was
slowly warmed to room temperature and stirred for 3 h, to which was added
50 ml of 10% aqueous HCl. The resulting reaction mixture was stirred for
another 10 min and subjected to extraction with ethyl acetate. The organic
layer was washed with water and brine, dried over anhydrous magnesium
sulfate, and filtered. Then the filtrate was concentrated under reduced pressure
and purified by column chromatography (silica gel, hexane/ethyl acetate = 3:1)
to yield 4.5 g (78%) of 3-cyclopentyl-2-cyclopenten-1-one as an oil. 1H NMR
(CDCl3, 300 MHz): d 5.94 (m, 1H), 2.82 (m, 1H), 2.61 (m, 2H), 2.41 (m, 2H), 1.96
(m, 2H), 1.77-1.5 (m, 6H); MS (EI): 150 (M+).
Table 2
In vitro TNF-a inhibitory activities of cyclopentenone oxime derivatives (1) in human
peripheral blood mononuclear cells (hPBMCs)
a
Compounds
TNF-a, IC50 (lM)
1ab
1ac
1ca
1db
0.26
0.24
4.59
2.92
0.27
Rolipram
3-Cyclopentyl-2-iodo-2-cyclopenten-1-one (3a). To a stirred solution of 4.35 g of
3-cyclopentyl-2-cyclopenten-1-one in 50 ml of carbon tetrachloride, were
added 15 g of iodine and 2.4 ml of pyridine, and the reaction mixture was
a
Values are the mean of at least two experiments.
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4
Y. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
stirred overnight. The mixture was first diluted with diethyl ether, washed in
3-Cyclohexyl-2-(4-fluorophenyl)-2-cyclopenten-1-one oxime (1ba).
1H NMR (CDCl3) d 7.20 (m, 2H), 7.08 (m, 2H), 6.78 (br s, 1H), 2.77 (m, 2H), 2.59
(m, 2H), 2.47 (m, 1H), 1.75–1.16 (m, 10H); MS (EI): 273 (M+).
3-Cyclohexyl-2-(3,4-difluorophenyl)-2-cyclopenten-1-one oxime (1bb).
1H NMR (CDCl3) d 7.19 (dt, J = 10.2 and 8.4 Hz, 1H), 7.06 (ddd, J = 2.1, 7.5 and
11.1 Hz, 1H), 6.97–6.91 (m, 2H), 2.77 (m, 2H), 2.58 (m, 2H), 2.46 (m, 1H), 1.76–
1.16 (m, 10H); MS (EI): 291 (M+).
3-Cyclohexyl-2-(3-chloro-4-fluorophenyl)-2-cyclopenten-1-one oxime (1bc).
1H NMR (CDCl3) d 7.28 (dd, J = 2.1 and 6.9 Hz, 1H), 7.16 (t, J = 8.7 Hz, 1H), 7.08
(ddd, J = 2.1, 4.8 and 8.7 Hz, 1H), 6.93 (br s, 1H), 2.77 (m, 2H), 2.59 (m, 2H), 2.45
(m, 1H), 1.75–1.16 (m, 10H); MS (EI): 307 (M+).
3-Pentyl-2-(4-fluorophenyl)-2-cyclopenten-1-one oxime (1ca).
7.41–7.36 (m, 2H), 7.32–7.22 (m, 3H), 6.85 (br s, 1H), 2.81 (m, 2H), 2.60 (m,
2H), 2.28 (t, J = 7.8 Hz, 2H), 1.47 (m, 2H), 1.24 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H);
MS (EI): 261 (M+).
3-Pentyl-2-(3,5-difluorophenyl)-2-cyclopenten-1-one oxime (1cb).
1H NMR (CDCl3) d 7.71 (br s, 1H), 6.77 (m, 3H), 2.79 (m, 2H), 2.60 (m, 2H), 2.28
(t, J = 7.8 Hz, 2H), 1.47 (m, 2H), 1.23 (m, 4H), 0.86 (t, J = 6.6 Hz, 3H); MS (EI):
279 (M+).
series with saturated aqueous sodium thiosulfate, aqueous sodium
bicarbonate, and brine. The organic layer was dried over anhydrous
magnesium sulfate and filtered. The filtrate was concentrated under reduced
pressure and purified by column chromatography (silica gel, hexane/ethyl
acetate = 6:1) to yield 4 g (50%) of 3-cyclopentyl-2-iodo-2-cyclopenten-1-one
as an oil. 1H NMR (CDCl3, 300 MHz): d 3.23 (m, 1H), 2.74 (m, 2H), 2.57 (m, 2H),
1.98 (m, 2H), 1.78 (m, 4H), 1.55 (m, 2H) MS (EI): 176 (M+).
3-Cyclopentyl-2-(4-fluorophenyl)-2-cyclopenten-1-one (4aa):
65 mg of 3-cyclopentyl-2-iodo-2-cyclopenten-1-one,
A
mixture of
40 mg of 4-
fluorophenylboronic acid, 10 mg of tetrakis(triphenylphosphine)palladium,
4 ml of toluene, 2 ml of ethanol and 1.5 ml of 2 N aqueous sodium carbonate
was stirred at 80 °C overnight. The reaction mixture was diluted with ethyl
acetate, washed with brine, dried over anhydrous magnesium sulfate, and
filtered. The filtrate was concentrated under reduced pressure and purified by
column chromatography (silica gel, hexane/ethyl acetate = 4:1) to yield 52 mg
(91%) of 3-cyclopentyl-2-(4-fluorophenyl)-2-cyclopenten-1-one as a solid. 1H
NMR (CDCl3, 300 MHz): d 7.22 (m, 2H), 7.09 (m, 2H), 3.15 (m, 1H), 2.68 (m, 2H),
2.55 (m, 2H), 1.81 (m, 4H), 1.64 (m, 4H) MS (EI): 244 (M+).
3-Cyclopentyl-2-(4-fluorophenyl)-2-cyclopenten-1-one oxime (1aa): A mixture of
50 mg of 3-cyclopentyl-2-(4-fluorophenyl)-2-cyclopenten-1-one and 20 mg of
hydroxylamine hydrochloride in 5 ml of pyridine was stirred at room
temperature overnight. Pyridine was removed under reduced pressure, and
the resulting residue was subjected to extraction with ethyl acetate and 10%
aqueous HCl. The organic layer was washed with aqueous sodium bicarbonate
and brine, dried over anhydrous magnesium sulfate, and filtered. Then the
filtrate was concentrated under reduced pressure and purified by column
chromatography (silica gel, hexane/ethyl acetate = 4:1) to yield 40 mg (75%) of
3-cyclopentyl-2-(4-fluorophenyl)-2-cyclopenten-1-one oxime as a off-white
solid. mp = 204–205 °C; 1H NMR (CDCl3, 300 MHz): d 7.24–7.19 (m, 2H), 7.11–
7.04 (m, 2H), 6.73 (br s, 1H), 2.89 (m, 1H), 2.80 (m, 2H), 2.61 (m, 2H), 1.70 (m,
4H), 1.55 (m, 4H); 13C NMR (125 MHz, CDCl3) d ppm 169.5, 163.3, 161.3, 161.2,
134.2, 131.2, 131.1, 130.1, 115.5, 115.3, 40.0, 32.1, 28.2, 26.2, 24.6; HRMS calcd
for C16H18FNO 259.1372 (M+), found 259.1394.
3-Pentyl-2-(3-pyridinyl)-2-cyclopenten-1-one oxime (1cc).
1H NMR (CDCl3) d 8.60 (br s, 1H), 8.68–8.51 (m, 2H), 7.61 (m, 1H), 7.30 (m, 1H),
2.83 (m, 2H), 2.63 (m, 2H), 2.30 (t, J = 7.8 Hz, 2H), 1.49 (m, 2H), 1.25 (m, 4H),
0.85 (t, J = 6.6 Hz, 3H); MS (EI): 244 (M+).
3-Butyl-2-(4-fluorophenyl)-2-cyclopenten-1-one oxime (1da).
1H NMR (CDCl3) d 7.20 (m, 2H), 7.07 (m, 2H), 2.79 (m, 2H), 2.59 (m, 2H), 2.26 (t,
J = 7.8 Hz, 2H), 1.45 (m, 2H), 1.26 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H); MS (EI): 247
(M+).
3-Butyl-2-(3,4-fluorophenyl)-2-cyclopenten-1-one oxime (1db).
1H NMR (CDCl3) d 6.95 (br s, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.43 – 6.68 (m, 2H),
5.96 (s, 2H), 2.78 (m, 2H), 2.60 (m, 2H), 2.27 (t, J = 7.7 Hz, 2H), 1.45 (m, 2H),
1.27 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); MS (EI): 265 (M+).
2-(4-Fluorophenyl)-3-propyl-2-cyclopenten-1-one oxime (1ea).
1H NMR (CDCl3) d 7.24–7.17 (m, 3H), 7.10–7.03 (m, 2H), 2.79 (m, 2H), 2.59 (m,
2H), 2.25 (t, J = 7.7 Hz, 2H), 1.50 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H); MS (EI): 233
(M+).
2-(3,4-Difluorophenyl)-3-propyl-2-cyclopenten-1-one oxime (1eb)
1H NMR (CDCl3) d 7.83 (br s, 1H), 7.17 (dt, J = 10.5 and 8.4 Hz, 1H), 7.07 (ddd,
J = 2.1, 7.8 and 11.1 Hz, 1H), 6.96 (m, 1H), 2.78 (m, 2H), 2.58 (m, 2H), 2.25 (t,
J = 7.8 Hz, 2H), 1.50 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H); MS (EI): 251 (M+).
3-Ethyl-2-(3.4-difluorophenyl)-2-cyclopenten-1-one oxime (1f).
1H NMR (CDCl3) d 7.24 (m, 2H), 7.08 (m, 1H), 6.89 (s, 1H), 2.81 (m, 2H), 2.61 (m,
2H), 2.30 (q, J = 7.8 Hz, 2H), 1.08 (t, J = 7.7 Hz, 3H); MS (EI): 237 (M+).
2-(3,4-Difluorophenyl)-3-methyl-2-cyclopenten-1-one oxime (1g).
1H NMR (CDCl3) d 7.19–7.10 (m, 2H), 7.04 (m, 1H), 6.75 (s, 1H), 2.81 (m, 2H),
2.60 (m, 2H), 1.94 (m, 3H); MS (EI): 223 (M+).
3-Cyclopentyl-2-(3,4-difluorophenyl)-2-cyclopenten-1-one oxime (1ab).
1H NMR (CDCl3) d 7.36 (br s, 1H), 7.16 (dt, J = 10.5 and 8.4 Hz, 1H), 7.07 (ddd,
J = 2.1, 7.8 and 11.1 Hz, 1H), 6.96 (m, 1H), 2.88 (m, 1H), 2.77 (m, 2H), 2.61 (m,
2H), 1.70 (m, 4H), 1.55 (m, 4H); MS (EI): 277 (M+).
3-Cyclopentyl-2-(3-nitrophenyl)-2-cyclopenten-1-one oxime (1ac)
1H NMR (CDCl3) d 8.19–8.14 (m, 2H), 7.62–7.53 (m, 2H), 6.78 (s, 1H), 2.84 (m,
3H), 2.66 (m, 2H), 1.74 (m, 4H), 1.56 (m, 4H); MS (EI): 286 (M+).
3-Cyclopentyl-2-(3,4-methylenedioxyphenyl)-2-cyclopenten-1-one oxime (1ad).
1H NMR (CDCl3) d 6.83 (d, J = 7.8 Hz, 1H), 6.43–6.68 (m, 2H), 5.96 (s, 2H), 2.92
(m, 1H), 2.60 (m, 2H), 2.77 (m, 2H), 1.70 (m, 4H), 1.54 (m, 4H); MS (EI): 285
(M+).
3-Cyclopentyl-2-(3-hydroxyphenyl)-2-cyclopenten-1-one oxime (1ae).
1H NMR (CDCl3) d 7.26–7.21 (m, 2H), 6.79–6.70 (m, 3H), 2.93 (m, 1H), 2.80 (m,
2H), 2.61 (m, 2H), 1.70 (m, 4H), 1.54 (m, 4H); MS (EI): 257 (M+).
3-Cyclopentyl-2-(4-trifluoromethylphenyl)-2-cyclopenten-1-one oxime (1af).
1H NMR (CDCl3) d 7.63 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.26 (m, 1H),
2.77 (m, 2H), 2.59 (m, 2H), 2.47 (m, 1H), 1.75–1.16 (m, 10H); MS (EI): 309 (M+).
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Please cite this article in press as: Kim, Y.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.115