Journal of Medicinal Chemistry
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temperature was measured with an IR sensor on the outside of the
reaction vessel.
toluene. The residue was worked up and purified by CCTLC in a
Chromatotron (dichloromethane/methanol 40:1) to yield 30 mg
(56%) of 14b as a white solid. Mp: 203−205 °C. EM (ES, positive
The synthesis of the different series of compounds has been
performed by applying the here described general procedures. A few
key compounds are described in this Experimental Section. Full details
and analytical and spectroscopic data for all the compounds are
included in the Supporting Information.
1
mode): m/z 336 (M + H)+. H NMR (DMSO-d6, 300 MHz): δ 1.02
(t, 3H, J = 7.3 Hz, CH3), 2.59−2.63 (m, 2H, H-4, H-6), 2.78−2.88 (m,
4H, H-4, H-6, CH2), 3.32 (m, 1H, H-5), 6.85 (m, 2H, Ar), 7.11 (m,
2H, Ar), 7.23 (m, 1H, Ar), 7.33 (d, 4H, J = 4.4 Hz, Ar), 9.81 (br s, 1H,
OH), 14.73 (br s, 1H, NH). 13C NMR (DMSO d6, 100 MHz): δ 13.0
(CH3), 23.7 (CH2), 36.5 (C-5), 46.5 (C-4, C-6), 107.1 (NHCC),
116.4, 127.0, 127.2, 127.3, 127.7, 128.9, 143.9, 157.5 (Ar), 178.0
(NHCC). Anal. Calcd for (C21H21NO3): C, 75.20; H, 6.31; N, 4.18.
Found: C, 74.98; H, 6.13; N, 4.37.
5-Oxo-1,2,5,6-tetrahydro-[1,1′-biphenyl]-3-yl propionate
(11). To a solution of 5-phenylcyclohexane-1,3-dione (300 mg, 1.59
mmol) and DMAP (59 mg, 0.48 mmol) in CH2Cl2 (1.6 mL) was
added Hunig’s base (DIPEA) (277 μL, 1.59 mmol). Then, propionyl
chloride (147 μL, 1.59) was added dropwise and the reaction mixture
was refluxed for 2 h. After cooling, HCl (1 N, 10 mL) was added, and
the crude mixture was extracted with ethyl acetate (10 mL × 3). The
organic layer was washed with brine (15 mL), dried over Na2SO4,
concentrated, and purified by flash chromatography (hexane/ethyl
acetate 3:1) to yield 250 mg (64%) of 11 as an oil. EM (ES, positive
2-(1-((2-Methoxyphenyl)amino)propylidene)-5-phenylcyclohex-
ane-1,3-dione (14c). Following the general procedure for the reaction
of 2-acyl-5-phenylcyclohexane-1,3-diones with anilines, a microwave
vial was charged with 5-phenyl-2-propionylcyclohexane-1,3-dione (12)
(35 mg, 0.14 mmol) and o-anisidine (24 μL, 0.21 mmol) in toluene.
The residue was worked up and purified by CCTLC in a
Chromatotron (hexane/ethyl acetate, 5:1) to yield 48 mg (98%) of
14c as a white solid. Mp 93−95 °C. EM (ES, positive mode): m/z 350
(M + H)+. 1H NMR (DMSO-d6, 400 MHz): δ 0.98 (t, 3H, J = 7.3 Hz,
CH3), 2.59−2.64 (m, 2H, H-4, H-6), 2.80−2.84 (m, 4H, H-4, H-6,
CH2), 3.36 (m, 1H, H-5), 3.82 (s, 3H, OCH3), 7.06 (td, 1H, J = 7.6,
1.2 Hz, Ar), 7.19−7.27 (m, 2H, Ar), 7.30 (dd, 1H, J = 7.7, 1.5 Hz, Ar),
7.33 (d, 2H, J = 1.4 Hz, Ar), 7.34 (s, 2H, Ar), 7.39−7.46 (m, 1H, Ar),
14.69 (br s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz): δ 12.2
(CH3), 25.5 (CH2), 36.0 (C-5), 46.1 (C-4, C-6), 55.8 (OCH3), 106.9
(NHCC), 112.4, 120.7, 124.2, 126.5, 126.7, 127.5, 128.5, 129.7,
143.5, 153.5 (Ar), 178.0 (NHCC). Anal. Calcd for (C22H23NO3):
C, 75.62; H, 6.63; N, 4.01. Found: C, 75.48; H, 6.52; N, 4.00.
Details of the synthesis and analytical and spectroscopic data for
compounds 14d−j are provided in the Supporting Information.
2-Butyryl-5-phenylcyclohexane-1,3-dione (15a). Following the
described procedure for the synthesis of 12, a microwave vial was
charged with 5-phenylcyclohexane-1,3-dione (10) (500 mg, 2.66
mmol), butyryl chloride (548 μL, 5.31 mmol), anhydrous K2CO3 (809
mg, 5.85 mmol), 1,2,4-triazole (73 mg, 1.06 mmol), and
tetrabutylammonium bromide (429 mg, 1.33 mmol) in anhydrous
acetonitrile (10 mL) to yield 200 mg (29%) of 15a as a white solid.
1
mode): m/z 245 (M + H)+. H NMR (DMSO-d6, 500 MHz): δ 1.07
(t, 3H, J = 7.4 Hz, CH3), 2.47 (dd, 1H, J = 16.6, 2.9 Hz, H-2), 2.57 (c,
2H, J = 7.5 Hz, CH2), 2.73 (dd, 1H, J = 16.2, 12.9 Hz, H-2), 2.63 (dd,
1H, J = 17.7, 4.3 Hz, H-6), 2.87 (ddd, 1H, J = 17.6, 10.9, 2.0 Hz, H-6),
3.28 (m, 1H, H-1), 5.91 (d, 1H, J = 2.1 Hz, H-4), 7.24 (t, 1H, J = 7.0
Hz, 4-Ar), 7.35 (m, 4H, Ar).
5-Phenyl-2-propionylcyclohexane-1,3-dione (12). A micro-
wave vial was charged with 5-phenylcyclohexane-1,3-dione (10) (500
mg, 2.66 mmol), propionyl chloride (490 μL, 5.31 mmol), anhydrous
K2CO3 (809 mg, 5.85 mmol), 1,2,4-triazole (73 mg, 1.06 mmol), and
tetrabutylammonium bromide (429 mg, 1.33 mmol) in anhydrous
acetonitrile (10 mL). The reaction vessel was sealed, stirred under
argon atmosphere for 10 min, and heated in a microwave reactor at 70
°C for 2 h. After cooling, the reaction mixture was acidified with 1 N
HCl and the mixture was extracted with ethyl acetate. The organic
layer was dried over Na2SO4, concentrated, and purified by flash
chromatography (hexane/ethyl acetate) to yield 330 mg (51%) of 12
as a white solid. Mp: 71−73 °C. EM (ES, positive mode): m/z 245 (M
+ H)+. 1H NMR (DMSO-d6, 300 MHz): δ (enol form) 1.05 (t, 3H, J =
7.3 Hz, CH3), 2.62−2.71 (m, 2H, H-4, H-6), 2.87−2.95 (m, 2H, H-4,
H-6), 3.01 (q, 2H, J = 7.2 Hz, CH2), 3.46 (m, 1H, H-5), 7.23−7.38
(m, 5H, Ar). Although this compound was mentioned in ref 28, no
analytical or spectroscopic data were provided.
1
Mp: 68−70 °C. EM (ES, positive mode): m/z 259 (M + H)+. H
NMR (DMSO-d6, 300 MHz): δ (enol form) 0.92 (t, 3H, J = 7.3 Hz,
CH3), 1.58 (m, 2H, CH2), 2.69 (m, 2H, H-4, H-6), 2.92 (m, 2H, H-4,
H-6), 2.97 (t, 2H, J = 7.4 Hz, CH2), 3.37−3.45 (m, 1H, H-5), 7.25 (m,
1H Ar), 7.33 (m, 4H, Ar). Note: Although this compound was
mentioned in ref 29, no analytical data were provided.
General Procedure for the Reaction of 2-Acyl-5-phenyl-
cyclohexane-1,3-diones with Anilines. A microwave vial was
charged with 2-acyl-5-phenylcyclohexane-1,3-dione (1.0 mmol), the
appropriate aniline (1.5 mmol), and 4 Å molecular sieves in toluene (2
mL). The reaction vessel was sealed and heated in a microwave reactor
at 150 °C for 2 h. After cooling, the solvent was evaporated. The
resulting residue was purified as specified.
2-Acetyl-5-phenylcyclohexane-1,3-dione (15b). Following the
described procedure for the synthesis of 12, a microwave vial was
charged with 5-phenylcyclohexane-1,3-dione (10) (500 mg, 2.66
mmol), acetyl chloride (417 μL, 5.31 mmol), anhydrous K2CO3 (809
mg, 5.85 mmol), 1,2,4-triazole (73 mg, 1.06 mmol), and
tetrabutylammonium bromide (429 mg, 1.33 mmol) in anhydrous
acetonitrile (10 mL) to yield 350 mg (54%) of 15b as a white solid.
2-(1-((3-Hydroxyphenyl)amino)propylidene)-5-phenylcyclohex-
ane-1,3-dione (14a). Following the general procedure for the reaction
of 2-acyl-5-phenylcyclohexane-1,3-diones with anilines, a microwave
vial was charged with 5-phenyl-2-propionylcyclohexane-1,3-dione (12)
(40 mg, 0.16 mmol) and 3-aminophenol (26 mg, 0.24 mmol) in
toluene. The residue was worked up and purified by CCTLC in a
Chromatotron (dichloromethane/methanol, 40:1) to yield 50 mg
(93%) of 14a as a white solid. Mp: 199−201 °C. EM (ES, positive
1
Mp: 100−102 °C. EM (ES, positive mode): m/z 231 (M + H)+. H
NMR (DMSO-d6, 300 MHz): δ (enol form) 2.55 (s, 3H, CH3), 2.66−
2.72 (m, 2H, H-4, H-6), 2.94 (m, 2H, H-4, H-6), 3.36−3.47 (m, 1H,
H-5), 7.22−7.34 (m, 5H, Ar). Note: Although this compound was
mentioned in ref 29, no analytical data were provided.
1
mode): m/z 336 (M + H)+. H NMR (DMSO-d6, 500 MHz): δ 1.06
(t, 3H, J = 7.3 Hz, CH3), 2.60−2.64 (m, 2H, H-4, H-6), 2.80−2.89 (m,
4H, H-4, H-6, CH2), 3.33 (m, 1H, H-5), 6.65 (t, 1H, J = 2.2 Hz, Ar),
6.70 (m, 1H, Ar), 6.81 (ddd, 1H, J = 8.2, 2.4, 0.9 Hz, Ar), 7.18−7.25
(m, 1H, Ar), 7.27 (t, 1H J = 8.0 Hz, Ar), 7.32 (d, 4H, J = 4.4 Hz, Ar),
9.90 (br s, 1H, OH), 14.94 (br s, 1H, NH). 13C NMR (DMSO-d6, 125
MHz): δ 12.8 (CH3), 23.4 (CH2), 36.0 (C-5), 46.0 (C-4, C-6), 106.7
(NHCC), 112.9, 115.8, 116.4, 126.5, 126.7, 128.5, 130.4, 136.8,
143.4, 158.2 (Ar), 177.0 (NHCC). Anal. Calcd for (C21H21NO3):
C, 75.20; H, 6.31; N, 4.18. Found: C, 75.33; H, 6.12; N, 4.36.
2-(1-((4-Hydroxyphenyl)amino)propylidene)-5-phenylcyclohex-
ane-1,3-dione (14b). Following the general procedure for the reaction
of 2-acyl-5-phenylcyclohexane-1,3-diones with anilines, a microwave
vial was charged with 5-phenyl-2-propionylcyclohexane-1,3-dione (12)
(40 mg, 0.16 mmol) and 4-aminophenol (26 mg, 0.24 mmol) in
2-(1-((2-Methoxyphenyl)amino)butylidene)-5-phenylcyclohex-
ane-1,3-dione (16a). A mixture of 2-butyryl-5-phenylcyclohexane-1,3-
dione (15a) (60 mg, 0.23 mmol) and o-anisidine (30 μL, 0.22 mmol)
in 1.5 mL of toluene was heated for 2 days under reflux in a flask
equipped with a Dean−Stark trap. Volatiles were removed, and the
crude reaction mixture was purified by CCTLC in a Chromatotron
(hexane/ethyl acetate, 5:1) to yield 70 mg (84%) of 16a as a pale
yelow solid. Mp: 108−110 °C. EM (ES, positive mode): m/z 364 (M
1
+ H)+. H NMR (DMSO-d6, 400 MHz): δ 0.74 (t, 3H, J = 7.3 Hz,
CH3), 1.40 (m, 2H, CH2), 2.59−2.63 (m, 2H, H-4, H-6), 2.77 (m, 4H,
H-4, H-6, CH2), 3.29−3.37 (m, 1H, H-5), 3.82 (s, 3H, OCH3), 7.05
(m, 1H, J = 7.6, 1.2 Hz, Ar), 7.21 (dd, 1H, J = 8.4, 1.2 Hz, Ar), 7.25
(m, 1H, Ar), 7.28 (dd, 1H, J = 7.7, 1.6 Hz, Ar), 7.33 (d, 2H, J = 1.3 Hz,
3934
dx.doi.org/10.1021/jm401939g | J. Med. Chem. 2014, 57, 3924−3938