Journal of Medicinal Chemistry
Article
under vacuum and precipitation from dichloromethane-hexane 1:1
afforded a pure product as colorless crystals.
(
)-5-Allyl-1-methyl-5-[3-(3-trifluoromethyl-3H-diazirin-3-
yl)-phenyl]-pyrimidine-2,4,6-trione (14). Colorless crystals, yield
1
60% (90% from 15). H NMR (CDCl3): δ 8.67 (brs, 1H, NH), 7.44
(4-Methoxyphenyl)phenyliodonium trifluoroacetate (2).
1
(t, J = 7.6 Hz, 1H), 7.40 (dt, J = 8.0, ∼1.8 Hz, 1H), 7.27 (d, J = 7.4 Hz,
1H), 7.14 (t, J ∼ 2 Hz), 5.69 (ddt, J = 17.1, 10.1, 7.2 Hz, 1H, CH),
5.28 (dq, J = 17.1, 1.4 Hz, 1H, CH), 5.20 (d, J = 10.1 Hz, 1H,
CH), 3.35 (s, 3H, NCH3), 3.16 (d, J = 7.2 Hz, 2H, CH2-CH). 13C
NMR (CDCl3): δ 169.9, 168.8, 149.4, 137.8, 130.6, 130.3, 129.8,
127.8, 127.1 (q, J = 1.3 Hz), 124.4 (q, J = 1.4 Hz), 121.9 (q, J = 274.6
Hz), 121.9, 60.7, 41.1, 28.4 (q, J = 40.7 Hz), 28.3. 19F NMR (CDCl3):
δ −65.1. HRMS (ESI): Calcd for C16H12F3N2O3 [M − N2 − H]−
337.0806. Found: 337.0797.
( )-1-Methyl-5-prop-2-ynyl-5-[3-(3-trifluoromethyl-3H-dia-
zirin-3-yl)-phenyl]-pyrimidine-2,4,6-trione (15). Colorless oil,
yield 51%. H NMR (CDCl3): δ 9.00 (brs, 1H, NH), 7.45 (t, J =
7.8 Hz, 1H), 7.38 (dt, J = 8.2, ∼1.4 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H),
7.09 (t, J ∼ 2 Hz), 3.40 (s, 3H, NCH3), 3.32−3.20 (m, J = 2.5 Hz, 2H,
CH2-CCH), 2.09 (t, J = 2.5 Hz, CH). 13C NMR (CDCl3): δ
169.3, 168.2, 149.5, 136.4, 130.5, 130.0, 127.6, 127.5, 124.1, 121.9 (q, J
= 275.0 Hz), 78.3, 72.0, 60.5, 28.6, 28.3 (q, J ∼ 40.7 Hz), 26.9. 19F
NMR (CDCl3): δ −65.1. HRMS (ESI): Calcd for C16H12F3N4O3 [M
− H]−: 363.07105. Found: 363.0700.
Yield 61%. H NMR (CDCl3): δ 7.92 (d, J = 7.6 Hz, 2H), 7.88 (d,
J = 8.9 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 6.91
(d, J = 9.0 Hz, 2H), 3.83 (s, 3H, OMe). 13C NMR (CDCl3): δ 162.4,
137.0, 134.2, 131.6, 131.5, 117.6, 117.0, 105.0, 55.6. 19F NMR
−
(CDCl3): δ −75.2 (CF3CO2 ). HRMS (ESI): Calcd. for C13H12IO [M
− CF3CO2]+: 310.9927. Found: 310.9939.
Phenyl-(2,4,6-trimethylphenyl)iodonium trifluoroacetate
(3).65 Yield 55%. 19F NMR (CDCl3): δ −75.3 (CF3CO2 ).
−
(4-Methoxyphenyl)-[3-(3-trifluoromethyl-3H-diazirin-3-yl)-
1
phenyl]-iodonium Trifluoroacetate (m-11). Yield 58%. H NMR
(CDCl3): δ 7.98 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.65 (s,
1H), 7.46 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz), 6.97 (d, J = 9.0 Hz,
2H), 3.87 (s, 3H, OMe). 13C NMR (CDCl3): δ 163.6, 137.7, 135.0,
133.4, 132.4, 131.6, 130.2, 121.4 (q, J = 274.7 Hz, CF3), 118.4, 114.4,
101.1, 55.7, 27.9 (q, J = 41.5 Hz, CN2CF3). 19F NMR (CDCl3): δ
1
−
−65.1 (3F, CN2CF3), −75.4 (3F, CF3CO2 ). HRMS (ESI): Calcd for
C15H11F3IN2O [M − CF3CO2]+: 418.98627. Found: 418.9858.
(4-Methoxyphenyl)-[4-(3-trifluoromethyl-3H-diazirin-3-yl)-
1
phenyl]-iodonium Trifluoroacetate (p-12). Yield 12%. H NMR
Chiral Separation and Crystallization of (+)-14. Barbiturate 14
was separated into its enantiomers by chromatography on a
preparative Daicell Chiralpack AD column (20 mm × 200 mm),
using 15% ethanol in hexane as an eluent at 6.5 mL/min flow rate.
Under those conditions, a baseline separation of enantiomers was
achieved with retention times of 15.5 min for the (−)-enantiomer and
21.0 min for the (+)-enantiomer. The (+)-enantiomer was crystallized
by slow evaporation of its 2:1 hexane−benzene solution.
(CDCl3): δ 7.95 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 9.1 Hz, 2H), 7.17 (d,
J = 8.4 Hz, 2H), 6.91 (d, J = 9.1 Hz, 2H), 3.84 (s, 3H, OMe). 13C
NMR (CDCl3): δ 162.6, 161.8 (q, J = 34.7), 137.2, 134.4, 132.7, 129.1,
−
−
126.1 (q, J = 278.6, CF3CO2 , 121.6 (q, J = 275.0 Hz, CF3CO2 ),
118.2, 117.6, 105.2, 55.6, 28.1 (q, J = 41.0 Hz, CN2CF3). 19F NMR
−
(CDCl3): δ −64.9 (3F, CN2CF3), −75.2 (3F, CF3CO2 ). HRMS
(ESI): Calcd for C15H11F3IN2O [M − CF3CO2]+: 418.98627. Found:
418.9855.
Hydrogenation of Barbiturates. Propargyl barbiturate 15 (12.0
mg, 0.033 mmol) was dissolved in methanol (1.2 mL) in a small
septum vial and solid Rh(PPh3)3Cl (8.0 mg, 0.0086 mmol) was added
at once. The reaction vial was purged with hydrogen and left stirred
5-Alkyl-1-methylbarbiturates. The solution of dimethyl allyl-
malonate or dimethyl propargylmalonate (10 mmol) and N-
methylurea (11 mmol) in methanol (5 mL) was treated with sodium
methoxide (15 mmol, 3.2 mL of 25% by wt in methanol) with stirring
under argon and heated under reflux for 48 h. The reaction mixture
was concentrated under vacuum, diluted with water (20 mL), and
extracted with dichloromethane (3 × 10 mL). The combined organic
phases were washed with brine, dried with MgSO4, and concentrated,
and the residue was chromatographed on silica gel using hexane−ethyl
acetate (3:1 to 2:1) as an eluent.
1
under H2 atmosphere from rubber balloon. The H NMR analysis of
an aliquote of the reaction mixture taken after 5 min showed the
completion of the reaction. The reaction mixture was filtered,
concentrated under vacuum and chromatographed on silica gel using
hexane−ethyl acetate (4:1) for elution. The progress of the
hydrogenation could also be more conveniently monitored using
silver-impregnated TLC plates. The plates were prepared by dipping
regular plates in 1% CF3CO2Ag in methanol and drying at room
temperature in the dark. Using hexane−ethyl acetate (4:1 v/v) for
elution, the mobilities (Rf values) were as follows: 16 (Rf 0.3), 14 (Rf
0.2), 15 (Rf <0.05). These compounds were nonseparable on normal
TLC plates. Compounds 14, 15, and 16 were also separated by HPLC
using Phenomenex Luna 5 μm C18(2) 100 Å column, 3.00 mm × 150
mm at 1.0 mL/min flow rate. During the first 2 min, isocratic 0.05 M
TFA was used as an eluent; starting at 2 min, the gradient of 0.05 M
TFA/MeOH (0−100%) was used to reach 100% MeOH at 17 min,
and elution was continued with isocratic MeOH. Using these
conditions the retention times for compounds 14, 15, and 16 were
17.7, 17.2, and 18.0 min, respectively.
( )-1-Methyl-5-propyl-5-[3-(3-trifluoromethyl-3H-diazirin-3-
yl)-phenyl]-pyrimidine-2,4,6-trione (16). Yield 60% (from 15). 1H
NMR (CDCl3): δ 8.27 (brs, 1H, NH), 7.43 (t, J = 7.6 Hz, 1H), 7.38
(dt, J = 8.0, ∼1.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.12 (t, J ∼ 2 Hz),
3.36 (s, 3H, NCH3), 2.45−2.31 (m, 2H), 1.43−1.21 (m, 2H), 1.00 (t, J
= 7.2 Hz, 3H, CH2CH3). 13C NMR (CDCl3): δ 170.4, 169.4, 149.5,
138.5, 130.2, 129.7, 127.6, 126.9, 124.2 (q, J ∼ 1.0 Hz), 121.9 (q, J =
275.0 Hz), 60.8, 39.5, 28.4 (q, J = 40.7 Hz), 28.4, 19.1, 14.1. 19F NMR
(CDCl3): δ −65.1. HRMS (ESI): Calcd. for C16H14F3N4O3 [M −
H]−: 367.10235. Found: 367.1017.
5-Allyl-1-methyl-pyrimidine-2,4,6-trione (4).66 Amorphous
1
solid, yield 69%. H NMR (CDCl3): 9.07 (brs, 1H), 5.75−5.62 (m,
1H, =CH), 5.22−5.10 (m, 2H, CH), 3.58 (t, J = 5.1 Hz, OCCH),
3.28 (s, 3H, NCH3), 2.96−2.88 (m, 2H, CH−CH2). 13C NMR
(CDCl3): δ 168.6, 168.1, 150.6, 131.2, 120.3, 48.8, 34.2, 27.8. HRMS
(ESI): Calcd for C8H11N2O3 [M + H]+: 183.07642. Found: 183.0766.
5-Allyl-1-methyl-5-phenyl-pyrimidine-2,4,6-trione (5). Yield
1
81%. H NMR (CDCl3): δ 9.20 (brs, 1H, NH), 7.42−7.30 (m, 5H,
Ph), 5.72 (ddt, J = 17.0, 10.2, 7.2 Hz, 1H, CH), 5.28 (dq, J = 17.0,
0.8 Hz, 1H, CH), 5.17 (dd, J = 10.2, 0.9 Hz, 1H, CH), 3.34 (s,
3H, N-Me), 3.28−3.13 (m, 2H). 13C NMR (CDCl3): δ 170.4, 169.7,
150.1, 137.0, 131.4, 129.3, 128.8, 126.2, 121.3, 61.1, 40.6, 28.3. Calcd
for C8H11N2O3 [M − H]−: 257.0932. Found: 257.0942.
1-Methyl-5-(prop-2-ynyl)-pyrimidine-2,4,6-trione (13). Col-
1
orless crystals, mp. 94−95 °C, yield 52%. H NMR (CDCl3): 9.21
(brs, 1H), 3.60 (t, J = 4.5 Hz, 1H, OC−CH), 3.33 (s, 3H, NCH3),
3.11−3.05 (m, 2H, CH2), 2.07 (t, J = 2.6 Hz, 1H, CCH). 13C NMR
(CDCl3): δ 167.8, 167.2, 150.4, 77.9, 72.0, 47.7, 28.0, 19.7. HRMS
(ESI): Calcd for C8H9N2O3 [M + H]+: 181.0608. Found: 181.0599.
Arylation of 5-Alkyl-1-methylbarbiturates. The solution of
barbiturate 4 or 13 (1.5 mmol) in dry DMF (2 mL) was cooled on
ice−salt bath under argon with stirring and NaH (60% in mineral oil,
48 mg, 1.2 mmol) was added portionwise over 5 min. The reaction
mixture was warmed up to room temperature, stirred until gas
evolution ceased completely, and diaryliodonium salt (1 mmol) was
added at once. Stirring continued for 2 days at 40−45 °C. followed by
evaporation in vacuum. The residual mass was chromatographed on
silica gel using hexane−ethyl acetate 4:1 as an eluent to afford 5-alkyl-
5-aryl-1-methylbarbiturate.
ASSOCIATED CONTENT
■
S
* Supporting Information
Chiral chromatography of ( )-14, HPLC of the mixture after
hydrogenation of compound 15, determination of pKa value of
14, and NMR data for all new synthesized compounds. This
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dx.doi.org/10.1021/jm300631e | J. Med. Chem. 2012, 55, 6554−6565