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DOI: 10.1055/s-0028-1088220
A Concise Synthesis of Alkoxy-Substituted Pyrimidine Derivatives Based upon a Three-Component Access to Functionalized Enamides
Publication History
Publication Date:
26 March 2009 (online)
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Abstract
Substituted enamides were prepared by a three-component reaction of lithiated alkoxyallenes, nitriles, and carboxylic acids. Their subsequent condensation with ammonium salts provided alkoxy-substituted pyrimidine derivatives. This two-step method is highly flexible with respect to the substitution pattern at C-2 and C-6. The C-4 and C-5 positions can smoothly be functionalized employing either Pd-catalyzed couplings or oxidation methods.
Key words
allenes - enamides - pyrimidines - ammonium salts - nonaflates - Pd catalysis
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References and Notes
Typical Procedure
for the Synthesis of Enamide 4c
Trimethylsilylethoxyallene
(2.45 g, 15.7 mmol) was dissolved in Et2O (32 mL) and n-BuLi (6.90 mL, 17.2 mmol, 2.5 M in
hexanes) was added at -40 ˚C. After 25
min at
-50 ˚C to -40 ˚C
benzonitrile (2.40 mL, 23.5 mmol) was added. After stirring for
4 h at this temperature benzoic acid (5.74 g, 47.0 mmol, dissolved
in 15 mL Et2O) was added, and the mixture was warmed
up over night to r.t. The mixture was quenched with sat. aq NaHCO3 soln
and extracted three times with Et2O (30 mL). The combined organic
layers were dried with Na2SO4, filtered, and concentrated.
Column chromatography (SiO2, EtOAc-hexane, 1:10)
and subsequent recrystallization in hexane provided 4c (2.14
g, 36%) as colorless solid (mp 65 ˚C).
Analytical Data for (
E
)-
N
-{3-Oxo-1-phenyl-2-[2-(trimethylsilyl)ethoxy]but-1-enyl}benzamide
(4c)
¹H NMR (400 MHz, CDCl3): δ = -0.15
(s, 9 H, SiMe3), 0.66-0.71 (m, 2 H, CH2Si),
2.40 (s, 3 H, CH3), 3.33-3.38 (m, 2 H, OCH2),
7.36-7.55, 7.95-7.98 (2 m, 10 H, Ph), 12.40 (br s,
1 H, NH) ppm. ¹³C NMR (101 MHz, CDCl3): δ = -1.7
(q, SiMe3), 18.6 (t, CH2Si), 27.5 (q, CH3),
71.5 (t, OCH2), 127.8, 128.4, 128.68, 128.73, 132.3,
132.6, 133.7 (5 d, 2 s, Ph)*, 137.6, 143.3 (2 s, C=C),
165.2, 202.9 (2 s, C=O) ppm; *overlapping Ph signals.
IR (KBr): ν = 3400 (NH), 3110-2995
(=CH), 2960-2895 (CH), 1730-1580 (C=O,
C=C)
cm-¹. Anal.
Calcd for C22H27NO3Si (381.5):
C, 69.25; H, 7.13; N, 3.67. Found: C, 69.05; H, 7.08; N, 3.69.
Typical Procedure
for the Synthesis of Pyrimidine 7c
Enamide 4c (350 mg, 0.917 mmol) and NH4OAc
(566 mg, 7.34 mmol) were placed in an ACE-sealed tube. The mixture was
dissolved in MeOH (5.0 mL) and stirred for 1 d at 65 ˚C. After
addition of H2O and CH2Cl2 (5.0
mL) the layers were separated, and the aqueous layer was extracted
twice with CH2Cl2 (5.0 mL). The combined organic
layers were dried with Na2SO4, filtered, and
concentrated. Column chromatography (SiO2, EtOAc-hexane,
1:10) provided 7c (285 mg, 86%)
as colorless oil.
Analytical Data
for 4-Methyl-2,6-diphenyl-5-[2-(trimethylsilyl)ethoxy]pyrimidine
(7c)
¹H NMR (500 MHz, CDCl3): δ = -0.08
(s, 9 H, SiMe3), 0.97-1.06 (m, 2 H, CH2Si),
2.64 (s, 3 H, CH3), 3.66-3.71 (m, 2 H, OCH2),
7.41-7.53, 8.16-8.19, 8.47-8.50 (3 m,
10 H, Ph) ppm. ¹³C NMR (101 MHz, CDCl3): δ = -1.6
(q, SiMe3), 18.9 (t, CH2Si), 19.6 (q, CH3),
71.1 (t, OCH2), 128.0, 128.3, 128.4, 129.1, 129.77, 129.84,
136.4, 137.8 (6 d, 2 s, Ph), 148.2 (s, C-5), 156.6, 158.7, 162.4
(3 s, C-2, C-4, C-6) ppm. IR (film): ν = 3090-2870
(=CH, CH), 1680-1540 (C=C, C=N)
cm-¹. Anal. Calcd for C22H26N2OSi
(362.5): C, 72.88; H, 7.23; N, 7.73. Found: C, 72.63; H, 7.12; N,
7.78.
Typical Procedure
for the Synthesis of Pyrimidyl Nonaflate 10
Pyrimidine 7c (285 mg, 0.786 mmol) was dissolved in
a 1:2 mixture of TFA and CH2Cl2 (3.0 mL) and
stirred for 30 min at r.t. After addition of H2O and
CH2Cl2 (5.0 mL) the layers were separated,
and the aqueous layer was extracted twice with CH2Cl2 (8.0
mL). The combined organic layers were dried with Na2SO4,
filtered, and concentrated. The crude product was dissolved in THF
(5.0 mL) and NaH (94 mg 2.36 mmol) was added. After 5 min NfF (0.42
mL, 2.36 mmol) was added, and the reaction mixture was stirred over night
at r.t. After slowly addition of H2O and EtOAc (5.0 mL)
the layers were separated, and the aqueous layer was extracted twice
with EtOAc (8.0 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated. Column
chromatography (SiO2, EtOAc-hexane, 1:10) provided 10 (257 mg, 60%) as colorless
oil.
Analytical Data for 4-Methyl-2,6-diphenylpyrimidin-5-yl
1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonate (10)
¹H
NMR (500 MHz, CDCl3): δ = 2.77
(s, 3 H, CH3), 7.49-7.56, 7.89-7.91,
8.52-8.55 (3 m, 10 H, Ph) ppm. ¹³C
NMR (101 MHz, CDCl3): δ = 20.5
(q, CH3), 128.56, 128.58, 128.7, 129.5, 130.8, 129.9,
134.3, 136.3 (6 d, 2 s, Ph), 140.7 (s, C-5), 159.0, 162.0, 162.3
(3 s, C-2, C-4, C-6) ppm. ¹9F NMR (470 MHz,
CDCl3): δ = -80.6, -109.8, -120.6, -125.8 (4
m, Nf) ppm. IR (film): ν = 3095-2855
(=CH, CH), 1605-1560 (C=C, C=N)
cm-¹. ESI-TOF: m/z calcd
for [M + H]+: 545.0576;
found: 545.0607. Anal. Calcd for C21H13F9N2O3S (544.4):
C, 46.33; H, 2.41; N, 5.15. Found: C, 46.93; H, 2.18; N, 5.06.