A Concise Synthesis of Alkoxy-Substituted Pyrimidine Derivatives Based upon a Three-Component Access to Functionalized Enamides

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.

allenes - enamides - pyrimidines - ammonium salts - ­nonaflates - Pd catalysis

References and Notes

<A NAME="RG00709ST-1A">1a</A> Karpov AS. Müller TJJ. Synthesis  2003,  2815 

<A NAME="RG00709ST-1B">1b</A> Bevk D. Grošelj U. Meden A. Svete J. Stanovnik B. Helv. Chim. Acta  2007,  90:  1737 

<A NAME="RG00709ST-1C">1c</A> Sagar R. Kim M.-J. Park SB. Tetrahedron Lett.  2008,  49:  5080 

<A NAME="RG00709ST-1D">1d</A> Xie F. Zhao H. Zhao L. Lou L. Hu L. Bioorg. Med. Chem. Lett.  2009,  19:  275 

<A NAME="RG00709ST-2A">2a</A> Brown DJ. In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  Chap. 2.13.

<A NAME="RG00709ST-2B">2b</A> Eicher T. Hauptmann S. Chemie der Heterocyclen   Thieme; Stuttgart: 1994.  p.398 

<A NAME="RG00709ST-2C">2c</A> Gilchrist TL. Heterocyclenchemie   Neunhoeffer H. Wiley-VCH; Weinheim: 1995.  p.270 

<A NAME="RG00709ST-2D">2d</A> Hoffmann MG. In Houben-Weyl, Methoden der Organischen Chemie   Vol. E9:  Schaumann E. Thieme; Stuttgart: 1996. 

<A NAME="RG00709ST-2E">2e</A> Angerer S. Science of Synthesis   Vol. 16:  Yamamoto Y. Thieme; Stuttgart: 2004.  p.379 

Recent pyrimidine derivative syntheses starting from enamides:

<A NAME="RG00709ST-3A">3a</A> Barthakur MG. Borthakur M. Devi P. Saikia CJ. Saikia A. Bora U. Chetia A. Boruah RC. Synlett  2007,  223 

<A NAME="RG00709ST-3B">3b</A> Hill MD. Movassaghi M. Chem. Eur. J.  2008,  14:  6836 

For reviews on alkoxyallenes, see:

<A NAME="RG00709ST-4A">4a</A> Zimmer R. Synthesis  1993,  165 

<A NAME="RG00709ST-4B">4b</A> Zimmer R. Khan FA. J. Prakt. Chem.  1996,  338:  92 

<A NAME="RG00709ST-4C">4c</A> Reissig H.-U. Hormuth S. Schade W. Okala Amombo MG. Watanabe T. Pulz R. Hausherr A. Zimmer R. J. Heterocycl. Chem.  2000,  37:  597 

<A NAME="RG00709ST-4D">4d</A> Zimmer R. Reissig H.-U. In Modern Allene Chemistry   Vol. 2:  Krause N. Hashmi ASK. Wiley-VCH; Weinheim: 2004.  p.425 

<A NAME="RG00709ST-4E">4e</A> Reissig H.-U. Zimmer R. Science of Synthesis   Vol. 44:  Krause N. , Ed.; Thieme; Stuttgart: 2007.  p.301 

<A NAME="RG00709ST-4F">4f</A> Brasholz M. Reissig H.-U. Zimmer R. Acc. Chem. Res.  2009,  42:  45 

For selected recent applications developed by our group, see:

<A NAME="RG00709ST-4G">4g</A> Al-Harrasi A. Reissig H.-U. Angew. Chem. Int. Ed.  2005,  44:  6227 ; Angew. Chem. 2005, 117, 6383

<A NAME="RG00709ST-4H">4h</A> Kaden S. Reissig H.-U. Org. Lett.  2006,  8:  4763 

<A NAME="RG00709ST-4I">4i</A> Sörgel S. Azap C. Reissig H.-U. Org. Lett.  2006,  8:  4875 

<A NAME="RG00709ST-4J">4j</A> Brasholz M. Reissig H.-U. Angew. Chem. Int. Ed.  2007,  46:  1634 ; Angew. Chem. 2007, 119, 1659

<A NAME="RG00709ST-4K">4k</A> Gwiazda M. Reissig H.-U. Synthesis  2008,  990 

<A NAME="RG00709ST-5A">5a</A> Flögel O. Dash J. Brüdgam I. Hartl H. Reissig H.-U. Chem. Eur. J.  2004,  10:  4283 

<A NAME="RG00709ST-5B">5b</A> Flögel O, and Reissig H.-U. inventors; DE 103 36 497.8  A1. 

<A NAME="RG00709ST-5C">5c</A> Dash J. Lechel T. Reissig H.-U. Org. Lett.  2007,  9:  5541 

<A NAME="RG00709ST-5D">5d</A> Lechel T. Dash J. Reissig H.-U. Eur. J. Org. Chem.  2008,  3647 

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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.

<A NAME="RG00709ST-7">7</A> Ferrini S. Ponticelli F. Taddei M. Org. Lett.  2007,  9:  69 

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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.

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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.

<A NAME="RG00709ST-10">10</A> For recent applications of the particularly useful alkenyl and aryl nonaflates, see: Högermeier J. Reissig H.-U. Chem. Eur. J.  2007,  13:  2410 ; and references cited therein