The First Tandem Acetalization/5-exo-dig Cyclization of 6-Phenylethynylpyrimidine-5-carbaldehydes: Efficient Synthesis of 5-Alkoxy-(7Z)-7-benzylidene-5,7-dihydrofuro[3,4-d]pyrimidines

Abstract

The first example of catalyst-free tandem acetalization/5-exo-dig cyclization reactions of 6-phenylethynylpyrimidine-5-carbaldehydes is presented. Efficient novel synthesis of 5,7-dihydrofuro[3,4-d]pyrimidine core is described.

Key words

acetalization - 5-exo-dig cyclization - 6-phenylethynylpyrimidine-5-carbaldehydes - tandem reactions - furo[3,4-d]pyrimidines

References and Notes

• 1a Modern Acetylene Chemistry   Stang PJ. Diederich F. Wiley-VCH; Weinheim, Germany: 1995. 
• 1b Chemistry of Triple-Bonded Functional Groups   Patai S. Wiley; New York: 1994. 
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• 6b Yue D. Della Ca N. Larock RC. J. Org. Chem.  2006,  71:  3381 
• 7a Susvilo I. Brukstus A. Tumkevicius S. Synlett  2003,  1151 
• 7b Tumkevicius S. Susvilo I. Brukstus A. Chem. Heterocycl. Compd. (Engl. Transl.)  2004,  40:  1335 
• 7c Susvilo I. Palskyte R. Tumkevicius S. Brukstus A. Chem. Heterocycl. Compd. (Engl. Transl.)  2005,  41:  268 
• 7d Cikotiene I. Pudziuvelyte E. Brukstus A. Tumkevicius S. Tetrahedron  2007,  63:  8145 
• 8a Clark J. Shahhet MS. Korakas D. Varvounis G. J. Heterocycl. Chem.  1993,  30:  1065 
• 8b Kasparec J. Adams JL. Sisko J. Silva D. Tetrahedron Lett.  2003,  44:  4567 
• 13 Altomare A. Burla MC. Camalli M. Cascarano GL. Giacovazzo C. Guagliardi AG. Moliterni AG. Spagna R. J. Appl. Crystallogr.  1999,  32:  115 
• 14 Sheldrick GM. SHELXL97: Program for the Refinement of Crystal Structures   University of Göttingen; Göttingen, Germany: 1997. 
• 15 Johnson CK. ORTEP-II, Report ORNL-5138   Oak Ridge National Laboratory; Oak Ridge, TN, USA: 1976. 

9

Crystal structure analysis for 3a: C₃₉H₄₆N₆O₅S₂, M_r = 742.952 g mol^-1, triclinic, space group P1, a = 11.8827(4), b = 12.5375(5), c = 15.1461(7) Å, α = 104.514(3)°, β = 102.61(2)°, γ = 110.72(2)°, V = 1922.04(13) ų, ρ = 1.284 g×cm³, F(000) = 788. X-ray diffraction data were collected on a Nonius Kappa CCD diffractometer at 293 K using graphite-monochromated MoK_α radiation (λ = 0.71073 Å). The structure of 3a was solved by direct methods with SIR97 program [13] and refined by full-matrix least squares techniques with anisotropic non-hydrogen atoms. Hydrogen atoms were refined in the riding model. The refinement calculations were carried out with the help of SHELX97 program. [14] ORTEP [15] view of the molecule is shown in Figure [1] . Crystallographic data for the structure of 3a have been deposited at the Cambridge Crystallographic Data Centre (CCDC number 681988).

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Typical Procedure for the Preparation of 2,4-Disubstituted 6-Phenylethynylpyrimidine-5-carbaldehydes 2a-k: A mixture of the corresponding compound 1a-k (1.15 mmol), PdCl₂(PPh₃)₂ (0.016 g, 0.023 mmol), CuI (0.0022 g, 0.0115 mmol), Et₃N (0.23 g, 2.30 mmol) and DMF (10 mL) was stirred under Ar atmosphere for 3 min. Then phenyl-acetylene (0.14 g, 1.38 mmol) was added, the mixture was flushed with Ar and heated under stirring at 40 °C for
3 h. After cooling to r.t., the precipitate was filtered off and recrystallized to give compounds 2a-k. 2-Methylthio-6-phenylethynyl-4-pyrrolidin-1-ylpyrimidine-5-carbaldehyde (2a): yield: 90%; mp 173-175 °C (2-PrOH). IR (KBr): 2219 (CºC), 1665 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.00 [br s, 4 H, (CH₂)₂], 2.57 (s, 3 H, SMe), 3.54 [br s, 4 H, N(CH₂)₂], 7.40-7.44 (m, 3 H, ArH), 7.63-7.66 (m, 2 H, ArH), 10.53 (s, 1 H, CHO). ¹³C NMR (75 MHz, CDCl₃): δ = 14.3, 25.3, 50.7, 84.5, 97.1, 111.4, 121.0, 128.4, 129.9, 132.3, 154.8, 156.6, 173.7, 188.2. Anal. Calcd for C₁₈H₁₇N₃OS: C, 66.85; H, 5.30; N, 12.99. Found: C, 66.75; H, 5.32; N, 13.03.
2-Methylthio-6-phenylethynyl-4-piperidin-1-ylpyrimidine-5-carbaldehyde (2b): yield: 85%; mp 122-123 °C (2-PrOH). IR (KBr): 2213 (CºC), 1661 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.73 [br s, 6 H, (CH₂)₃], 2.56 (s, 3 H, SMe), 3.65 [br s, 4 H, N(CH₂)₂], 7.40-7.44 (m, 3 H, ArH), 7.62-7.66 (m, 2 H, ArH), 10.44 (s, 1 H, CHO). ¹³C NMR (75 MHz, CDCl₃): δ = 14.4, 24.1, 26.0, 49.8, 84.6, 97.5, 111.1, 121.0, 128.5, 130.0, 132.4, 156.7, 158.9, 174.3, 187.7. Anal. Calcd for C₁₉H₁₉N₃OS: C, 67.63; H, 5.68; N, 12.45. Found: C, 67.45; H, 5.75; N, 12.39. 2-Methylthio-4-morpholin-4-yl-6-phenylethynyl-pyrimidine-5-carbaldehyde (2c): yield: 80%; mp 137-139 °C (2-PrOH). IR (KBr): 2212 (CºC), 1662 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.58 (s, 3 H, SMe), 3.73 [t, J = 4.0 Hz, 4 H, N(CH₂)₂], 3.87 [t, J = 4.0 Hz, 4 H, O(CH₂)₂], 7.43-7.46 (m, 3 H, ArH), 7.64-7.66 (m, 2 H, ArH), 10.48 (s, 1 H, CHO). ¹³C NMR (75 MHz, CDCl₃): δ = 14.4, 49.0, 66.7, 84.4, 98.2, 111.1, 120.8, 128.6, 130.2, 132.4, 157.0, 159.2, 174.9, 187.8. Anal. Calcd for C₁₈H₁₇N₃O₂S: C, 63.70; H, 5.05; N, 12.38. Found: C, 63.49; H, 5.09; N, 12.44. 4-Anilino-2-methylthio-6-phenylethynylpyrimidine-5-carbaldehyde (2k): yield: 82%; mp 139-140 °C (2-PrOH). IR (KBr): 3456 (NH), 2211 (CºC), 1665 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.61 (s, 3 H, SMe), 7.21 (t, J = 7.5 Hz, 1 H, ArH), 7.39-7.48 (m, 5 H, ArH), 7.66-7.69 (m, 2 H, ArH), 7.73-7.76 (m, 2 H, ArH), 10.54 (s, 1 H, CHO), 11.08 (s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.9, 83.9, 98.6, 108.8, 120.9, 122.6, 125.3, 128.9 (2 × C), 129.1 (2 × C), 130.7, 132.8, 137.5, 157.4, 178.1, 192.1. Anal. Calcd for C₂₀H₁₅N₃O₂S: C, 69.54; H, 4.38; N, 12.17. Found: C, 69.48; H, 4.39; N, 12.32.

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Typical Procedure for the Preparation of 2,4-Disubstituted 5-Alkoxy-(7 Z )-7-benzylidene-5,7-dihydrofuro[3,4- d ]pyrimidines 3a-p: To a solution of the corresponding 6-phenylethynylpyrimidine-5-carbaldehyde 2a-g (0.3 mmol) in an alcohol (5 mL) a solution of the base (0.3 mmol) in appropriate alcohol (2 mL) was added. The resulting reaction mixture was refluxed for the indicated period of time (Table [1] ). The solvent was evaporated under reduced pressure, the residue washed with H₂O, filtered and recrystallized to give compounds 3a-p. (7 Z )-7-Benzylidene-5-methoxy-2-methylthio-4-pyrrolidin-1-yl-5,7-dihydrofuro[3,4- d ]pyrimidine (3a): yield: 49% (using t-BuNH₂), 73% (using K₂CO₃), 95% (using MeONa); mp 122-124 °C (2-PrOH). ¹H NMR (300 MHz, CDCl₃): δ = 1.97-2.00 [m, 4 H, (CH₂)₂], 2.60 (s, 3 H, SMe), 3.49 (s, 3 H, OMe), 3.72-3.88 [m, 4 H, N(CH₂)₂], 6.48 (s, 1 H, CH), 6.64 (s, 1 H, CH), 7.25 (t, J = 7.5 Hz, 1 H, ArH), 7.39 (t, J = 7.5 Hz, 2 H, ArH), 7.81 (d, J = 7.5 Hz, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 16.3, 26.2, 28.1, 48.8, 49.8, 55.5, 103.5, 108.0, 108.2, 128.8, 130.4, 131.2, 137.1, 152.6, 157.6, 163.0, 175.1. Anal. Calcd for C₁₉H₂₁N₃O₂S: C, 64.20; H, 5.95; N, 11.82. Found: C, 64.17; H, 6.00; N, 11.97. (7 Z )-7-Benzylidene-5-methoxy-2-methylthio-4-piperidin-1-yl-5,7-dihydrofuro[3,4- d ]pyrimidine (3c): yield: 72% (using K₂CO₃), 90% (using MeONa); mp 130-132 °C (2-PrOH). ¹H NMR (300 MHz, CDCl₃): δ = 1.69-1.74 [m, 6 H, (CH₂)₃], 2.60 (s, 3 H, SMe), 3.45 (s, 3 H, OMe), 3.77 [br s, 4 H, N(CH₂)₂], 6.49 (s, 1 H, CH), 6.62 (s, 1 H, CH), 7.25 (t, J = 7.5 Hz, 1 H, ArH), 7.40 (t, J = 7.5 Hz, 2 H, ArH), 7.82 (d, J = 7.5 Hz, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.2, 24.6, 25.9, 46.5, 43.1, 101.3, 105.4, 106.3, 126.7, 128.4, 129.2, 134.9, 150.4, 156.8, 161.9, 173.1. Anal. Calcd for C₂₀H₂₃N₃O₂S: C, 65.01; H, 6.27; N, 11.37. Found: C, 65.07; H, 6.41; N, 11.30. (7 Z )-7-Benzylidene-5-methoxy-2-methylthio-4-morpholin-4-yl-5,7-dihydrofuro[3,4- d ]pyrimidine (3h): yield: 24% (using Et₃N), 72% (using K₂CO₃), 92% (using MeONa), 93% (using (MeOK); mp 160-162 °C (2-PrOH). ¹H NMR (300 MHz, CDCl₃): δ = 2.65 (s, 3 H, SMe), 3.44 (s, 3 H, OMe), 3.81-3.84 [m, 8 H, N(CH₂)₄O], 6.52 (s, 1 H, CH), 6.63 (s, 1 H, CH), 7.27 (t, J = 7.5 Hz, 1 H, ArH), 7.41 (t, J = 7.5 Hz, 2 H, ArH), 7.81 (d, J = 7.5 Hz, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.3, 45.5, 53.0, 66.6, 101.9, 105.5, 105.9, 126.9, 128.4, 129.3, 134.7, 150.1, 157.4, 162.3, 174.4. Anal. Calcd for C₁₉H₂₁N₃O₃S: C, 61.44; H, 5.70; N, 11.31. Found: C, 61.55; H, 5.69; N, 11.28.

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Compounds 2d-h and 3b,c-g,k-p were also fully characterized by IR, ¹H NMR, ¹³C NMR spectroscopic and microanalytical data.