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LETTER
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): d = 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 (C≡C), 1662 (C=O) cm–1. 1H
NMR (300 MHz, CDCl3): d = 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): d = 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 (C≡C), 1665 (C=O) cm–1. 1H
NMR (300 MHz, CDCl3): d = 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): d =
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.
References and Notes
(1) (a) Modern Acetylene Chemistry; Stang, P. J.; Diederich, F.,
Eds.; Wiley-VCH: Weinheim, Germany, 1995. (b)
Chemistry of Triple-Bonded Functional Groups; Patai, S.,
Ed.; Wiley: New York, 1994.
(2) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J.
Am. Chem. Soc. 2002, 124, 764. (b) Nakamura, H.; Ohtaka,
M.; Yamamoto, Y. Tetrahedron Lett. 2002, 43, 7631.
(3) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69, 5193.
(4) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P.
Chem. Eur. J. 2007, 13, 5632.
(5) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez,
J. M. J. Am. Chem. Soc. 2003, 125, 9028.
(6) (a) Yue, D.; Della Ca, N.; Larock, R. C. Org. Lett. 2004, 6,
1581. (b) Yue, D.; Della Ca, N.; Larock, R. C. J. Org. Chem.
2006, 71, 3381.
(7) (a) Susvilo, I.; Brukstus, A.; Tumkevicius, S. Synlett 2003,
1151. (b) Tumkevicius, S.; Susvilo, I.; Brukstus, A. Chem.
Heterocycl. Compd. (Engl. Transl.) 2004, 40, 1335.
(c) Susvilo, I.; Palskyte, R.; Tumkevicius, S.; Brukstus, A.
Chem. Heterocycl. Compd. (Engl. Transl.) 2005, 41, 268.
(d) Cikotiene, I.; Pudziuvelyte, E.; Brukstus, A.;
Tumkevicius, S. Tetrahedron 2007, 63, 8145.
(8) (a) Clark, J.; Shahhet, M. S.; Korakas, D.; Varvounis, G. J.
Heterocycl. Chem. 1993, 30, 1065. (b) Kasparec, J.; Adams,
J. L.; Sisko, J.; Silva, D. Tetrahedron Lett. 2003, 44, 4567.
(9) Crystal structure analysis for 3a: C39H46N6O5S2, Mr =
742.952 g mol–1, triclinic, space group P1, a = 11.8827(4),
b = 12.5375(5), c = 15.1461(7) Å, a = 104.514(3)°, b =
102.61(2)°, g = 110.72(2)°, V = 1922.04(13) Å3, r = 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 MoKa radiation (l = 0.71073 Å).
The structure of 3a was solved by direct methods with SIR97
program13 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 ORTEP15 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).
(11) Typical Procedure for the Preparation of 2,4-
Disubstituted 5-Alkoxy-(7Z)-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.
(7Z)-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): d = 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): d = 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.
(7Z)-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): d = 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): d = 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.
(10) 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 (C≡C), 1665 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 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): d = 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.
(7Z)-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): d = 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,
2-Methylthio-6-phenylethynyl-4-piperidin-1-
ylpyrimidine-5-carbaldehyde (2b): yield: 85%; mp 122–
123 °C (2-PrOH). IR (KBr): 2213 (C≡C), 1661 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.73 [br s, 6 H, (CH2)3],
Synlett 2008, No. 11, 1693–1697 © Thieme Stuttgart · New York