Angewandte
Chemie
vacuo the residue was chromatographed on deactivated silica gel
starting material was recovered. Finally, after considerable
experimentation, we found that stirring the electron-deficient
aryl iodide 1e for 5 days with only 1 mol% of [Pd(PPh3)2Cl2]
and in the absence of CuI predominantly led to the formation
of carbonylative alkynylation product, which was subjected to
the cyclocondensation, providing the desired pyrimidine in
28% yield (entry 5).
(ethanol/ammonia 9:1) with ethyl acetate/ethanol (9:1) to give 6b
(93 mg; 73%) as a light yellow solid (recrystallized from pentane).
M.p. 238–2408C (103–1068C).[10] 1H NMR ([D6]DMSO, 300 MHz):
d = 6.52 (br, 2H, NH2), 7.00 (d, J = 5.1 Hz, 1H, H-5’), 7.29 (dd, J = 1.8,
8.5 Hz, 1H, H-6), 7.41 (d, J = 8.8 Hz, 1H, H-7), 8.10 (d, J = 5.1 Hz,
1H, H-6’), 8.26 (br, 1H, H-2), 8.76 (d, J = 1.8 Hz, 1H, H-4), 11.87 ppm
(brs, 1H, NH); 13C NMR ([D6]DMSO, 75 MHz): d = 105.3 (CH),
113.3 (Cquat.), 113.4 (Cquat.), 113.8 (CH), 124.5 (CH), 124.6 (CH), 127.1
(Cquat.), 129.6 (CH), 135.8 (Cquat.), 157.2 (CH), 162.3 (Cquat.), 163.6 ppm
(Cquat.); elemental analysis calcd (%) for C12H9BrN4 (289.1): C 49.85,
H 3.14, N 19.38; found: C 50.10, H 3.24, N 18.87.
Although this pyrimidine synthesis based upon consec-
utive carbonylative alkynylation and cyclocondensation is
lower yielding than the synthesis starting from acid chlor-
ides,[11] it still can be considered as a complementary approach
when acid-sensitive functionality cannot be tolerated.
In conclusion, we have developed concise syntheses of
naturally occuring meridianins and derivatives based upon
carbonylative alkynylation and subsequent cyclocondensa-
tion. Meridianins were found to inhibit “metabolic syn-
drome” and oncologically relevant protein kinases at low
micromolar and even nanomolar levels. Furthermore, we
have developed a novel one-pot four-component synthesis of
2,4,6-trisubstituted pyrimidines based upon a consecutive
carbonylative coupling–cyclocondensation sequence. Studies
addressing the methodological scope of this synthesis and
syntheses of other unknown analogs of meridianins and
variolins as well as thorough studies of the structure–activity
relationship are currently underway.
8a: In a Schlenk flask [Pd(PPh3)2Cl2] (35 mg, 0.05 mmol), CuI
(4 mg, 0.02 mmol), para-iodoanisole (1a; 234 mg, 1.00 mmol), and
THF (5 mL) were placed under nitrogen. Carbon monoxide was
bubbled through the solution for 5 min, and then hexyne 2a (0.14 mL,
1.20 mmol) and triethylamine (0.28 mL, 2.00 mmol) were added
successively. The reaction mixture became dark red and was stirred at
room temperature for 48 h under 1 atm of carbon monoxide (balloon
filled with CO). Then the suspension was treated with Na2CO3
(265 mg, 2.50 mmol), amidinium salt 7a (195 mg, 1.20 mmol), water
(0.5 mL), and CH3CN (5 mL), and the reaction mixture was heated at
reflux for 24 h. After cooling to room temperature, the reaction
mixture was diluted with brine (20 mL) and extracted with dichloro-
methane (5 20 mL). The combined organic layers were dried with
sodium sulfate, concentrated to dryness, and subjected to column
chromatography on silica gel (hexane/ethyl acetate, 6:1) to give 8a
(166 mg; 51%) as a light yellow solid. M.p. 84–868C. 1H NMR
(CDCl3, 300 MHz): d = 0.97 (t, J = 7.4 Hz, 3H), 1.38–1.56 (m, 2H),
1.74–1.85 (m, 2H), 2.80 (t, J = 7.9 Hz, 2H), 3.87 (s, 3H), 7.01 (d, J =
8.9 Hz, 2H), 7.14 (dd, J = 5.0 Hz, 3.7 Hz, 1H), 7.29 (s, 1H), 7.45 (dd,
J = 5.0 Hz, 1.1 Hz, 1H), 8.08 (dd, J = 3.7 Hz, 1.1 Hz, 1H), 8.14 ppm (d,
J = 8.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d = 13.9 (CH3), 22.5
(CH2), 30.9 (CH2), 37.8 (CH2), 55.4 (CH3), 111.6 (CH), 114.1 (CH),
128.0 (CH), 128.5 (CH), 128.7 (CH), 129.2 (CH), 129.5 (Cquat.), 144.4
(Cquat.), 161.0 (Cquat.), 161.8 (Cquat.), 163.1 (Cquat.), 171.4 ppm (Cquat.);
EI-MS (70 eV): m/z (%): 324 [M]+ (2); 309 [MÀCH3]+ (4); 295
[MÀC2H5]+ (7); 282 [MÀC3H6]+ (100); elemental analysis calcd (%)
for C19H20N2OS (324.3): C 70.34, H 6.21, N 8.63, S 9.88; found: C
69.95, H 6.17, N 8.59, S 9.86.
Experimental Section
5b: In a Schlenk flask [Pd(PPh3)2Cl2] (35 mg, 0.05 mmol), [Pd-
(dppf)Cl2·CH2Cl2] (8 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol), Boc-
protected iodo indole 4b (422 mg, 1.00 mmol), and THF (5 mL) were
placed under nitrogen. Carbon monoxide was bubbled through the
solution for 5 min, and then TMS-acetylene (0.21 mL, 1.50 mmol) and
triethylamine (0.14 mL, 1.00 mmol) were added successively. The
reaction mixture became dark red and was stirred at room temper-
ature for 48 h under 1 atm of carbon monoxide (balloon filled with
CO). The reaction mixture was then diluted with brine (20 mL) and
extracted with dichloromethane (5 20 mL). The combined organic
layers were dried with sodium sulfate, concentrated to dryness, and
subjected to column chromatography on silica gel (hexane/ethyl
acetate, 12:1) to give 5b (287 mg; 68%) as colorless crystals. M.p.
157–1598C. 1H NMR (300 MHz, CDCl3): d = 0.32 (s, 9H), 1.70 (s,
9H), 7.47 (dd, J = 8.8 Hz, 1.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.36 (s,
1H), 8.48 ppm (d, J = 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d =
À0.7 (CH3), 28.0 (CH3), 86.1 (Cquat.), 97.0 (Cquat.), 101.3 (Cquat.), 116.5
(CH), 118.4 (Cquat.), 120.8 (Cquat.), 125.0 (CH), 128.1 (Cquat.), 128.9
(CH), 134.6 (Cquat.), 136.4 (CH), 148.4 (Cquat.), 171.5 ppm (Cquat.); EI-
MS (70 eV): m/z (%): 421 [M]+, 81Br, (7); 419 [M]+, 79Br, (5); 365
[MÀC4H9]+, 81Br, (58); 363 [MÀC4H9]+, 79Br, (49); 321
[MÀC4H9ÀCO2ÀH]+, 81Br, (100); 319 [MÀC4H9ÀCO2ÀH]+, 79Br,
(84); 306 (23); 304 (19); 57 [C4H9]+ (99); elemental analysis calcd (%)
for C19H22BrNO3Si (420.4): C 54.29, H 5.28, N 3.33, Br 19.01; found: C
54.00, H 5.33, N 3.37, Br 19.27.
Received: May 18, 2005
Published online: October 5, 2005
À
Keywords: C C coupling · carbonylation · heterocycles ·
multicomponent reactions · natural products
.
[1] For reviews, see, for example, a) “The Pyrimidines”: D. J. Brown
in The Chemistry of Heterocyclic Compounds, Vol. 16 (Ed.: A.
Weissberger), Wiley-Interscience, New York, 1970; b) “Fused
Pyrimidines, Part II, The Purines”: J. H. Lister in The Chemistry
of Heterocyclic Compounds, Vol. 24 (Eds.: A. Weissberger, E. C.
Taylor), Wiley-Interscience, New York, 1971; c) M. G. Hoff-
mann in Houben-Weyl, Methoden der Organischen Chemie,
Vol. E9 (Ed.: E. Schaumann), Thieme, Stuttgart, 1996; d) D. T.
Hurst in An Introduction to the Chemistry and Biochemistry of
Pyrimidines, Purines and Pteridines, Wiley, Chichester, 1980;
e) J. T. Bojarski, J. L. Mokrosz, H. J. Bartón, M. H. Paluchowska,
Adv. Heterocycl. Chem. 1985, 38, 229; f) D. J. Brown in
Comprehensive Heterocyclic Chemistry, Vol. 3 (Eds.: A. R.
Katritzky, C. W. Rees), Pergamon, Oxford, 1984, chap. 2.13.
[2] For the significance of 2,4-disubstituted pyrimidines as tyrosine
kinase inhibitors see, for example, a) P. Traxler, G. Bold, E.
Buchdunger, G. Caravatti, P. Furet, P. Manley, T. OꢀReilly, J.
Wood, J. Zimmermann, Med. Res. Rev. 2001, 21, 499; b) J.
6b: To a solution of 5b (185 mg, 0.44 mmol) in acetonitrile
(1.5 mL) was added in succession sodium carbonate (47 mg,
0.44 mmol), tert-butyl alcohol (1.5 mL), and a 5m aqueous solution
of guanidine (0.22 mL, 1.1 mmol; prepared by dissolving guanidine
hydrochloride (9.55 g, 0.10 mol) in water (20 mL) and neutralizing
with sodium hydroxide (4.10 g, 0.10 mol). The reaction mixture was
stirred at 808C for 38 h. After conversion to the meridianin was
complete (TLC), brine was added and the mixture was extracted with
dichloromethane (3 20 mL). The combined organic layers were
dried with sodium sulfate, and after evaporation of the solvents in
Angew. Chem. Int. Ed. 2005, 44, 6951 –6956
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