Worlikar et al.
SCHEME 4
Phenyl 3-p-Tolylprop-2-yn-1-yl ether (4). This compound was
obtained as a white solid: mp 71-72 °C; H NMR (300 MHz,
1
CDCl3) δ 2.30 (s, 3H), 4.86 (s, 2H), 6.94-7.08 (m, 5H), 7.18-
7.33 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 21.7, 56.9, 83.5, 87.5,
115.2, 119.5, 121.6, 129.3, 129.7, 132.0, 139.0, 158.1; IR (neat,
cm-1) 3032, 2914, 1598, 1490, 1214, 1029; HRMS m/z 222.10477
(calcd C16H14O, 222.10447).
General Procedure for the Palladium/Copper-Catalyzed
Reaction of Terminal Alkynes with Iodobenzene. To a solution
of 4.5 mmol of iodobenzene in Et3N (15 mL) was added PdCl2-
(PPh3)2 (2 mol %) and CuI (1.5 mol %), and the mixture was stirred
for 30 min under Ar. A solution of 3.0 mmol of the terminal alkyne
in 2 mL of Et3N was then added dropwise, and the reaction mixture
was allowed to stir at room temperature for the desired time. After
the reaction was over, the resulting solution was diluted with H2O
(10 mL) and extracted with diethyl ether (3 × 15 mL). The
combined ether fractions were dried over anhydrous Na2SO4 and
concentrated under vacuum to yield the crude product. The crude
product was purified by flash chromatography on silica gel using
ethyl acetate/hexanes as the eluent.
SCHEME 5
4-(3-Phenylprop-2-yn-1-yloxy)benzaldehyde (9). This com-
1
pound was obtained as a brown solid: mp 86-87 °C; H NMR
(300 MHz, CDCl3) δ 5.00 (s, 2H), 7.14 (d, J ) 8.8 Hz, 2H), 7.25-
7.32 (m, 3H), 7.41-7.44 (m, 2H), 7.87 (d, J ) 8.8 Hz, 2H), 9.90
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 57.0, 82.9, 88.1, 115.4,
122.0, 128.5, 129.1, 130.6, 132.0, 132.1, 162.8, 191.0; IR (neat,
cm-1) 3078, 2827, 1690, 1598, 1250, 1009; HRMS m/z 236.08409
(calcd C16H12O2, 236.08373).
General Procedure for the Triphenylphosphine/Diethyl Azodi-
carboxylate-Promoted Formation of the Substituted Phenyl
Propargylic Ethers. To a solution of 1.31 g of PPh3 (5.0 mmol)
in dry benzene (15 mL) was added the substituted propargylic
alcohol (5.0 mmol) and the substituted phenol (5.0 mmol) under
an inert atmosphere with stirring. Diethyl azodicarboxylate (0.87
g, 5.0 mmol) was then added slowly, and the reaction mixture was
stirred at rt for 18-36 h. After the reaction was complete, the
solvent was evaporated under reduced pressure, and the crude
product was purified by flash chromatography on silica gel using
hexanes/ethyl acetate as the eluent.
3-tert-Butylphenyl 3-Phenylprop-2-yn-1-y1 Ether (11). This
compound was obtained as a yellow oil: 1H NMR (300 MHz,
CDCl3) δ 1.30 (s, 9H), 4.86 (s, 2H), 6.83 (dd, J ) 8.0, 2.3 Hz,
1H), 6.96-7.02 (m, 1H), 7.08 (t, J ) 1.9 Hz, 1H), 7.19-7.25 (m,
4H), 7.39-7.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 31.4, 34.8,
56.6, 84.3, 87.2, 111.2, 113.1, 118.6, 122.4, 128.4, 128.7, 129.1,
131.9, 153.0, 157.7; IR (neat, cm-1) 3067, 2955, 2868, 1588, 1485,
1270, 1029; HRMS m/z 264.15187 (calcd C19H20O, 264.15142).
General Procedure for Iodocyclization. To a solution of 0.25
mmol of the ether and 3 mL of CH3NO2, 2.0 equiv of NaHCO3
and 3.0 equiv of I2 dissolved in 2 mL of CH3NO2 was added
gradually. The reaction mixture was allowed to stir at room
temperature for the desired time. Alternatively, to a solution of 0.25
mmol of the ether and 3 mL of CH3NO2 at -25 to -30 °C, 1.5
equiv of ICl dissolved in 2 mL of CH3NO2 was added gradually.
The reaction mixture was allowed to stir at -25 to -30 °C for the
desired time. The excess I2 or ICl was removed by washing with
saturated aq Na2S2O3. The mixture was then extracted by diethyl
ether (3 × 10 mL). The combined ether layers were dried over
anhydrous Na2SO4 and concentrated under vacuum to yield the
crude product, which was purified by flash chromatography on silica
gel using hexanes/ethyl acetate as the eluent.
rans, like the ones prepared here, have recently been further
elaborated by palladium-catalyzed cross-coupling reactions.27
To further prove the utility of our methodology, we have carried
out the palladium/copper-catalyzed reaction of our product 2
with 5-ethynyl-2-fluorotoluene to obtain 44 in an 87% yield.
Palladium-catalyzed CO insertion in our product 42 gave
compound 45 in an overall 72% yield (Scheme 5).
Conclusion
3,4-Disubstituted 2H-benzopyrans have been obtained from
starting materials that are easy to synthesize. The reaction
conditions are mild, and the products are easy to isolate in good
yields. The iodine moiety in the products provides a useful
handle for further functionalization of the resulting heterocycles.
A polycyclic Sonogashira product 44 has been obtained in good
yield. Our methodology tolerates functional groups, including
alcohol, aldehyde, methoxy, and nitro groups. In addition to I2
and ICl, PhSeBr has also been used as the electrophile. The
structure of 3-iodo-4-phenyl-2H-benzopyran (2) has been con-
firmed by X-ray crystallography.
Experimental Section
General Procedure for the Palladium/Copper-Catalyzed
Reaction of Phenyl Propargyl Ether with Aryl Halides. To a
solution of 2.5 mmol of the aryl halide in Et3N (15 mL) was added
PdCl2(PPh3)2 (2 mol %), which was then stirred for 5 min. CuI
(1.5 mol %) was then added, and the flask was sealed and flushed
with Ar. The reaction was stirred for 20 min. A solution of 3.0
mmol of phenyl propargyl ether in 2 mL of Et3N was then added
dropwise, and the reaction mixture was allowed to stir at room
temperature for the desired time. After the reaction was over, the
resulting solution was diluted with H2O (10 mL) and extracted with
diethyl ether (3 × 15 mL). The combined ether fractions were dried
over anhydrous Na2SO4 and concentrated under vacuum to yield
the crude product. The crude product was purified by flash
chromatography on silica gel using ethyl acetate/hexanes as the
eluent.
3-Iodo-4-phenyl-2H-benzopyran (2). This compound was
1
obtained as a pale yellow solid: mp 99-100 °C; H NMR (300
MHz, CDCl3) δ 5.06 (s, 2H), 6.61 (dd, J ) 7.7, 1.6 Hz, 1H), 6.76
(dt, J ) 7.7, 1.1 Hz, 1H), 6.85 (dd, J ) 8.0, 1.0 Hz, 1H), 7.14 (dd,
J ) 7.9, 1.6 Hz, 1H), 7.18-7.22 (m, 2H), 7.39-7.46 (m, 3H); 13
C
NMR (75 MHz, CDCl3) δ 75.1, 91.2, 116.1, 121.7, 124.2, 126.5,
128.3, 128.7, 129.5, 129.7, 140.0, 142.0, 153.3; IR (neat, cm-1
)
1352 J. Org. Chem., Vol. 72, No. 4, 2007