RegioselectiVe Synthesis of 4- and 7-Alkoxyindoles
aqueous solution was extracted with Et2O (3 × 25 mL), and the
combined organic layers were dried (Na2SO4) and evaporated under
reduced pressure. The crude product was purified by column
chromatography (hexane/EtOAc, 20/1) on silica gel to afford 3a
(2.42 g, 90%) as a white solid: mp 51-53 °C (lit.30 mp 53.5 °C);
1H NMR (300 MHz, CDCl3) δ 7.21 (t, J ) 8.0 Hz, 1H), 7.06 (dd,
J ) 8.0, 1.4 Hz, 1H), 6.67 (dd, J ) 8.0, 1.4 Hz, 1H), 3.86 (s, 3H);
13C NMR (75.4 MHz, CDCl3) δ 159.8 (C), 139.7 (C), 129.8 (CH),
121.8 (CH), 108.5 (CH), 91.2 (C), 56.8 (CH3); EI-LRMS m/z 270
(M+ + 2, 32), 268 (M+, 100), 253 (21), 126 (24); HRMS calcd
for C7H6ClIO, 267.9152; found, 267.9166. Anal. Calcd for
C7H6ClIO: C, 31.32; H, 2.25. Found: C, 31.20; H, 2.20.
tions gave rise to 2-(1-butynyl)-3-chloroanisole 4h. Amination
of this o-alkynylchloroarene derivative with benzylamine in the
presence of base and the N-heterocyclic carbene palladium
complex yielded N-benzylindole 7f. O-Demethylation was again
accomplished by treatment with BBr3, and the 4-hydroxyindole
10d was obtained in high yield. Its treatment with NaH and
further alkylation with t-butyl bromoacetate in DMF afforded
t-butyl oxyethanoate derivative 13. The corresponding 3-gly-
oxylamide derivative 14 was easily prepared by treatment with
oxalyl chloride followed by hexamethyldisilazane.29 Finally,
deprotection of the t-butyl ester with TFA yielded almost
quantitatively the targeted N-benzyl-2-ethylindole derivative 15
in good overall yield and in only seven steps from commercially
available 3-chloroanisole (Scheme 6). This synthesis favorably
competes with the reported sequences, which make use of
expensive starting materials or require several steps.27,28 It is
important to remark that this synthetic strategy could be applied
to the synthesis of a small library of related compounds from
easily available starting materials.
Alternative Procedure for the Synthesis of 2,3-Dihalophenyl
Ethers 3a and 3e: Synthesis of 3-Bromo-2-iodoanisole (3e).13
To a solution of lithium 2,2,6,6-tetramethylpiperidide (20 mmol,
generated from n-BuLi and 2,2,6,6-tetramethylpiperidine) in dry
THF (30 mL),
a solution of t-Bu2Zn (22 mmol, gener-
ated from t-BuLi and ZnCl2) in dry THF (30 mL) was added at
-78 °C, and the reaction mixture was stirred at 0 °C for 30 min.
Then 3-bromoanisole (1.87 g, 10 mmol) was added at -78 °C,
and the reaction mixture was allowed to reach -30 °C and was
stirred at this temperature overnight. To this was added iodine (17.78
g, 70 mmol) in THF (30 mL), and the mixture was stirred at room
temperature for 2 h. The reaction was quenched with saturated
Na2S2O3, and the aqueous solution was extracted with Et2O (3 ×
30 mL). The combined organic layers were dried (Na2SO4), and
evaporated under reduced pressure. The crude product was purified
by column chromatography (hexane/EtOAc, 20/1) on silica gel to
afford 3e (2.60 g, 83%) as a white solid: mp 63-65 °C (lit.13b mp
Conclusions
In summary, we have presented an efficient route to indoles
regioselectively functionalized at 4- or 7-positions with oxygen-
bearing substituents. The starting materials, 2,3-dihalophenyl
ethers 3, are easily prepared by directed ortho-metalation
reactions from commercially available 3-halophenols or
3-haloanisoles. The copper-free Sonogashira cross-coupling
reaction has the advantage of producing only trace amounts of
homocoupling products of terminal alkynes and affords the
corresponding o-alkynylhalobenzene derivatives. Finally, Pd-
catalyzed amination and subsequent cyclization allow the
synthesis of the oxygen-functionalized indoles in good
overall yields. A short synthesis of an indole inhibitor of
phospholipase A2 with this strategy as the key step shows that
this methodology may be expected to find application in
medicinal chemistry programs and for the synthesis of many
indole derivatives.
1
61.5-62 °C); H NMR (300 MHz, CDCl3) δ 7.24 (dd, J ) 8.0,
1.4 Hz, 1H), 7.16 (t, J ) 8.0 Hz, 1H), 6.70 (dd, J ) 8.0, 1.4 Hz,
1H), 3.86 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 160.0 (C), 131.1
(C), 130.2 (CH), 125.1 (CH), 108.9 (CH), 94.3 (C), 56.9 (CH3);
EI-LRMS m/z 314 (M+ + 2, 100), 312 (M+, 100), 299 (21), 297
(20), 172 (42), 170 (40); HRMS calcd for C7H6BrIO, 311.8647;
found, 311.8635.
Typical Procedure for the Synthesis of 2-Alkynyl-3-chlo-
rophenyl Ethers 4, 2-Alkynyl-3-bromophenyl Ether 5a, and
3-Alkynyl-2-chlorophenyl Ethers 6: Synthesis of 3-Chloro-2-
phenylethynylanisole (4a; Table 2, Entry 1).15e A mixture of
3-chloro-2-iodoanisole 3a (1.34 g, 5 mmol), phenylacetylene (1.02
g, 10 mmol), PdCl2(PPh3)2 (0.211 g, 0.30 mmol), and TBAF‚3H2O
(4.73 g, 15 mmol) was stirred under N2 at 60 °C for the desired
time until complete consumption of starting material as monitored
by GC-MS (2-3 h). After the mixture was washed with water,
extracted with Et2O (3 × 15 mL), and evaporated, the residue was
purified by flash column chromatography (hexane/EtOAc, 20/1)
to afford 4a (1.12 g, 92%) as a brown oil: Rf 0.18 (hexane/EtOAc,
Experimental Section
Optimized reaction conditions for our previously reported10
synthesis of O-2,3-dihalophenyl carbamates 2 are given in the
Supporting Information.
Typical Procedure for the Synthesis of 2,3-Dihalophenyl
Ethers 3: Synthesis of 3-Chloro-2-iodoanisole (3a; Table 1,
Entry 1). To a solution of 3-chloro-2-iodophenyl N,N-diethylcar-
bamate 2a (3.54 g, 10 mmol) in EtOH (100 mL) was added a large
excess of NaOH (4 g, 0.1 mol), and the mixture was heated to
reflux for 8 h (completion of the hydrolysis was monitored by GC-
MS). After the mixture was cooled to room temperature, most of
the EtOH was removed under reduced pressure, and the residue
was diluted with Et2O and water. The organic phase was rejected,
and then the aqueous solution was carefully neutralized with a 1
M HCl solution. The aqueous solution was extracted with Et2O (3
× 30 mL), and the combined organic layers were washed with brine,
dried (Na2SO4), and evaporated under reduced pressure. Without
further purification the residue was dissolved in CH3CN (30 mL),
and then iodomethane (1.70 g, 12 mmol) and K2CO3 (1.52 g, 11
mmol) were added. The mixture was refluxed overnight and then
cooled to room temperature. Most of the CH3CN was evaporated
under reduced pressure, and the residue was diluted with H2O. The
1
20/1); H NMR (300 MHz, CDCl3) δ 7.65-7.57 (m, 2H), 7.39-
7.32 (m, 3H), 7.21 (t, J ) 8.3 Hz, 1H), 7.06 (dd, J ) 8.3, 1.1 Hz,
1H), 6.81 (dd, J ) 8.3, 1.1 Hz, 1H), 3.92 (s, 3H); 13C NMR (75.4
MHz, CDCl3) δ 161.1 (C), 137.2 (C), 131.8 (CH), 129.5 (CH),
128.5 (CH), 128.3 (CH), 123.3 (C), 121.5 (CH), 112.8 (C), 108.8
(CH), 98.9 (C), 82.7 (C), 56.2 (CH3); EI-LRMS m/z 244 (M+ + 2,
37), 242 (M+, 100), 199 (19), 178 (24), 165 (33); HRMS calcd for
C15H11ClO, 242.0498; found, 242.0504.
Typical Procedure for the Synthesis of 4-Alkoxyindoles 7 and
7-Alkoxyindoles 8: Synthesis of 1-Benzyl-4-methoxy-2-phenyl-
1H-indole (7a; Table 3, Entry 1).20a To a solution of Pd(OAc)2
(22.4 mg, 0.10 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium
chloride (HIPrCl) (42.5 mg, 0.1 mmol), and KOt-Bu (0.67 g, 6
mmol) in toluene (6 mL) were added 3-chloro-2-phenylethynyl-
anisole 4a (0.49 g, 2 mmol) and benzylamine (0.26 g, 2.4 mmol)
at room temperature. The resulting mixture was stirred at reflux
for 2.5 h, after which GC/MS analysis indicated complete conver-
sion of the starting material. CH2Cl2 (25 mL) and aqueous HCl
(25 mL of a 2 M solution) were added to the cooled reaction
(29) (a) Roy, S.; Roy, S.; Gribble, G. W. Org. Lett. 2006, 8, 4975-
4977. (b) Ren, H.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462-
3465.
(30) Hodgson, H. H.; Kershaw, A. J. Chem. Soc. 1928, 191-193.
J. Org. Chem, Vol. 72, No. 14, 2007 5117