G. L. Frayne, G. M. Green / Tetrahedron Letters 49 (2008) 7328–7329
7329
Table 2
is 4 ꢀ 5 ꢀ 6 ꢁ 2 ꢀ 7, and the yields of indoles with electron-donat-
ing groups were generally higher than those of on indoles
with electron-withdrawing groups. Lastly, in groups prone to
hydrolyses, it is advisable to reduce the reaction temperature to
minimize this side reaction.
N-arylation of various substituted indoles and activated aryl fluorides
F
37% KF/Al2O3
18-crown-6
microwave
R
R
+
N
N
Typical procedure for the N-arylation of indoles: To a 20 mL vial
equipped with a teflon-coated stir bar were added 5-methoxy-
indole (1 mmol), 4-fluorobenzamide (2 mmol), 18-crown-6
(2 mmol), 37% KF/Al2O3 (2.0 g) (see note 13 for a method for prep-
aration of 37% KF/Al2O3), and DMSO (15 mL). The vial was flushed
with nitrogen, sealed with a cap, placed in the microwave and
heated at 180 °C for 2 h12 (An Emrys Optimizer was used in these
reactions,15 and the power varied between 0 and 300 W while
the pressure for these reactions did not exceed 5 atm). The vial
was uncapped, and the mixture was diluted with ethyl acetate
(20 mL) and filtered. The filtrate was washed with water (20 mL)
and brine (20 mL), and then dried with MgSO4. After filtration
and concentration, the crude mixture was purified by preparative
HPLC.
180 oC, DMSO
H
EWG
EWG
Yield
Example EWG
R
Yield
(%)
Example EWG
R
(%)
1
3
5
7
9
–CN
–CN
–CN
2-CO2Et
2-Me
4-CN
10
48
33
40
40
78
78
79
24
0b
2
4
6
8
–CONH2 2-Me
–CONH2 4-CN
–NO2
–CONH2 4-CN
–CN 4-Me
–CONH2 4-Me
–CONH2 5-Br
–CONH2 5-CHO
–CO2Me 5-CN
–CONH2 5-CN
–CO2Me 5-CO2Me 53
–CO2H
–CO2Me 5-H
–CONH2 5-OMe
–CO2Et
–NO2
–CONH2 6-Me
–CONH2 6-OMe
17
23
44
23
71
40
30
10a
57
35c
4-CN
–CONH2 4-CN
–CO2Et
–NO2
4-Me
4-Me
–CONH2 4-OMe
–CONH2 5-CHO
–CO2Me 5-Cl
–CONH2 5-CN
–CONH2 5-CO2Et
5-CO2Me 24
–CONH2 5-H
10
12
14
16
18
20
22
24
26
28
30
32
34
36
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
41
Acknowledgments
47
–CN
5-CO2Me
0
The authors wish to thank Drs. Jason D. Speake and William J.
Smith for their insightful discussions in preparation for this manu-
script, and also Andrew Larkin for his invaluable assistance in pro-
cessing NMR data. GLF also thanks The GlaxoSmithKline Summer
Talent Identification Program for the financial support on his
internship.
45
68
64
0
0
35
49
71
37
0
72
45
50
12
–CN
5-OMe
–CO2Me 5-OMe
5-OMe
5-OMe
–CO2H
–CONH2 6-CN
–CN 6-NO2
5-OMe
–CO2Me 7-Br
–CONH2 7-Br
–CONH2 7-OMe
Trace 38
Trace 40
15
–CN
7-Br
–CONH2 7-Me
Supplementary data
a
Commercially purchased 40% KF/Al2O3 was used.
Cyano group on the product had hydrolyzed.
Reaction temperature at 130 °C.
b
c
Supplementary data associated with this article can be found, in
KF was used (examples 7 and 12, Table 1). Lastly, it was found that
yields improved when 2 equiv of the aryl fluoride (example 12, Ta-
ble 1) was used in comparison to when 1 equiv (example 8, Table
1) was used (71% vs 30% yield).
References and notes
1. For reviews on indoles, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
106, 2875–2911; (b) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417–1432.
2. Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862–8865.
3. Chapman, C. J.; Matusuno, A.; Frost, C. G. Chem. Commun. 2007, 38, 3903–3905.
4. Beach, M. J.; Hope, R.; Klaubert, D.; Russell, R. K. Syn. Commun. 1995, 25, 2165–
2183.
5. Smith, W. J., III; Sawyer, J. S. Tetrahedron Lett. 1995, 37, 299–302.
6. Li, Q.; Li, T.; Woods, K. W.; Gu, W.-Z.; Cohen, J.; Stoll, V. S.; Galicia, T.; Hutchins,
C.; Frost, D.; Rosenberg, S. H.; Sham, H. L. Biorg. Med. Chem. Lett. 2005, 15, 2918–
2922.
In coupling substituted indoles with activated aryl fluorides
(Table 2), it was found that positions 4–6 gave similar yields to
each other in comparative reactions. However, positions 2 and 7
gave much lower yields than the other investigated ones, which
is most likely due to adverse steric interactions. It was also found
that electron-donating groups on the indole generally gave higher
yields than when electron-withdrawing groups were present. Gi-
ven that the presumptive mechanism is SNAr,5,14 it was expected
that the more electron-rich indoles with electron-donating groups
would generally have higher yields in comparison to the indoles
with electron-withdrawing groups. Something to note is the vari-
ability of yields in ester containing substrates, as it is likely in some
cases that the esters may have been hydrolyzed to a carboxylic
acid. Also, it should be noted that cyano-substituted indoles were
prone to hydrolyses. In one example, lowering the reaction
temperature from 180 °C to 130 °C (examples 19 and 20, Table 2)
reduced the extent of hydrolyses, where the yields went from 0%
to 35%.
7. Sano, H.; Noguchi, T.; Tanatani, A.; Hoshimoto, Y.; Miyachi, H. Biorg. Med. Chem.
2005, 13, 3079–3091.
8. Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.;
Kasai, M. J. Chem. Soc., Perkin Trans. 1 1995, 2677–2678.
9. For
a review of KF/Al2O3 mediated organic synthesis, see: Blass, B. E.
Tetrahedron 2002, 58, 9301–9320.
10. Smith, Michael B; March, Jerry, March’s Advanced Organic Chemistry, 5th Ed.,
2001, p 860.
11. For reviews on microwave assisted synthesis, see: (a) Polshettiwar, V.; Varma,
R. Acc. Chem. Res. 2008, 41, 629–639; (b) Polshettiwar, V.; Varma, R. S. Chem.
Soc. Rev. 2008, 37, 1546–1557; (c) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127–
1139.
12. Reaction temperatures over 180 °C led to decomposition of reagents and
solvent, resulting in pressure accumulation in the vial.
13. In a communication with Aldrich Technical Support, it was found that the
potassium fluoride was loaded on neutral alumina. For an example of
preparing 37% potassium fluoride supported on basic alumina, see:
Schmittling, E. A.; Sawyer, J. Tetrahedron Lett. 1991, 32, 7207–7210.
14. Clark, J. H.; Owen, N. D. S. Tetrahedron Lett. 1987, 28, 2627–3630.
In summary, we have explored the scope and reactivity of
variously substituted indoles using an N-arylation methodology
mediated with potassium fluoride on basic alumina using micro-
wave-assisted technology. The reactivity of the substituted indoles