One-Pot N-Arylation of indoles directly from N-arylsulfonylindoles via consecutive deprotection and SnAr reactions with activated aryl halides

Article abstract of DOI:10.1248/cpb.57.321

An efficient one-pot step by step t-BuOK-mediated procedure for the synthesis of N-arylindoles has been developed in moderate to good yields. The protocol involves the consecutive deprotection of N-arylsulfonylindoles as latent indoles and subsequent SnAr

Full text of DOI:10.1248/cpb.57.321

March 2009
Notes
Chem. Pharm. Bull. 57(3) 321—323 (2009)
321
One-Pot N-Arylation of Indoles Directly from N-Arylsulfonylindoles via
Consecutive Deprotection and SNAr Reactions with Activated Aryl
Halides
Hui XU* and Ling-Ling FAN
Laboratory of Pharmaceutical Synthesis, College of Sciences, Northwest A&F University; Yangling 712100, China.
Received December 9, 2008; accepted December 15, 2008; published online December 16, 2008
An efficient one-pot step by step t-BuOK-mediated procedure for the synthesis of N-arylindoles has been de-
veloped in moderate to good yields. The protocol involves the consecutive deprotection of N-arylsulfonylindoles
as latent indoles and subsequent SNAr reactions with activated aryl halides. This tandem reaction affords an effi-
cient and convenient preparation of N-arylindoles that benefit from prior indoles protection by arylsulfonyl
group, and can shorten a reaction sequence and improve synthetic efficiency.
Key words N-arylindole; N-arylsulfonylindole; one-pot reaction
N-Arylindoles are known to be important subunits due to Results and Discussion
their key role in medically biological activities, such as those
Initially, the reaction rate of the deprotection of N-tosylin-
displaying antiestrogen,1) analgesic,2) antimicrobial,3) neu- doles (R2ꢀH, Me, CN and NO2) in the presence of t-BuOK
roleptic,4) antiallergy,5) 5-HT6 receptor antagonists,6) FTase to liberate the corresponding intermediates (4), the indolyl
inhibitors (FTIs),7) and anti-human immunodeficiency virus anions, was examined as shown in Table 1. It was found that
(HIV)-1 activities.8) Although the development of new the reaction rate of the deprotection of N-tosylindoles is very
methodologies for the N-arylation of indoles catalyzed by sensitive to electronic and steric effects of the substituents on
palladium or copper has received much attention in recent the corresponding substrates. For example, the deprotection
years,9—14) the nucleophilic aromatic substitutions (SNAr) of of N-tosylindole was essentially complete in 1 h at reflux (en-
aryl halides, activated by electron-withdrawing substituents, tries 1—4, 15, 16). The complete deprotection of N-tosyl-5-
with indoles represent an alternate route to N-arylindoles for nitroindole and N-tosyl-5-cyanoindole, having electron-with-
certain substrate combinations.15—17) Meanwhile, the fact that drawing substituents (e.g., NO2 and CN) on the indole’s ring,
the strategic use of protective groups is a necessary and time- was achieved only in 0.5 h at reflux (entries 5—7, 14). In
consuming tactic in organic synthesis is well-known; how- contrast, when electron-rich substituent (e.g., methyl group)
ever, a merging of protective group chemistry with other was introduced on the 3-position of N-tosylindole, the corre-
transformations via one-pot step by step reaction that can sponding deprotective rate could slow down sharply. For ex-
shorten a reaction sequence and improve synthetic efficiency ample, it took 12 h to give a 64% conversion of N-tosyl-3-
and convenience is always of great interest.18—21) The arylsul- methylindole to 3-methylindole at reflux (entries 9, 10).31)
fonyl groups are useful for protecting groups for the NH But to our surprise, when methyl group was introduced on
group of the indoles because of their robust behavior under a the 4- or 6-position of N-tosylindole, the corresponding de-
wide variety of reaction conditions.22—25) Recently, many protective rates were not affected in comparison to that of
methods for the deprotection of N-tosylated indoles have N-tosyl-3-methylindole, and the complete deprotection was
been described, such as highly basic NaOH or KOH in alco- finished in 1 h (entries 11, 12). Mainly due to steric effect,
hol,26) tetra-n-butylammonium fluoride (TBAF) in refluxing the deprotective rates of N-tosyl-2-methyl- and N-tosyl-7-
tetrahydrofuran (THF),27) and Mg in MeOH.28) However, to methylindole were very slow, and no corresponding free in-
the best of our knowledge, N-arylsulfonylindoles have never doles were formed even after 25 and 28 h, respectively (en-
been used as latent indoles in the SNAr reactions with aryl tries 8, 13).
halides to prepare N-arylindoles directly. In the meantime,
Next, we investigated the synthesis of N-arylindoles via
Rubiralta et al. reported that the indolyl anion could be effi- the deprotection of N-tosylindoles (R2ꢀH, Me, CN and NO2)
ciently formed by the deprotection of N-benzenesulfonylin- and sequent SNAr reactions with activated aryl halides (XꢀF,
dole in the presence of t-BuOK.29) Consequently, as part of Cl and Br, R3ꢀCN and NO2) in the presence of t-BuOK. N-
our program aimed at the development of one-pot step by Arylindoles (3a—k) were obtained in 14—94% yields (en-
step reactions,30) in this paper we want to explore the synthe- tries 1—7, 9—12, 14—16). As we all know that the cross-
sis of N-arylindoles directly from N-arylsulfonylindoles and coupling of electron-deficient indoles with aryl halides was
activated aryl halides in the presence of t-BuOK for the first
time. On the other hand, in order to examine the consecutive
two reaction conditions for the deprotection of N-arylsul-
fonylindoles (1) and the SNAr reactions with activated aryl
halides (2), respectively, a set of the experiments was per-
formed as shown in Chart 1. Fortunately, we were pleased to
find that N-arylindoles (3) could be obtained smoothly via
the deprotection of 1 followed by direct SNAr reactions with
2 in the presence of t-BuOK.
Chart 1. The Synthetic Route of N-Arylindoles 3
∗ To whom correspondence should be addressed. e-mail: orgxuhui@nwsuaf.edu.cn © 2009 Pharmaceutical Society of Japan

322
Vol. 57, No. 3
Table 1. t-BuOK-Mediated Construction of N-Arylindoles (3) from N-Arylsulfonylindoles (1) and Activated Aryl Halides (2)a)
1
2
Isolated yield
of 3 (%)
Time (h)b)
Entry
R1
R2
R3
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
H
H
H
H
H
4-NO2
2-NO2
2-CN
4-CN
2-NO2
4-NO2
2-NO2
—
4-NO2
2-NO2
2-CN
2-CN
—
2-NO2
2-NO2
4-NO2
4-NO2
2-NO2
2-CN
2-NO2
2-NO2
2-NO2
2-NO2
F
F
F
F
F
F
F
—
F
F
F
F
—
Cl
Cl
Br
F
1ꢂ2
1ꢂ3
1ꢂ2
3a (93)
3b (94)
3c (93)
3d (93)
3e (88)
3f (78)
3g (87)
No reaction
3h (49)
3i (42)
1ꢂ0.5
0.5ꢂ2.5
0.5ꢂ2.5
0.5ꢂ3.5
25c)
5-NO2
5-NO2
5-CN
2-Me
3-Me
3-Me
4-Me
6-Me
7-Me
5-NO2
H
H
H
H
H
H
H
H
5-NO2
12d)ꢂ2
12d)ꢂ2
1ꢂ1
3j (91)
1ꢂ1.5
3k (96)
No reaction
3e (ꢁ18)
3b (34)
3a (14)
3a (91)
3b (82)
3c (83)
3b (89)
3b (78)
3b (13)
3e (86)
28c)
0.5ꢂ8
1ꢂ8
1ꢂ12
1ꢂ2
1ꢂ2
1ꢂ2
H
H
4-Cl
4-Et
3-NO2
H
F
F
F
F
F
F
1ꢂ3
0.5ꢂ2
1.5e)ꢂ3
0.5ꢂ3.5
a) A mixture of 1 (0.5 mmol) and t-BuOK (1.0 mmol) in anhydrous THF (2.5 ml) was stirred at refux under argon. When the deprotection of arylsulfonyl group of 1 was es-
sentially complete and checked by TLC, 2 (0.5 mmol) was added to the above mixture, which continued to reflux under argon monitored by TLC. b) “1ꢂ2” means 1 h for the de-
protection of arylsulfonyl group of 1 and 2 h for the sequent SNAr reactions with 2, respectively. c) No corresponding free indoles were monitored by TLC when the deprotection
of N-tosyl-2-methylindole or N-tosyl-7-methylindole was after 25 and 28 h, respectively. d) Even after 12 h, the deprotection of N-tosyl-3-methylindole was partially complete
and checked by TLC. e) Although the deprotection of N-(3-nitrobenzene)sulfonylindole was essentially complete for 1.5 h, many by-products were produced and checked by
TLC analysis.
very troublesome because of the lower nucleophilicity of the reacted with 4-fluoro- and 4-bromonitrobenzene, the corre-
corresponding anion at the indoles’ nitrogen. But it is note- sponding yields of 3a were 93% only for 2 h and 14% even
worthy in our reaction that it took only 3 h to obtain N-(2-ni- for 12 h, respectively (entries 1 vs. 16).
trobenzene)-5-nitroindole (3e) and N-(4-nitrobenzene)-5-ni-
Finally, the cross-coupling reactions of other N-arylsul-
troindole (3f) in 88% and 78% yields, respectively, when N- fonylindoles (R1ꢀH, Cl, Et and NO2; R2ꢀH and NO2) with
tosyl-5-nitroindole was reacted with 2-fluoro- or 4-fluoroni- activated fluoroarenes in the presence of t-BuOK were also
trobenzene (entries 5, 6). N-(2-Nitrobenzene)-5-cyanoindole explored (entries 17—23). The deprotection of arylsul-
(3g) was also obtained in a 87% yield when N-tosyl-5- fonylindoles was essentially complete in the presence of t-
cyanoindole was reacted with 2-fluoronitrobenzene for 4 h BuOK in 1 h at reflux, and N-arylindoles were obtained in
(entry 7). When N-tosyl-3-methylindole was reacted with 2- 78—91% yields. However, when N-(3-nitrobenzene)sul-
fluoro- or 4-fluoronitrobenzene even after 14 h, the corre- fonylindole was reacted with 2-fluoronitrobenzene, the corre-
sponding yields of 3h and 3i were only 49% and 42%, re- sponding yield of 3b was only 13% (entry 22) because many
spectively, mainly because the deprotection of N-tosyl-3- byproducts were produced during the deprotection of N-(3-
methylindole to liberate the corresponding anion (4) was dif- nitrobenzene)sulfonylindole.
ficult due to electronic effect (entries 9, 10). As shown in
Table 1, the activated fluoroarenes underwent SNAr reactions Conclusion
with 4 much easier than those chloro and bromo analogues.
In summary, we have developed an efficient procedure for
For example, when the anion liberated from N-tosylindole the synthesis of N-arylindoles via the consecutive deprotec-
was reacted with 2-fluoro- and 2-chloronitrobenzene, the cor- tion of N-arylsulfonylindoles and SNAr reactions with acti-
responding yields of 3b were 94% for 3 h and 34% for 8 h, vated aryl halides (XꢀF, Cl and Br) in the presence of t-
respectively (entries 2 vs. 15); when the anion liberated from BuOK. This one-pot tandem reaction affords an efficient and
N-tosyl-5-nitroindole was reacted with 2-fluoro- and 2- convenient preparation of N-arylindoles that benefit from
chloronitrobenzene, the corresponding yields of 3e were 88% prior indoles protection by arylsulfonyl group, and can
for 2.5 h and ꢁ18% for 8 h, respectively (entries 5 vs. 14). shorten a reaction sequence and improve synthetic efficiency.
Similarly, when the anion liberated from N-tosylindole was

March 2009
323
Experimental
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(1.0 mmol) in THF (2.5 ml) was stirred at reflux under argon for 12 h.
After cooling, the solvent was evaporated under reduced pressure, and
the residue was purified by preparative TLC to give 3-methylindole in
a 64% yield.