A convenient synthesis of 2-nitroindoles

Article abstract of DOI:10.1016/j.tetlet.2004.12.112

The reaction of 2-iodo- and 2-bromoindoles with silver nitrite in aqueous acetone affords the corresponding 2-nitroindoles in modest to good yields.

Full text of DOI:10.1016/j.tetlet.2004.12.112

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1325–1328
A convenient synthesis of 2-nitroindoles
Sujata Roy and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA
Received 24 November 2004; revised 21 December 2004; accepted 21 December 2004
Available online 12 January 2005
Abstract—The reaction of 2-iodo- and 2-bromoindoles with silver nitrite in aqueous acetone affords the corresponding 2-nitro-
indoles in modest to good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Both 2- and 3-nitroindoles are important building
blocks for the synthesis of pyrrolo[2,3-b]indoles and pyr-
rolo[3,4-b]indoles, via the Barton–Zard pyrrole synthe-
sis1 and 1,3-dipolar cycloaddition reactions with
tard and co-workers have reported the ipso-nitration
of 2-stannylindoles to afford 2-nitroindoles in moderate
yields (30–48%).7 In an alternative approach to 2-nitro-
indoles, we found that C-2 lithiated indoles 5 can be
quenched with dinitrogen tetroxide (N2O4) to give 2-
nitroindoles 6 in 63–78% yields (Scheme 2).8 This
Ômelt-and-reactÕ process is technically difficult to per-
form and dinitrogen tetroxide is a very expensive gas.
mesoionic munchnones.2 These electron-deficient
¨
indoles also undergo normal–demand Diels–Alder reac-
tions leading to carbazoles3 and nucleophilic addition
reactions.4
+
Other potential sources of NO2 failed to yield 2-
nitroindoles.
Whereas 3-nitroindoles are readily obtained by standard
electrophilic nitration of N-protected indoles,5 the syn-
thesis of 2-nitroindoles is less straightforward. Indeed,
2-nitroindole was an unknown compound when we
began our work in this area.6
Prompted by an early report on the conversion of 2-bro-
mofurans to 2-nitrofurans with silver nitrite,9 we now
describe a new synthesis of 2-nitroindoles using silver ni-
trite that avoids the above problems. Thus, the reaction
of 2-haloindoles with silver nitrite in aqueous acetone
gives the corresponding 2-nitroindoles in variable yield
(Scheme 3 and Table 1).10 The products obtained are
highly pure and the recovered starting materials can be
recovered and reused.
Our original synthesis of 2-nitroindoles involved a four-
step sequence from 2-nitrobenzaldehyde (1) (Scheme 1).6
Unfortunately, the carcinogenic solvent HMPAis neces-
sary for best results in the reaction of 1 with sodium
azide, and the intermediate 2-azido-b-nitrostyrene (2)
is a powerful skin and eye irritant not unlike Ôpepper
sprayÕ (ÔCSÕ, 2-chlorobenzalmalonitrile). Thermolysis of
2 in xylenes gives 2-nitroindole (3) in 54% yield. Quin-
The reaction works best for N-ethoxycarbonyl-substi-
tuted indoles 7 and 11, but less well for the more
CHO
NO2
xylenes²
54 %
1. NaN3, HMPA, 92%
2. CH3NO2, KOH,
NO2
N
H
NO2
N3
EtOH, 0 ˚C
3. Ac2O, pyr
1
3
2
75% (3 steps)
Scheme 1.
Keywords: 2-Nitroindole; Silver nitrite; 2-Haloindoles.
*
Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946; e-mail: ggribble@dartmouth.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.112

1326
S. Roy, G. W. Gribble / Tetrahedron Letters 46 (2005) 1325–1328
R
Li
R
R
t-BuLi
N2O4
-78 ˚C
-120 ˚C to rt
N
N
N
NO2
PG
PG
63-78%
PG
4
5
6
(R = H, CH3;
PG = SO2Ph, Boc)
Scheme 2.
2-haloindole and reactivity for the replacement reac-
tion.14 The reaction of 3-bromo- and 3-iodoindoles with
silver nitrite does not give the corresponding 3-nitro-
indoles and starting materials are recovered. Likewise,
the reactions of 8 with both sodium nitrite in place of
silver nitrite and sodium nitrite/silver nitrate return only
starting material. Likewise, there was no reaction of 8
with silver cyanide.
AgNO2
65 ˚C
acetone/water (4:1)
dark, 48 h
N
NO2
N
X
PG
PG
7-13
3, 14-16
5-63%
Scheme 3.
Apossible mechanism for this reaction is shown in
Scheme 4. Initial p-complexation is followed by forma-
tion of the C-3 silver r-complex 17. Addition of nitrite
to C-2 and loss of silver halide affords the 2-nitroindole.
Some related chemistry is worth noting. The formation
of 1-nitroisoquinoline from the reaction of isoquinoline
with acetic anhydride, DMSO, and potassium nitrite has
been reported,15 and the reaction of 3-iodoindole with
silver acetate in acetic acid affords indoxyl acetate.16
The use of silver(I) to induce cyclizations of amino
allenes and amino alkynes to form nitrogen heterocycles
has been described,17 and the silver(I)-induced rear-
rangements of strained sigma bonds is well known.18
Noteworthy is that a pyrrole iminium ion analogous
to 17 has been proposed recently.17f Moreover, silver ni-
trite in aqueous acetone converts primary alkyl halides
to nitroalkanes.19
Table 1. Synthesis of 2-nitroindoles from 2-haloindoles with silver
nitrite
2-Haloindole
X
PG
Product
Yield (%)
7
I
CO2Et
SO2Ph
Me
1410
1511
1612
313
14
52a
10b
5c
8
I
9
I
10
11
12
13
I
Boc
57c
63d
5e
Br
Br
Br
CO2Et
SO2Ph
Boc
15
—
0c
a 33% of 7 was recovered.
b 80% of 8 was recovered.
c No starting material was recovered.
d 20% of 11 was recovered.
e 80% of 12 was recovered.
The requisite 2-haloindoles 7–13 were prepared as sum-
marized in Scheme 5.20 All are known compounds
except 2-bromo-1-ethoxycarbonylindole (11). The excel-
lent Katritzky–Bergman method for synthesizing 2-iodo-
indole (18) and 2-bromoindole (19)21 was used to
prepare 7, 9, 11–13, and 2-haloindoles 8 and 10 were
synthesized from the corresponding N-protected
indoles.
electron-withdrawing N-phenylsulfonyl-substituted in-
doles 8 and 12. The N-Boc-substituted 2-iodoindole 10
gives N-deprotected 2-nitroindole (3) in 57% yield, rep-
resenting a superior synthesis of 2-nitroindole. The reac-
tion of 2-iodo-1-methylindole (9) affords only a low
yield of 1-methyl-2-nitroindole (16) because of the ex-
treme instability of this particular 2-iodoindole. Like-
wise, attempted reaction of N-Boc-2-bromoindole 13
under the usual conditions leads to decomposition of
labile 2-bromoindole. The N-ethoxycarbonyl group
possesses the ideal blend of providing stability for the
In summary, 2-nitroindoles 3 and 14 are conveniently
synthesized from suitable 2-haloindoles (7, 10, and 11)
by reaction with silver nitrite in aqueous acetone.
Ag
Ag+
-
NO2
Ag
X
N
X
N
X
N
PG
PG
PG
17
Ag
-AgX
X
N
NO2
N
NO2
PG
PG
Scheme 4.

S. Roy, G. W. Gribble / Tetrahedron Letters 46 (2005) 1325–1328
1327
KOH, MeI
(n-Bu)4HSO4
THF, rt, 14 h
99%
EtOCOCl
DMAP, THF
N
I
N
I
N
I
0 oC, 2 h, to rt, 14 h
H
Me
CO2Et
93%
9
7
18
1. KOH, DMF
0 oC, 10 min
1. NaH, DMF
0 oC, 30 min
2. PhSO2Cl
0
14 h
N
Br
N
Br
2. ClCO2Et
0 oC, 2 h, to rt
14 h
N
Br
oC to rt
H
SO2Ph
CO2Et
11
19
12
63%
96%
1. DMAP, THF, rt, 5 min
2. (Boc)2O, 0 oC to rt, 14 h
99%
N
Br
Boc
13
1. LDA, THF
-78 oC, 2 h
1. NaOH
(n-Bu)4HSO4 (cat)
CH2Cl2
2. I2, THF
N
N
I
-78 oC to rt, 14 h
SO2Ph
SO2Ph
2. PhSO2Cl, CH2Cl2
0 oC, 1 h, to rt, 4 h
89%
8
80%
N
1. DMAP, THF
H
1. t-BuLi, THF
-78 oC, 1 h
2. Boc2O
rt, 14 h
2. I2, THF
N
I
N
98%
-78 oC, 3 h
Boc
Boc
67%
10
Scheme 5.
6. Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38,
5603–5606.
Acknowledgements
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This work was supported by the Donors of the Petro-
leum Research Fund (PRF), administered by the Amer-
ican Chemical Society, and by Wyeth. We thank
Professors John Joule, Vic Snieckus, and Dr. Tomasz
Janosik for helpful correspondence.
8. Jiang, J.; Gribble, G. W. Tetrahedron Lett. 2002, 43, 4115–
4117.
9. DÕAuria, M.; Piancatelli, G.; Scettri, A. Tetrahedron 1980,
36, 1877–1878.
References and notes
10. Compound 14: To a stirred solution of 7 (315 mg,
1.00 mmol) in 4:1 acetone–water (20 mL) was added silver
nitrite (923 mg, 6.00 mmol). The mixture was stirred in the
dark for 48 h at 65 °C. Ether (30 mL) was added, the
solution was filtered to remove insoluble material, and
the filtrate was washed with water. The organic phase was
dried (Na2SO4) and the residue was purified by flash
column chromatography (4:1 hexanes–ethyl acetate) to
yield 14 (122 mg, 52%) as a yellow solid: mp 47–49 °C
(lit.2b mp 55–57 °C); 1H NMR (CDCl3) d 8.05–8.03 (m,
1H), 7.70–7.68 (m, 1H), 7.58–7.55 (m, 1H), 7.43 (s, 1H),
7.38–7.35 (m, 1H), 4.50 (q, 2H, J = 7 Hz), 1.43 (t, 3H,
J = 7 Hz). During column chromatography, 33% (104 mg)
of the starting material was also recovered, which eluted
before the product.
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1328
S. Roy, G. W. Gribble / Tetrahedron Letters 46 (2005) 1325–1328
1
11. Compound 15: mp 158–159 °C (lit.6 mp 157–160 °C); H
NMR (CDCl3) d 8.19–8.17 (m, 1H), 8.09–8.07 (m, 2H),
7.69–7.66 (m, 2H), 7.63–7.56 (m, 3H), 7.45 (d, 1H,
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S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62,
2312–2313). Compound 8: mp 95–97 °C (lit. mp 96–98 °C:
Ketcha, D. M.; Lieurance, B. A.; Homan, D. F. J.;
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1H), 7.49–7.48 (m, 1H), 7.29–7.21 (m, 2H), 7.02 (s, 1H),
1.77 (s, 9H); LRMS (EI): m/z 343 (M+), 287, 243, 217, 161,
117, 89, 57 (100%); HRMS (EI): Anal. Calcd for
C13H14NO2I: 343.0069. Found 343.0064. Compound 11:
mp 33–34 °C; 1H NMR (CDCl3): d 8.14–8.11 (m, 1H),
7.53–7.49 (m, 1H), 7.37–7.24 (m, 2H), 6.80 (s, 1H), 4.59 (q,
2H, J = 7.1 Hz), 1.56 (t, 3H, J = 7.1 Hz); LRMS (EI): m/z
267 (M+), 210, 195 (100%), 116, 89; HRMS (EI): Anal.
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5.33, Br, 28.11. Found: C, 49.28; H, 3.76; N, 5.22; Br,
29.80. Compound 12: mp 50–51 °C (lit. mp 62–64 °C:
Ketcha, D. M.; Lieurance, B. A.; Homan, D. F. J.;
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(CDCl3): d 8.13 (d, 1H, J = 8.3 Hz), 7.52–7.49 (m, 1H),
7.35–7.23 (m, 2H), 6.78 (s, 1H), 1.75 (s, 9H); LRMS (EI):
m/z 295 (M+), 195 (100%), 115, 77; HRMS (EI): Anal.
Calcd for C13H14NO2Br: 295.0208. Found: 295.0201.
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the literature values.7b
13. Compound 3: To a stirred solution of 10 (344 mg,
1.00 mmol) in 4:1 acetone–water (20 mL) was added silver
nitrite (923 mg, 6.00 mmol). The mixture was stirred in
the dark for 48 h at 65 °C. Ether (30 mL) was added,
the solution was filtered to remove insoluble material,
and the filtrate was washed with water. The organic
phase was dried (Na2SO4) and the residue was purified
by flash column chromatography (3:1 hexanes–ethyl
acetate) to yield 3 (92 mg, 57%) as a yellow solid: mp
116–118 °C (lit.6 mp 116–118 °C); 1H NMR (CDCl3) d
9.27 (br s, 1H), 7.77–7.73 (m, 1H), 7.51–7.44 (m, 3H),
7.29–7.23 (m, 1H).
14. We previously discovered that this indole N-protecting
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pyrrole synthesis to give pyrrolo[3,4-b]indoles.1b
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