A new synthesis of 2-nitroindoles

Article abstract of DOI:10.1016/S0040-4039(02)00696-2

The C-2 lithiation of N-Boc- and N-(phenylsulfonyl)indoles (4-7) followed by reaction with dinitrogen tetroxide at low temperature affords the corresponding 2-nitroindoles 10-13 in 63-78% yields. Deprotection of the N-Boc-2-nitroindoles (10, 11) with trifluoroacetic acid gives 2-nitroindole (3) and 3-methyl-2-nitroindole (14) in essentially quantitative yields.

Full text of DOI:10.1016/S0040-4039(02)00696-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4115–4117
A new synthesis of 2-nitroindoles
Jun Jiang and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 28 January 2002; accepted 20 March 2002
Abstract—The C-2 lithiation of N-Boc- and N-(phenylsulfonyl)indoles (4–7) followed by reaction with dinitrogen tetroxide at low
temperature affords the corresponding 2-nitroindoles 10–13 in 63–78% yields. Deprotection of the N-Boc-2-nitroindoles (10, 11)
with trifluoroacetic acid gives 2-nitroindole (3) and 3-methyl-2-nitroindole (14) in essentially quantitative yields. © 2002 Elsevier
Science Ltd. All rights reserved.
Both 2- and 3-nitroindoles have provided novel routes
to pyrrolo[2,3-b]indoles and pyrrolo[3,4-b]indoles, via
both the Barton–Zard pyrrole synthesis1 and Mu¨nch-
none cycloaddition reactions.2 Moreover, these elec-
tron-deficient indoles undergo both nucleophilic
addition reactions3 and normal Diels–Alder cycloaddi-
tion reactions.4 Whereas 3-nitroindoles are easily pre-
pared by nitration of N-protected indoles,5 the
synthesis of 2-nitroindoles (3), which were essentially
unknown when we began our investigations, require a
four-step synthesis from 2-nitrobenzaldehyde (1)
(Scheme 1).6 Furthermore, an intermediate, o-azido-b-
nitrostyrene (2), in this synthesis is a powerful skin and
eye irritant, not unlike ‘pepper spray’ (‘CS’, o-
chlorobenzalmalonitrile). In addition, we found that for
best results the carcinogenic solvent HMPA was neces-
sary in this synthesis. Recently, an ipso-nitration reac-
tion of 2-stannylindoles to make 2-nitroindoles was
reported, but with only moderate yields (30–48%).7
reaction mixture and then a facile melt-and-react pro-
cess affords the corresponding 2-nitroindoles 10–13 in
10
good yields. Our results are summarized in Table 1.
This method is superior in the nitration of 2-lithioin-
doles to other obvious electrophilic nitration reagents
such as nitronium triflate,15 nitronium boron tetra-
fluoride, acetyl nitrate or pivaloyl nitrate. These reac-
tions always resulted in either recovered starting
materials or 2-acylindoles, and a similar observation
was described before in other systems.16 Low tempera-
ture (−120°C) is necessary to maximize the yields by
reducing the possible oxidation of 2-lithioindoles to C-2
radicals by N2O4.
The N-Boc or phenylsulfonyl protecting groups are
necessary in this reaction not only in directing metala-
tion at the C-2 position but also in stabilizing the indole
ring from the powerful oxidative property of N2O4. For
example, both 1-methylindole (8) and indole are
decomposed by treating with N2O4 on the melting
surface of their THF solutions to give an intractable
mixture. This could explain why the attempted N2O4
nitrations of lithioindoles 8 and 9 were unsuccessful
and led to decomposition.
To circumvent these problems, we now describe a direct
lithiation–nitration sequence from the readily available
N-protected indoles8 (Scheme 2). Thus, using Eaton’s
method,9 C-2 lithiation of indoles 4–7 followed by
adding dinitrogen tetroxide (N2O4) onto the frozen
NO2
CHO
xylenes, ∆
1. NaN3, HMPA, 92%
2. CH3NO2, KOH,
EtOH, 0 °C
3. Ac2O, py, 81% (2 steps)
54 %
N3
NO2
N
H
NO2
1
2
3
Scheme 1.
Keywords: N2O4; 2-lithioindoles; nitration; 2-nitroindoles; dinitrogen tetroxide.
* Corresponding author. Tel.: 1-603-646-3118; fax: 1-603-646-3946; e-mail: grib@dartmouth.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00696-2

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J. Jiang, G. W. Gribble / Tetrahedron Letters 43 (2002) 4115–4117
R
Li
R
R
t-BuLi
-78°C
N2O4
-120°C to rt
N
N
N
NO2
PG
PG
PG
4-9
10-13
Scheme 2.
Table 1. Synthesis of 2-nitroindoles 10–13 from 4–7
3. (a) Pelkey, E. T.; Barden, T. C.; Gribble, G. W. Tetra-
hedron Lett. 1999, 40, 7615–7619; (b) Kishbaugh, T. L.
S.; Gribble, G. W. manuscript in preparation; (c) See also
Ref. 5 for an example.
4. Kishbaugh, T. L. S.; Gribble, G. W. Tetrahedron Lett.
2001, 42, 4783–4785.
5. Pelkey, E. T.; Gribble, G. W. Synthesis 1999, 1117–1122.
6. Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38,
5603–5606.
Indole
PG
R
Product
Yield (%)
4
5
6
7
8
9
Boc
Boc
H
CH3
H
CH3
H
H
10
78
74
67
63
0
1111
1212
1313
–
PhSO2
PhSO2
Me
CO2Lia
–
0
7. Favresse, F.; Fargeas, V.; Charrue, P.; Lebret, B.; Piteau,
M.; Quintard, J.-P. J. Organomet. Chem. 2000, 598,
187–190.
a This was generated by bubbling CO2 into 1-lithioindole (known as
Katritzky’s method).14
8. Compounds 4 and 5 were made in quantitative yields by
stirring indole or 3-methylindole (100 mmol) with di-t-
butyl-dicarbonate (100 mmol) and 4-dimethylaminopy-
ridine (DMAP, 0.5 mmol) in THF (200 mL) for 12 h.
Removal of solvent and drying under vacuum of the
resulting oil gave pure sample which was used without
further purification.
Although the synthesis of 2-nitroindole (3) via
Katritzky’s method14 was unsuccessful, 3 was readily
made by deprotection of its N-Boc derivative 10 in
almost quantitative yield.17 Thus, we have synthesized
2-nitroindole (3) from indole in three steps in 76%
overall yield (compared to our previous four-step syn-
thesis in 40% yield). The known 3-methyl-2-
nitroindole6,19 (14), whose prior synthesis was not
practical, was also made in a similar way18 with an
overall yield of 74% (Scheme 3).
9. Tani, K.; Lukin, K.; Eaton, P. E. J. Am. Chem. Soc.
1997, 119, 1476–1477.
10. Compound 10 (general procedure for 2-nitration): To a
–78°C stirred solution of 4 (4.0 mmol) in dry THF under
nitrogen was added t-butyllithium (4.4 mmol) dropwise
and the mixture was stirred at –78°C for 1 h before it was
frozen by external liquid nitrogen. Liquid N2O4 (1.6 g, 17
mmol, condensed from commercial cylinder) was allowed
to evaporate slowly and condensed onto the frozen sur-
face of the reaction mixture. Liquid nitrogen bath was
removed and the reaction mixture was allowed to melt
and warm up to rt over 45 min before it was poured into
aqueous NaHCO3 and extracted by ethyl acetate. The
organic phase was dried (Na2SO4) and purified by flash
chromatography to give yellowish solid 10 (3.13 mmol,
78%) mp 98–99°C, IR (KBr) wmax 1747, 1512, 1446, 1296,
1159 cm−1; UV (EtOH) umax 216, 326 nm; 1H NMR
(CDCl3) l 8.07 (m, 1H), 7.69 (m, 1H), 7.56 (m, 1H), 7.37
(m, 2H), 1.62 (s, 9H) ppm; 13C NMR (CDCl3) l 148.0,
137.0, 129.5, 124.9, 124.7, 123.7, 114.9, 111.4, 86.6, 27.8
ppm. MS m/z 262 (M+), 162, 57 (100%); HRMS m/z
calcd for C13H14N2O4 (M+): 262.0955; found: 262.0955.
Anal. calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68.
Found: C, 59.24; H, 5.36; N, 10.73.
R
R
TFA
CH2Cl2, rt
N
NO2
N
H
NO2
Boc
10 R=H
3 R=H
( 98%)
11 R=CH3
14 R=CH3 (100%)
Scheme 3.
Acknowledgements
The authors would like to acknowledge the Donors of
the Petroleum Research Fund (PRF), administered by
the American Chemical Society for support of this
research. We also thank Professor Jean-Paul Quintard
for helpful correspondence and spectra of 10.
11. Compound 11: mp 63.5–65°C, IR (KBr) wmax 1748, 1517,
1
1447, 1372, 1156 cm−1; UV (EtOH) umax 220, 328 nm; H
References
NMR (CDCl3) l 8.06 (m, 1H), 7.64 (m, 1H), 7.55 (m,
1H), 7.36 (m, 2H), 2.52 (s, 3H), 1.60 (s, 9H) ppm; 13C
NMR (CDCl3) l 148.2, 135.8, 129.6, 126.8, 124.2, 121.9,
121.7, 114.9, 86.1, 27.8, 9.8 ppm. MS m/z 276 (M+), 176,
57 (100%); HRMS m/z calcd for C14H16N2O4 (M+):
276.1110; found: 276.1108. Anal. calcd for C14H16N2O4:
C, 60.86; H, 5.84; N, 10.14. Found: C, 60.74; H, 5.82; N,
10.20.
1. (a) Pelkey, E. T.; Chang, L.; Gribble, G. W. Chem.
Commun. 1996, 1909–1910; (b) Pelkey, E. T.; Gribble, G.
W. Chem. Commun. 1997, 1873–1874.
2. (a) Gribble, G. W.; Pelkey, E. T.; Switzer, F. L. Synlett
1998, 1061–1062; (b) Gribble, G. W.; Pelkey, E. T.;
Simon, W. M.; Trujillo, H. A. Tetrahedron 2000, 56,
10133–10140.

J. Jiang, G. W. Gribble / Tetrahedron Letters 43 (2002) 4115–4117
4117
12. Compound 12: mp 167.5–169°C (lit.6 157–160°C); NMR
data is identical to the literature values.6
hedron Lett. 1993, 34, 6669–6672.
16. Zhang, M.-X.; Eaton, P. E.; Gilardi, R. Angew. Chem.,
Int. Ed. 2000, 39, 401–404.
13. Compound 13: mp 154.5–156°C, IR (KBr) wmax 1506,
1
1367, 1180, 944 cm−1; UV (EtOH) umax 207, 318 nm; H
17. Compound 3 (general procedure for N-Boc deprotec-
tion): To a rt stirred solution of 10 (1.00 mmol) in
CH2Cl2 (20 mL) was added trifluoroacetic acid (0.5 mL)
and the mixture was stirred at rt for 48 h. The solvent
and acid was removed under reduced pressure to gave an
TLC and NMR pure compound. Flash chromatography
gave pure 3 (0.98 mmol, 98%): mp 115–116.5°C, (lit.6
116–118°C), NMR data identical to the literature.6
18. Compound 14: mp 139–140°C, (lit.19 140–141.5°C);
NMR data is identical to the literature values19
19. Berti, G.; Da Settimo, A.; Nannipieri, E. J. Chem. Soc. C
1968, 2145–2151.
NMR (CDCl3) l 8.09 (m, 1H), 7.95 (m, 2H), 7.58 (m,
4H), 7.50 (m, 2H), 7.38 (m, 1H), 2.45 (s, 3H), ppm; 13C
NMR (CDCl3) l 137.4, 136.4, 134.5, 129.8, 129.2, 128.1,
127.5, 125.3, 124.5, 122.1, 116.3, 9.92 ppm. MS m/z 316
(M+, 100%), 300, 175, 141, 77; HRMS m/z calcd for
C15H12N2O4S (M+): 316.0518; found: 316.0519. Anal.
calcd for C15H12N2O4S: C, 56.95; H, 3.82; N, 8.86, S,
10.13. Found: C, 57.10; H, 3.89; N, 9.04; S, 10.14.
14. Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985,
26, 5935–5938.
15. Adams, C. M.; Sharts, C. M.; Shackelford, S. A. Tetra-