Convenient synthesis of masked aminoindoles by indium mediated one-pot reductive acylation of 3- and 2-nitroindoles

Article abstract of DOI:10.3987/com-06-s(w)8

Unstable 3- and 2-aminoindoles arc generated in situ by indium mediated reduction of 3- and 2-nitroindoles and capped as the stable amides (or carbamate) in moderate to high yields under mild conditions in a one-pot procedure.

Full text of DOI:10.3987/com-06-s(w)8

HETEROCYCLES, Vol. 70, 2006
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HETEROCYCLES, Vol. 70, 2006, pp. 51 - 56. © The Japan Institute of Heterocyclic Chemistry
Received, 16th June, 2006, Accepted, 24th July, 2006, Published online, 25th July, 2006. COM-06-S(W)8
CONVENIENT SYNTHESIS OF MASKED AMINOINDOLES BY INDIUM
MEDIATED ONE-POT REDUCTIVE ACYLATION OF 3- AND
2-NITROINDOLES †
Sujata Roy and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA;
ggribble@dartmouth.edu
Abstract – Unstable 3- and 2-aminoindoles are generated in situ by indium
mediated reduction of 3- and 2-nitroindoles and capped as the stable amides (or
carbamate) in moderate to high yields under mild conditions in a one-pot
procedure.
As a class of indoles, both 3- and 2-aminoindoles are virtually unexplored as novel heterocyclic enamines.
They could be useful precursors for the other important classes of indoles and novel fused heterocycles.
1-Methyl-3-aminoindole, generated in situ by deacetylation of 1-methyl-3-acetylaminoindole, has been
shown to react with 1,3-dicarbonyl compounds in an easy one-pot process to yield δ-carbolines.1 These
δ-carbolines were subsequently used to synthesize annelated pyridoindole NADH models. In these
syntheses, 3-acetylaminoindoles were prepared via the Beckmann rearrangement of the corresponding
oximes which in turn were made from the 3-acetylindoles.1-2 In fact, efficient synthesis of
3-aminoindoles are scarce due to their known instability.3 Kurilo and co-workers had reported the
synthesis of 3-acetylaminoindoles from 2-carbethoxyindoles. In their synthesis, the diazo coupling of
2-carbethoxyindoles with benzene diazonium chloride gave 2-carbethoxy-3-phenylazoindoles which were
treated with Zn and acetic acid in the presence of acetic anhydride to produce
2-carbethoxy-3-acetamidoindoles. Basic hydrolysis of 2-carbethoxy-3-acetamidoindoles followed by
thermal decarboxylation of carboxylic acid gave 3-acetylaminoindoles.3 Recently, an
N-substituted-3-acetylaminoindole was tested as a potential inhibitor against type 2 diabetes; however, the
synthesis of 3-acetylaminoindole was not described.4
† Dedicated to Professor Steven M. Weinreb in celebration of his 65th birthday and his many outstanding
contributions to synthetic organic chemistry.

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Our research group has long been interested in the synthesis of the 3- and 2-aminoindoles. Since we
have already reported several synthesis of 3- and 2-nitroindoles from indole,5,6 the reduction of these
nitroindoles would be the straightforward way to furnish the corresponding aminoindoles. In this
direction, we have made several attempts (H2, 10% Pd-C/ EtOH;7 Na2S2O4;8 In, NH4Cl/EtOH9) to reduce
nitroindoles to the corresponding amines, but without success. Due to this lack of success to obtain free
aminoindoles and because of the known instability of the aminoindoles, we decided to protect the amino
group of the aminoindoles by acylation in situ as they form in the reaction.
In an initial study, inspired by the reported indium mediated conversion of nitroarenes to
N-arylacetamides,10 1-methyl-3-nitroindole (1) was treated with indium in the presence of acetic acid and
acetic anhydride in methanol. To our delight, the desired acetamide (2) was obtained in excellent yield
(Scheme 1).11 Compound (2) is stable and can be stored indefinitely, but can be readily converted in
situ to the 3-aminoindole by methanolic HCl when required for the reaction.1
O
H
N
NO2
In, AcOH, Ac2O
CH3
MeOH, Δ
N
N
Me
Me
1
2 (88%)
Scheme 1.
We have chosen to use indium as a reducing agent because it is a non-toxic metal and highly suitable for
green chemistry processes. Moreover, it does not readily form oxides when exposed to air and most
importantly, it is insensitive to moisture which provides greater operational simplicity in the indium
mediated reaction.12
After this initial success, we subjected different N-protected 3-nitroindoles (3-5) to the same reaction
conditions (Scheme 2). To our satisfaction, the corresponding protected amines (9-11) were obtained in
good to excellent yield from the corresponding 3-nitroindoles (Table 1).13 Also, (NH)-free nitroindole
(6) furnished the desired product (12) in excellent yield.14 However, lower yields of (13) and (14) were
obtained from 2-nitroindoles (7) and (8), respectively.15
O
In, AcOH, Ac2O
NO2
NH
MeOH, Δ
CH3
N
R
N
R
3-8
9-14
Scheme 2.

HETEROCYCLES, Vol. 70, 2006
53
Table 1. Synthesis of acetylaminoindoles (9-14) from nitroindoles (3-8) with In, AcOH, Ac2O.
Entry
Nitroindole
3-NO2
R
Bn
Product
9
Yield
86%
68%
71%
82%
30%
33%
3
4
5
6
7
8
3-NO2
SO2Ph
Boc
H
10
3-NO2
11
3-NO2
12
2-NO2
SO2Ph
Boc
13
2-NO2
14
The required nitroindoles for reduction were prepared from indole by N-protection followed by nitration
(Scheme 3).16 The parent 3-nitroindole (6) was prepared from 3-nitro-1-(phenylsulfonyl)indole (4) by
deprotection with 10% ethanolic NaOH solution in 71% yield.
(i)
(ii)
NO2
N-Protection
nitration
N
R
N
H
N
R
15 (R = Me, 90%)
16 (R = Bn, 80%)
17 (R = SO2Ph, 89%)
18 (R = Boc, 98%)
1 (3-NO2, R = Me, 38%)
3 (3-NO2, R = Bn, 71%)
4 (3-NO2, R = SO2Ph, 83%)
5 (3-NO2, R = Boc, 70%)
7 (2-NO2, R = SO2Ph, 51%)
8 (2-NO2, R = Boc, 60%)
i) for 15: KOH, MeI, THF; for 16: NaH, BnBr, DMF; for 17: Boc2O, DMAP (cat), THF;
for 18: NaOH, n-Bu4HSO4 (cat), PhSO2Cl, CH2Cl2.
Scheme 3.
ii) for 1, 3-5: AcONO2 (from Ac2O and HNO3); for 7-8: t-BuLi, N2O4.
Reduction of 1-methyl-3-nitroindole (1) by indium in acetic acid in the presence of Boc-anhydride
furnished the Boc-protected amine (19) in 66% yield.17 A small amount of compound 2 (16%) was
obtained as a byproduct in this reaction (Scheme 4).
O
H
N
In, AcOH,
Boc2O
NH
NO2
Boc
CH3
+
MeOH, Δ
N
N
N
Me
Me
Me
1
19 (66%)
2 (16%)
Scheme 4.

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HETEROCYCLES, Vol. 70, 2006
Similarly, in the presence of hexanoic and benzoic anhydrides, 1-methyl-3-nitroindole (1) furnished the
corresponding amides (20) and (21) (Scheme 5).18 In both cases, N-acetylaminoindole (2) was also
obtained as a byproduct.
O
H
N
O
In, AcOH,
a or b
NO2
NH
CH3
R
+
MeOH, Δ
N
N
N
Me
Me
Me
1
a) Hexanoic anhydride : (R=C5H11) 20 (75%)
b) Benzoic anhydride : (R= Ph)
2 (12%)
2 (41%)
21 (56%)
Scheme 5.
In conclusion, we have described a method to reduce 3- and 2-nitroindoles to the corresponding
N-acylated aminoindoles. The desired products are obtained in moderate to excellent yield. The
chemistry involving these aminoindoles is ongoing in our laboratory and will be reported in due course.
ACKNOWLEDGEMENTS
This work was supported by the Donors of the Petroleum Research Fund (PRF), administered by the
American Chemical Society, and by Wyeth.
REFERENCES AND NOTES
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3. G. N. Kurilo, O. N. Boyarintseva, and A. N. Grinev, Chem. Heterocycl. Compd. (Engl. Transl.),
1975, 579; V. S. Velezheva, A. V. Yarosh, T. A. Kozik, and N. N. Suvorov, Chem. Heterocycl.
Compd. (Engl. Transl.), 1978, 1217; V. S. Velezheva, A. V. Yarosh, T. A. Kozik, and N. N. Suvorov,
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and T. Barf, Bioorg. Med. Chem. Lett., 2004, 14, 4445.
5. E. T. Pelkey and G. W.Gribble, Synthesis, 1999, 1117.
6. S. Roy and G. W. Gribble, Tetrahedron Lett., 2005, 46, 1325; J. Jiang and G. W. Gribble,
Tetrahedron Lett., 2002, 43, 4115; E. T. Pelkey and G. W. Gribble, Tetrahedron Lett., 1997, 38,
5603.
7. D. L. Boger and H. Zarrinmayeh, J. Org. Chem., 1990, 55, 1379; M. G. Ferlin, B.Gatto, G.
Chiarelotto, and M. Palumbo, Bioorg. Med. Chem., 2000, 8, 1415; P. A. Ple, T. P.Green, L. F.

HETEROCYCLES, Vol. 70, 2006
55
Hennequin, J. Curwen, M. Fennell, J. Allen, C. Lambert, and G. Costello, J. Med. Chem., 2004, 47,
871; Y. K. Yee, P. R. Bernstein, E. J. Adams, F. J. Brown, L. A. Cronk, K. C. Hebbel, E. P. Vacek,
R. D. Krell, and D. W. Snyder, J. Med. Chem., 1990, 33, 2437.
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9. M. R. Pitts, J. R. Harrison, and C. J. Moody, J. Chem. Soc., Perkin Trans. 1, 2001, 955; C. J. Moody
and M. R. Pitts, Synlett, 1998, 1028.
10. B. H. Kim, R. Han, F. Piao, Y. M. Jun, W. Baik, and B. M. Lee, Tetrahedron Lett., 2003, 44, 77.
11. Representative Procedure: Compound (2): AcOH (0.17 mL, 3 mmol) was added to a mixture
of In powder (172 mg, 1.5 mmol), 1-methyl-3-nitroindole (53 mg, 0.3 mmol) and Ac2O (77 mg, 0.75
o
mmol) in MeOH (1.5 mL). The reaction mixture was stirred at rt for 2 h and then at 45 C for 5
min. The progress of the reaction was monitored by TLC. The reaction mixture was cooled,
poured into saturated aqueous NaHCO3 solution and extracted with AcOEt (3 x 20 mL). The
combined organic extracts were dried (MgSO4) and concentrated in vacuo. The solid residue was
purified by flash column chromatography (hexanes : AcOEt = 1:3) to give the desired product (50
o
o
1
mg, 88%) as white crystals: mp 189-191 C (lit.,2 191-192 C); H NMR (DMSO-d6) δ 9.87 (br s,
1H), 7.81-7.79 (m, 1H), 7.72 (s, 1H), 7.37 (d, 1H, J = 8 Hz), 7.18-7.13 (m, 1H), 7.06-7.00 (m, 1H),
13
3.73 (s, 3H), 2.11 (s, 3H); C NMR (DMSO-d6) δ 166.8, 133.8, 121.5, 120.5, 119.4, 118.1, 118.0,
114.6, 109.4, 32.3, 23.0.
12. C. J. Li and T. H. Chan, 'Organic Reactions in Aqueous Media' Wiley-Interscience, New York,
1997; C. J. Li, Tetrahedron, 1996, 52, 5643; A. Lubineau, J. Augé, and Y. Queneau Synthesis, 1993,
741.
13. Compound (9): mp 174-175 oC; 1H NMR (DMSO-d6) δ 9.94 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H, J =
7.9 Hz), 7.42 (d, 1H, J = 8.2 Hz), 7.28 (t, 2H, J = 7.5 Hz), 7.21-7.24 (m, 1H), 7.17 (d, 2H, J = 7.3
Hz), 7.12 (t, 1H, J = 7.6 Hz), 7.03 (t, 1H, J = 7.5 Hz), 5.37 (s, 2H), 2.11 (s, 3H); 13C NMR
(DMSO-d6) δ 166.9, 138.4, 133.3, 128.5, 127.3, 127.0, 121.8, 120.7, 118.6, 118.3, 118.2, 115.2,
109.9, 109.3, 48.9, 23.0; LRMS (EI) m/z 264 (M+), 221, 149, 131, 91 (100%); HRMS (EI) calcd for
C17H16N2O: 264.1263, found: 264.1256. Compound (10): mp 218-220 oC ; 1H NMR (DMSO-d6) δ
10.24 (br s, 1H), 8.11 (s, 1H), 7.98 (d, 1H, J = 8.2 Hz), 7.93 (d, 1H, J = 7.9 Hz), 7.89-7.87 (m, 2H),
7.67-7.64 (m, 1H), 7.57-7.54 (m, 2H), 7.42-7.39 (m, 1H), 7.33-7.30 (m, 1H), 2.14 (s, 3H); 13C NMR
(DMSO-d6) δ 168.4, 136.7, 134.5, 132.4, 129.8, 126.5, 125.7, 124.5, 123.4, 122.0, 119.3, 113.4,
113.3, 23.1; LRMS (EI) m/z 314 (M+), 173, 131 (100%), 103, 77; HRMS (EI) calcd for
C16H14N2O3S: 314.0725, found: 314.0727. Compound (11): mp 163-165 oC; 1H NMR (DMSO-d6)
δ 10.11 (brs, 1H), 8.09-8.06 (m, 2H), 7.96 (d, 1H, J = 7.8 Hz), 7.38-7.25 (m, 2H), 2.15 (s, 3H), 1.60
(s, 9H); 13C NMR (DMSO-d6) δ 168.0, 149.2, 132.5, 124.9, 124.0, 122.3, 119.7, 118.6, 114.7, 113.3,

56
HETEROCYCLES, Vol. 70, 2006
83.4, 27.7, 23.0; LRMS (EI) m/z 274 (M+), 218, 174, 132 (100%), 103, 77; HRMS (EI) calcd for
C15H18N2O3: 274.1317, found: 274. 1320.
o
o
1
14. Compound (12): mp 159-161 C (lit.3 162-163 C); H NMR (acetone-d6) δ 10.05 (br s, 1H), 9.32
(br s, 1H), 7.90 (d, 1H, J = 2.4 Hz), 7.74 (d, 1H, J = 8.1 Hz), 7.38 (d, 1H, J = 8.3 Hz), 7.13-7.10 (m,
13
1H), 7.02-6.99 (m, 1H), 2.17 (s, 3H); C NMR (acetone-d6) δ 168.1, 135.0, 122.6, 121.7, 119.3,
118.2, 116.7, 116.1, 112.2, 23.3.
1
15. Compound (13): oil; H NMR (CDCl3) 8.09 (br s, 1H), 7.83-7.80 (m, 1H), 7.60-7.40 (m, 5H),
o
1
7.31-7.26 (m, 1H), 7.19-7.16 (m, 2H), 3.74 (s, 3H). Compound (14): mp 132-134 C; H NMR
(CDCl3) δ 10.65 (s, 1H), 7.85 (d, 1H, J = 8.2 Hz), 7.46-7.47 (m, 1H), 7.16-7.23 (m, 3H), 2.26 (s, 3H),
1.74 (s, 9H); LRMS (EI) m/z 274 (M+), 218, 174, 132 (100%); HRMS (EI) calcd for C15H18N2O3:
274.1318, found: 274. 1320.
16. All compounds were characterized and NMR data are identical to the literature values.5,6
17. Compound (19): mp 96-98 oC; 1H NMR (CDCl3) δ 7.50 (d, 1H, J = 7.8 Hz), 7.42 (s, 1H), 7.24-7.31
13
(m, 2H), 7.13 (t, 1H, J = 7.4 Hz), 6.54 (br s, 1H), 3.75 (s, 3H), 1.58 (s, 9H); C NMR (CDCl3) δ
153.7, 134.8, 122.1, 121.3, 119.2, 118.8, 116.9, 114.0, 109.4, 80.3, 32.8, 28.6; LRMS (EI) m/z 246
(M+), 190 (100%), 173, 146, 131, 103, 77; HRMS (EI) calcd for C14H18N2O2: 246.1368, found:
246.1373.
o
1
18. Compound (20): mp 91-93 C; H NMR (CDCl3) δ 7.74 (br s, 1H), 7.69 (s, 1H), 7.56 (d, 1H, J =
7.8 Hz), 7.24-7.31 (m, 2H), 7.09-7.12 (m, 1H), 3.72 (s, 3H), 2.44 (t, 2H, J = 7.6 Hz), 1.75-1.81 (m,
13
2H), 1.36-1.39 (m, 2H), 0.93 (t, 3H, J = 6.9 Hz); C NMR (CDCl3) δ 171.1, 134.5, 122.2, 121.1,
120.6, 118.9, 116.9, 113.7, 109.5, 37.1, 32.8, 31.7, 25.8, 22.6, 14.1; LRMS (EI) m/z 244 (M+), 191,
146 (100%); HRMS (EI) calcd for C15H20N2O: 244.1576, found: 244.1571. Compound (21): mp
159-161 oC; 1H NMR (CDCl3) δ 8.16 (brs, 1H), 7.93-7.95 (m, 2H), 7.84 (s, 1H), 7.61 (d, 1H, J = 7.9
Hz), 7.54-7.57 (m, 1H), 7.47-7.51 (m, 2H), 7.34 (d, 1H, J = 8.2 Hz), 7.27-7.30 (m, 1H), 7.14-7.17 (m,
1H), 3.77 (s, 3H); 13C NMR (CDCl3) δ 165.0, 134.8, 134.6, 131.7, 128.9, 127.2, 122.3, 121.1, 120.8,
119.1, 116.8, 113.8, 109.7, 32.9; LRMS (EI) m/z 250 (M+), 244, 145 (100%), 105, 77; HRMS (EI)
calcd for C16H14N2O: 250.1106, found: 250.1110.