Efficient reductive acylation of 3-nitroindoles

Article abstract of DOI:10.1016/j.tetlet.2007.12.108

3-Nitroindoles are catalytically reduced by hydrogen on palladium/carbon to furnish the relatively unstable aminoindoles, which in the presence of carboxylic acid anhydrides afford good to excellent yields of the corresponding N-acylaminoindoles. 2-Nitroi

Full text of DOI:10.1016/j.tetlet.2007.12.108

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Tetrahedron Letters 49 (2008) 1531–1533
Efficient reductive acylation of 3-nitroindoles
Sujata Roy, Sudipta Roy, Gordon W. Gribble *
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 13 September 2007; accepted 19 December 2007
Available online 25 December 2007
Abstract
3-Nitroindoles are catalytically reduced by hydrogen on palladium/carbon to furnish the relatively unstable aminoindoles, which in
the presence of carboxylic acid anhydrides afford good to excellent yields of the corresponding N-acylaminoindoles. 2-Nitroindoles give
lower yields of N-acylated 2-aminoindoles.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Aminoindoles; Acylaminoindoles; Reduction; Nitroindoles; Hydrogenation
Although the indole nucleus is found in myriad alkal-
oids and biologically active heterocycles, 3- and 2-amino-
indoles are virtually unexplored as novel heterocyclic
enamines due to their relative instability.1–3 Nevertheless,
these aminoindoles could potentially serve as important
vehicles for the synthesis of other indoles and fused indole
heterocycles. For example, in a reported synthesis of d-
carbolines,4 the requisite 3-aminoindoles were generated
and suitably trapped by in situ hydrolysis of 3-acetylamino-
indoles, which were prepared via a Beckmann rearran-
gement of the corresponding 3-acetylindole oximes. An
efficient and direct synthesis of derivatized 3- and 2-amino-
indoles would be of enormous value for the study of their
chemistry.
In this regard, and in connection with our interest in the
chemistry of nitroindoles,5 we recently reported a one-pot
indium-mediated reductive acylation of 3- and 2-nitro-
indoles affording the respective 3- and 2-acylaminoindoles.1
Although several reducing conditions are available for
the reduction and subsequent acylation of nitro com-
pounds, the reports of achieving this two-step conversion
in a one-pot procedure are limited. Such methods include
PtCl2(PPh3)2–SnCl4 in the presence of CO and carboxylic
acids,6a Fe(III)-exchanged montmorillonite with NaI and
carboxylic acids,6b Ni(CO)4 with carbon monoxide and
acetic or propionic acid,6c Ru3(CO)12 with methyl formate
or formic acid,6d molybdenum hexacarbonyl and carb-
oxylic acids,6e and iodine or iodides with red phosphorus
and carboxylic acids.6f Most of these methods require high
temperatures, toxic reagents, and/or expensive catalysts.
Because our indium-mediated reduction of nitroindoles
requires an excess of expensive indium,1 we have examined
tin and zinc with acetic anhydride as cheaper alternatives in
this reductive acylation (Scheme 1). Although the desired
product 2 is obtained with both metals, the yields are lower
than the indium-mediated reduction.
Therefore, we turned to catalytic hydrogenation using
palladium on carbon to accomplish this one-pot reductive
acylation of 3- and 2-nitroindoles, which were synthesized
O
H
N
Sn or Zn or In,
AcOH, Ac2O
NO2
Me
N
Me
N
Me
MeOH, 40-60 °C
83%, for Sn
66%, for Zn
88% for In
2
1
*
Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946.
Scheme 1.
E-mail address: ggribble@dartmouth.edu (G. W. Gribble).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.108

1532
S. Roy et al. / Tetrahedron Letters 49 (2008) 1531–1533
O
R
Me
N
H
N
H2, 10% Pd/C
(RCO)2O
NO2
H2, 10% Pd/C
MeOH, 40-60 °C
NO2
N
Me
N
PG
N
PG
MeOH, 40-60 °C
52-100%
O
N
Me
SO2Ph
SO2Ph
Me
1, 3-6
2, 7-13
O
14
4
77%
Scheme 2.
Scheme 3.
Table 1
Synthesis of acetylaminoindoles (2, 7–13) from nitroindoles (1, 3–5) using
H2, Pd/C
H2, 10% Pd/C, Ac2O
MeOH, 40-60 °C
O
3-Nitroindole PG
Anhydride
used
Product
R
Yield
(%)
N
NO2
N
PG
N
H
Me
PG
1
1
1
1
3
4
5
6
Me
Me
Me
Me
Bn
Ac2O
Boc2O
(C6H11O)2O
(PhCO)2O
Ac2O
2
7
Me
Boc
(CH2)4CH3
Ph
Me
Me
Me
Me
100
99
95
91
76
52
61
80
15 (PG = SO2Ph)
16 (PG = Boc)
17 (PG = SO2Ph) 14%
18 (PG = Boc) 37%
8
9
Scheme 4.
10
11
12
13
SO2Ph Ac2O
CO2Et Ac2O
Boc
conditions using In, Sn, and Zn, and higher yields in all
cases. Moreover, the catalytic hydrogenation method
precludes the formation of mixed anhydrides that are
generated in situ when other anhydrides are used in the
presence of acetic acid as in, for example, the indium-
mediated reduction. At this point, the method is less useful
for the reductive acylation of 2-nitroindoles.
In summary, we have found an efficient method for the
catalytic reduction of 3-nitroindoles and their subsequent
acylation in the same reaction vessel. The resulting N-acyl-
ated 3-aminoindoles are obtained in good to excellent
yield.
Ac2O
as described earlier.7 In the event, treatment of 1-methyl-
3-nitroindole (1) with hydrogen on 10% Pd/C in methanol
in the presence of acetic anhydride afforded 2 in nearly
quantitative yield (Scheme 2, Table 1).8,9 In contrast to
the corresponding 3-aminoindole, 2 is quite stable and
can be stored indefinitely, but, as reported by Dupas and
co-workers,4 can be readily converted in situ to the 3-amino-
indole by methanolic HCl as necessary. This simple reduc-
tive-acylation of 3-nitroindoles is quite general. Thus, as
shown in Table 1, the reaction of 1 with H2 and Pd/C in
the presence of Boc-anhydride provides Boc-protected
amine 7 in 99% yield.10 Similarly, hexanoic anhydride
and benzoic anhydride furnish 8 and 9, respectively, in
excellent yield.
Acknowledgments
This work was supported by the Donors of the Petro-
leum Research Fund (PRF), administered by the American
Chemical Society, and by Wyeth.
Treatment of different N-protected 3-nitroindoles 3–6
affords the corresponding acetylated amines 10–13 in 52–
80% yield.10,11
References and notes
The Paal–Knorr pyrrole synthesis12 is widely used to
prepare pyrroles from amines and 1,4-dicarbonyl com-
pounds, and a multitude of acidic and other conditions
(p-TSA,13 Al2O3,14 zeolites,15 montmorillonite clay,16 and
microwave,17 to name a few) have been used to promote
this simple and general pyrrole synthesis. As might be
anticipated, the treatment of 3-nitro-1-(phenylsulfonyl)-
indole (4) under our reductive acylation conditions gives
the novel 3-(1-pyrrolyl)indole 14 in 77% yield (Scheme
3).18,19 Pyrrolylindole 14 is relatively unstable and was
stored under À4 °C.
1. Roy, S.; Gribble, G. W. Heterocycles 2006, 70, 51–56.
2. Madelung, W. Justus Liebig Ann. Chem. 1914, 405, 58–95.
3. (a) Kurilo, G. N.; Boyarintseva, O. N.; Grinev, A. N. Chem.
Heterocycl. Compd. (Engl. Transl.) 1975, 579–580; (b) Suvorov, N.
N.; Velezheva, V. S.; Yarosh, A. V.; Erofeev, Yu. V.; Kozik, T. A.
Chem. Heterocycl. Compd. (Engl. Transl.) 1975, 959–964; (c) Yarosh,
A. V.; Velezheva, V. S.; Kozik, T. A.; Suvorov, N. N. Chem.
Heterocycl. Compd. (Engl. Transl.) 1977, 386–390; (d) Velezheva, V.
S.; Yarosh, A. V.; Kozik, T. A.; Suvorov, N. N. Chem. Heterocycl.
Compd. (Engl. Transl.) 1978, 1217–1223; (e) Velezheva, V. S.; Gunar,
V. I.; Balyakina, M. V.; Suvorov, N. N. Chem. Heterocycl. Compd.
(Engl. Transl.) 1978, 757–760; (f) Velezheva, V. S.; Yarosh, A. V.;
Kozik, T. A.; Suvorov, N. N. J. Org. Chem. USSR (Engl. Transl.)
1978, 1596–1607.
Although 2-nitroindoles 15 and 16 also undergo this
reductive-acylation, the yields of 17 and 18 are lower
(Scheme 4),10 which is a result similar to our previous
observations for the indium-mediated reduction of these
2-nitroindoles.1
´
4. Papamicae¨l, C.; Queguiner, G.; Bourguignon, J.; Dupas, G. Tetra-
hedron 2001, 57, 5385–5391.
5. (a) Roy, S.; Kishbaugh, T. L. S.; Jasinski, J. P.; Gribble, G. W.
Tetrahedron Lett. 2007, 48, 1313–1316; (b) Roy, S.; Gribble, G. W.
Tetrahedron Lett. 2007, 48, 1003–1007; For a review, see: (c) Gribble,
G. W. et al Curr. Org. Syn. 2005, 9, 1493–1519.
The advantages of this catalytic hydrogenation method
are mild and neutral conditions, in contrast to the acidic

S. Roy et al. / Tetrahedron Letters 49 (2008) 1531–1533
1533
6. (a) Watanabe, Y.; Tsuji, Y.; Kondo, T.; Takeuchi, R. J. Org. Chem.
1984, 49, 4451–4455; (b) Choudary, B. M.; Kantam, M. L.;
Ranganath, K. V. S.; Rao, K. K. Angew. Chem., Int. Ed. 2005, 44,
322–325; (c) Kajimoto, T.; Tsuji, J. Bull. Chem. Soc. Jpn. 1969, 42,
827–828; (d) Nahmed, E. M.; Jenner, G. Tetrahedron Lett. 1991, 32,
4917–4920; (e) Ho, T.-L. J. Org. Chem. 1977, 42, 3755; (f) Du, X.;
Zheng, M.; Chen, S.; Xu, Z. Synlett 2006, 1953–1955.
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Jiang, J.; Gribble, G. W. Tetrahedron Lett. 2002, 43, 4115–4117; (c)
Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603–
5606; (d) Pelkey, E. T.; Gribble, G. W. Synthesis 1999, 1117–
1122.
11. Compound 12: mp 148–150 °C; 1H NMR (acetone-d6): d 9.43 (br s,
1H), 8.27 (s, 1H), 8.21 (d, 1H, J = 7.6 Hz), 7.81 (d, 1H, J = 7.9 Hz),
7.38 (t, 1H, J = 7.8 Hz), 7.27 (t, 1H, J = 7.5 Hz), 4.49 (q, 2H, J =
7.0 Hz), 2.18 (s, 3H), 1.45 (t, 3H, J = 7.0 Hz); 13C NMR (acetone-d6):
d 168.6, 151.7, 134.2, 125.9, 125.2, 123.4, 121.1, 118.7, 115.9, 114.4,
63.9, 23.4, 14.7; LRMS (EI): m/z 246 (M+), 204, 176, 159, 131 (100%),
103, 77; HRMS (EI): calcd for C13H14N2O3: 246.1005, found:
246.1004.
12. (a) Knorr, L. Chem. Ber. 1884, 17, 546; (b) Knorr, L. Justus Liebig
Ann. Chem. 1886, 236, 290; For a review, see: (c) Gribble, G. W. In
Name Reactions in Heterocyclic Chemistry; Li, J. J., Ed.; John Wiley
& Sons: Hoboken, New Jersey, 2004; pp 79–88.
8. Representative procedure: To a solution of 1-methyl-3-nitroindole (1)
(44 mg, 0.25 mmol) and acetic anhydride (77 mg, 0.75 mmol) in
anhydrous methanol (3 mL) was added 10% palladium on carbon
(10 mg). Using a hydrogen filled balloon, the atmosphere of the flask
was replaced by hydrogen gas. After three vacuum/hydrogen cycles to
remove air from the reaction flask, the reaction mixture was heated at
40 °C (60 °C for other cases) at atmospheric pressure for 1 h,
maintaining the hydrogen atmosphere with a balloon. The catalyst
was removed by filtration through Celite. The filtrate was evaporated
and the crude product was purified by column chromatography
(hexanes/ethyl acetate = 1:5) to give the desired product 2 (47 mg,
100%) as a white solid: mp 189–191 °C (lit.9 mp 191–192 °C); spectral
data are identical to our previously reported values.1
13. Raghavan, S.; Anuradha, K. Synlett 2003, 711–713.
14. Texier-Boullet, F.; Klein, B.; Hamelin, J. Synthesis 1986, 409–411.
15. Sreekumar, R.; Padmakumar, R. Synth. Commun. 1998, 28, 1661–
1665.
16. Samajdar, S.; Becker, F. F.; Banik, B. K. Heterocycles 2001, 55, 1019–
1022.
17. Danks, T. N. Tetrahedron Lett. 1999, 40, 3957–3960.
18. The synthesis of three other 3-(1-pyrrolyl)indoles from isatin has been
reported: Hudson, C. B.; Robertson, A. V. Aust. J. Chem. 1967, 20,
1699–1704.
19. Compound 14: oil; 1H NMR (DMSO-d6): d 8.15 (s, 1H), 8.03–8.07
(m, 3H), 7.69 (t, 1H, J = 7.3 Hz), 7.59 (t, 2H, J = 7.3 Hz), 7.43 (t, 1H,
J = 7.8 Hz), 7.28 (t, 1H, J = 7.2 Hz), 7.07 (d, 1H, J = 7.6 Hz), 5.85 (s,
2H), 1.85 (s, 6H); 13C NMR (DMSO-d6): d 136.5, 134.8, 133.5, 129.8,
128.4, 127.9, 126.8, 125.8, 124.5, 121.9, 118.8, 113.8, 106.4, 12.2;
LRMS (EI): m/z 350 (M+), 322, 209 (100%), 181, 168; HRMS (EI):
calcd for C20H18N2O2S: 350.1089; found: 350.1084.
9. Albini, F. M.; Oberti, R.; Caramella, P. J. Chem. Res. (S) 1983,
4–5.
10. All compounds were fully characterized and the NMR and other data
are identical to our previously reported values.1