Mn(III)-based radical addition reactions of 2-nitroindole with activated CH compounds

Article abstract of DOI:10.1016/j.tetlet.2008.09.020

2-Nitroindole undergoes addition reactions with the radicals generated from active CH compounds upon treatment with Mn(OAc)₃·2H₂O to afford the corresponding 3-substituted-2-nitroindoles in 27-66% yields. Products of the methylene addition reactions undergo a subsequent in situ Nef reaction to afford 2-oxoindolin-3-ylidenes.

Full text of DOI:10.1016/j.tetlet.2008.09.020

Tetrahedron Letters 49 (2008) 6621–6623
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mn(III)-based radical addition reactions of 2-nitroindole
with activated CH compounds
Dmitry A. Androsov a, Tara L. S. Kishbaugh b, Gordon W. Gribble a,
*
a Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
b Department of Chemistry, Eastern Mennonite University, Harrisonburg, VA 22802, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Nitroindole undergoes addition reactions with the radicals generated from active CH compounds upon
treatment with Mn(OAc)3Á2H2O to afford the corresponding 3-substituted-2-nitroindoles in 27–66%
yields. Products of the methylene addition reactions undergo a subsequent in situ Nef reaction to afford
2-oxoindolin-3-ylidenes.
Received 8 August 2008
Revised 3 September 2008
Accepted 4 September 2008
Available online 10 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Over the past 40 years manganese(III)-promoted oxidative free-
radical reactions have emerged as a powerful and versatile method
for organic synthesis.1 Recent applications include the tandem
malonate and cyclohexanone (anionic addition) to give 3-alkyl-2-
nitroindoles. However, those adducts are stable under the reaction
conditions (NaH, THF, low temperature), and do not undergo a Nef
reaction.11
Interestingly, 3-nitroindole is unreactive under these conditions
(Mn(OAc)3Á2H2O, AcOH, reflux) with the same active CH com-
pounds, which is perhaps due to the absence of a captodative
stabilizing effect that the radical intermediate A generated from
2-nitroindole enjoys, whereas radical intermediate B does not
(Fig. 1).
The structures of 2a–b and 4a–f are supported by spectral data
(MS, NMR),12 and the 1H- and 13C-NMR data are consistent with lit-
erature values for similar compounds.13,14 Alkylidenes 4e,f, which
bear different substituents (R1 – R2), are obtained as mixtures of E-
and Z-isomers. The stereochemistry at the C3–C8 double bond
of isomeric 4e could be deduced by comparison of the 1D-NOE
malonyl radical alkene addition and cyclization onto indole,2
a
catalytic-based addition of carboxyalkyl radicals to alkenes,3 and
the key step in the first total synthesis of mersicarpine,4 to name
but a few.
In continuation with our interest in the chemistry of 2- and 3-
nitroindoles,5 we now report that 2-nitroindole (1)6 undergoes
manganese(III) acetate-promoted radical addition reactions with
activated methylene and methine compounds in refluxing acetic
acid (Scheme 1). Our results are summarized in Table 1. Whereas
the reactions of 1 with 3-methylpentane-2,4-dione and 5-oxo-4-
propionylheptane-nitrile with Mn(OAc)3Á2H2O (HOAc, reflux) af-
ford the anticipated 3-substituted 2-nitroindoles 2a and 2b,
respectively, the same reaction conditions with pentane-2,4-dione,
malonitrile, dimethyl malonate, 1,3-diphenylpropane-1,3-dione,
1-phenylbutane-1,3-dione, and methyl 3-oxobutanoate unexpect-
edly give the corresponding 2-oxoindolin-3-ylidenes (4a–f), the
products of an in situ Nef reaction7 of intermediate 2. Presumably,
2-nitroindole 2 undergoes tautomerization to a 2-aci-nitro species
3 followed by hydrolysis to 4.
R2
R1
R1
R3
R2
R3
H
NO2
NO2
N
H
.
N
Mn(OAc)3 2H2O,
AcOH, reflux
Our synthesis of 4 provides an alternative route to these 2-oxo-
indolin-3-ylidenes that typically involves condensation of isatin
with activated methylene compounds.8 It might be noted that
some 2-oxoindolin-3-ylidenes demonstrate selective inhibition of
H
2
1
R3=H
R2
R1
tyrosine kinases,9 and 3-methyleneindolin-2-one, which is
a
R1
R2
O
metabolite of indole-3-acetic acid, exhibits cytotoxicity and has
potential for use in cancer therapy.10 We had previously found that
2-nitro-1-(phenylsulfonyl)indole reacts with enolates of diethyl
H2O, H+
OH
+
N
-
N
H
N
H
O
4
3
* Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946.
E-mail address: ggribble@dartmouth.edu (G. W. Gribble).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.020

6622
D. A. Androsov et al. / Tetrahedron Letters 49 (2008) 6621–6623
Table 1
In summary, we have described the Mn(III)-promoted free
radical addition of active methylene compounds to 2-nitroindole
followed by a spontaneous in situ Nef reaction to provide a novel
synthesis of 2-oxoindolin-3-ylidenes, which have found recent
utility in the synthesis of the maremycins,16 spirocyclic 2-oxin-
doles,17 new Cdc25 phosphatase inhibitors,18 and b-carbolines.19
In the case of active methine compounds the radical addition reac-
tion affords the 2-nitro-3-substituted indole.
3-Alkyl-2-nitroindoles 2a–b and 2-oxoindolin-3-ylidenes 4a–f produced using
Mn(OAc)3 via Scheme 1a
Entry
Compound
R1
R2
R3
Time
(min)
Yield
(%)
1
2
2a
2b
4a
4b
4c
4d
CO(O)Me
C(O)Et
C(O)Me
CN
CO(O)Me
C(O)Ph
C(O)Ph
C(O)Me
CO(O)Me
C(O)Me
CO(O)Me
C(O)Et
C(O)Me
CN
CO(O)Me
C(O)Ph
C(O)Me
C(O)Ph
C(O)Me
CO(O)Me
Me
(CH2)2CN
30
60
15
60
10
30
15
53
48
52
66
55
49
27
40
61
3
H
H
H
H
H
4b
5
6
7
Acknowledgments
4e1 (E-isomer)
4e2 (Z-isomer)
4f1 (E+Z) 1.7:1
4f2 (E+Z) 1.7:1
8
We thank Mr. Wayne Casey for assistance with the NOE exper-
iments. This work was supported by the Donors of the Petroleum
Research Fund (PRF), and administered by the American Chemical
Society, and by Wyeth.
9c
H
20
a
For procedures see Ref. 12a.
Literature data—Refs. 8d,13.
The mixture of E- and Z-isomers.
b
c
References and notes
1. (a) Snider, B. B. Chem. Rev. 1996, 96, 339–363; (b) Snider, B. B. In
Manganese(III)-based Oxidative Free-Radical Cyclizations in Transition Metals for
Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2004; Vol. 1, pp 483–490; (c) Renaud, P.; Sibi,
M. P. Radicals in Organic Synthesis; Vol. 1, Basic Principles, Vol. 2, Applications,
Wiley-CCH: New York, 2001.
2. (a) Byers, J. H.; Kosterlitz, J. A.; Steinberg, P. L. C. R. Acad. Sci. Paris, Chimie/
Chemistry 2001, 4, 471–476; (b) Chuang, C.-P.; Wang, S.-F. Synth. Commun.
1994, 24, 1493–1505.
R2
R1
O
O
N
R3
R1
O
N
R2
N
N
O
H
H R3
A (more stable)
B (less stable)
3. Hirase, K.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2003, 68, 5974–5976.
4. Magolan, J.; Carson, C. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437–1440.
5. (a) Roy, S.; Roy, S.; Gribble, G. W. Tetrahedron Lett. 2008, 49, 1531–1533; (b)
Roy, S.; Kishbaugh, T. L. S.; Jasinski, J. P.; Gribble, G. W. Tetrahedron Lett. 2007,
48, 1313–1316; (c) Roy, S.; Gribble, G. W. Tetrahedron Lett. 2007, 48, 1003–
1007. For a review of our earlier work, see: (d) Gribble, G. W. et al Curr. Org.
Synth. 2005, 9, 1493–1519.
Figure 1. Relative stability of radicals A and B.
spectra of both isomers. Thus, irradiation of the methyl protons of
4e2 (Z-isomer) at dH = 2.64 results in a significant NOE of H4 at
dH = 8.15; whereas irradiation of the methyl protons of 4e1 (E-iso-
mer) at dH = 2.50 results in no NOE of H4 at dH = 7.65. In this iso-
mer, the phenyl group is shielding H4 (Fig. 2). Similar NOE
experiments were carried out on the mixture of 4f: irradiation of
the H-4 proton at dH = 8.21 causes NOE on the protons of CO(O)CH3
at dH = 3.90, while irradiation of the H-4 proton at dH = 7.93 results
in an NOE of the protons of C(O)CH3 dH = 2.48. The latter result re-
veals that carbomethoxy deshields H4 more than acetyl does
(Fig. 2).
As additional structural proof, we synthesized 4c independently
from isatin and dimethyl malonate using the Knoevenagel method
reported by Jones.8a
Unfortunately, attempts to increase the yields by employing the
co-oxidant Cu(OAc)2 were unsuccessful and the yields of 4 were
virtually unchanged.12b Copper acetate in conjunction with
Mn(OAc)3 is known to increase the rate of oxidation of the inter-
mediate secondary radical (i.e., A).1a,15
6. Roy, S.; Gribble, G. W. Tetrahedron Lett. 2005, 46, 1325–1328.
7. (a) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047; (b) Jia, Y.-M.; Liang,
X.-M.; Chang, L.; Wang, D.-Q. Synthesis 2007, 744–748; (c) Burés, J.; Vilarrasa, J.
Tetrahedron Lett. 2008, 49, 441–444.
8. (a) Jones, G.; Rae, W. J. Tetrahedron 1966, 22, 3021–3026; (b) Redkin, R. G.;
Shemchuk, L. A.; Chernykh, V. P.; Shishkin, O. V.; Shishkina, S. V. Tetrahedron
2007, 63, 11444–11450; (c) Abdel-Rahman, A. H.; Keshk, E. M.; Hanna, M. A.;
El-Bady, Sh. M. Bioorg. Med. Chem. 2004, 12, 2483–2488; (d) Katritzky, A. R.;
Fan, W.-Q.; Liang, D.-S.; Li, Q.-L. J. Heterocycl. Chem. 1989, 26, 1541–1545.
9. (a) Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. J. Med.
Chem. 1998, 41, 2588–2603; (b) Kent, L. L.; Hull-Campbell, N. E.; Lau, T.; Wu, J.
C.; Thompson, S. A.; Nori, M. Biochem. Biophys. Res. Commun. 1999, 260, 768–
774.
10. Rossiter, S. Tetrahedron Lett. 2002, 43, 4671–4673.
11. Pelkey, T. E.; Barden, T. C.; Gribble, G. W. Tetrahedron Lett. 1999, 40, 7615–7619.
12. (a) General procedure for the synthesis of 3-alkyl-2-nitroindoles 2a-b and 2-
oxoindolin-3-ylidenes 4a–f. 2-Nitroindole (1) (0.05 g; 0.309 mmol),
Mn(OAc)3Á2H2O (5 equiv, 0.414 g, 1.543 mmol), and the corresponding
methylene or methylidene compound (5 equiv, 1.543 mmol) and AcOH
(10 mL) were charged into a 50 mL round bottom flask. The mixture was
refluxed for 10–60 min. After completion of the reaction, water was added
(200 mL) and the water phase was extracted with AcOEt (3 Â 50 mL). The
organic phase was washed with water (3 Â 100 mL), the solvent was removed
under reduced pressure, and the residue was purified via column
chromatography (SiO2, EtOAc/hexane (1:1) or (1:2)) to afford the
corresponding 3-alkyl-2-nitroindole 2a–b or 2-oxoindolin-3-ylidene 4a–f.
(for yields see Table 1. (b) General procedure using Cu(OAc)2 H2O: 2-(2-Oxo-
1,2-dihydroindol-3-ylidene)malonic acid dimethyl ester 4c (Procedure B): 2-
Nitroindole (1) (0.05 g; 0.309 mmol), Mn(OAc)3Á2H2O (5 equiv, 0.41 g,
1.543 mmol), Cu(OAc)2ÁH2O (0.1 equiv, 0.006 g, 0.0309 mmol), NaOAcÁ3H2O
(10 equiv, 0.42 g, 1.543 mmol), dimethyl malonate (5 equiv, 0.2 g,
1.543 mmol), and AcOH (10 mL) were charged into a 50 mL round bottom
flask. The mixture was stirred and heated at 80 °C for 5 h. After completion of
the reaction, water was added (200 mL) and the water phase was extracted
with AcOEt (3 Â 50 mL). The organic phase was washed with water
(3 Â 100 mL), the solvent was removed under reduced pressure, and the
residue was purified via column chromatography (SiO2, EtOAc/hexane (1:2)) to
afford 38 mg of compound 4c (47%) as an orange solid.
O
O
δ
2.64
O
O
Ph
δ
2.50
H3C
H4 = δ 8.15
H4
= δ 7.65
CH3
Ph
O
O
N
N
H
H
4e1 (
E-isomer)
4e2 (
Z
-isomer)
O
O
O
O
δ
2.48
δ
3.90
H3C
H4 = δ 7.93
H3CO
8.21
δ
3.96
δ
2.56
2-Methyl-2-(2-nitro-1H-indol-3-yl)malonic acid dimethyl ester 2a: This was
purified via column chromatography (SiO2, EtOAc/hexane (1:2)) to give a
yellow solid, 50 mg (53%), mp 120–122 °C. 1H NMR (300 MHz, CDCl3) d 2.00 (s,
3H), 3.81 (s, 6H), 7.16–7.22 (m, 1H), 7.38–7.44 (m, 3H), 9.48 (br s, 1H); 13C NMR
(75 MHz, CDCl3) d 22.0, 53.7, 55.4, 113.1, 117.1, 121.9, 122.9, 124.6, 128.7,
133.7, 170.5; m/z (EI+ mode) 306 (M+, 43%), 260 (100), 247 (20), 219 (8), 201
(40), 186 (69), 157 (17), 146 (20), 115 (27), 101 (10), 84 (16), 59 (33); HRMS
(EI+ mode) calcd for C14H14N2O6M+ 306.0852, found 306.0852.
H4 =
δ
OCH3
CH3
O
O
N
N
H
H
4f1 (Z-isomer)
4f2 (E-isomer)
Figure 2. Structures of E- and Z-isomers of 4e and 4f.

D. A. Androsov et al. / Tetrahedron Letters 49 (2008) 6621–6623
6623
2-(2-Cyanoethyl)-2-(2-nitro-1H-indol-3-yl)malonic acid diethyl ester 2b: This
was purified via column chromatography (SiO2, EtOAc/hexane (1:2)) to give a
yellow solid, 55 mg (48%), mp 161–162 °C. 1H NMR (300 MHz, CDCl3) d 1.22 (t,
6H), 2.47 (t, 2H), 2.93 (t, 2H), 4.22 (m, 2H), 4.35 (m, 2H), 7.20 (m, 1H), 7.34–
7.46 (m, 3H); 13C NMR (CDCl3) d 14.1, 30.4, 58.2, 63.2, 111.9, 113.6, 119.4,
121.3, 123.2, 125.5, 128.6, 133.6, 138.7, 168.7 m/z (EI+ mode) 373 (M+, 15%),
327 (32), 299 (6), 271 (5), 254 (12), 225 (100), 199 (21), 169 (11), 156 (9), 132
(12), 105 (16), 77 (15); HRMS (EI+ mode) calcd for C18H19N3O6 M+ 373.1274,
found 373.1273.
3-(2-Oxo-1,2-dihydroindol-3-ylidene)-2,4-dione 4a: This was purified via
column chromatography (SiO2, EtOAc/hexane (1:2)) to give an orange solid,
37 mg (52%), mp 125–126 °C. 1H NMR (300 MHz, CDCl3) d 2.51 (s, 3H), 2.56 (s,
3H), 6.87 (d, 1H), 6.98 (t, 1H), 7.30 (t, 1H), 7.41 (d, 1H), 8.59 (br s, 1H); 13C NMR
(75 MHz, CDCl3) d 30.3, 31.3, 77.3, 111.0, 919.8, 123.3, 125.3, 126.8, 132.4,
142.9, 149.0, 168.6, 198.8, 201.5; m/z (EI+ mode) 229 (M+, 76%), 214 (21), 187
(28), 172 (100), 159 (27), 144 (44), 130 (18), 116 (29), 89 (17); HRMS (EI+
mode) calcd for C13H11NO3 M+ 229.0739, found 229.0737.
(EI+ mode) 353 (M+, 19%), 296 (4), 248 (7), 220 (6), 122 (45), 105 (100), 84 (86);
HRMS (EI+ mode) calcd for C23H15NO3 M+ 353.1052, found 353.1053.
(E)-2-(2-Oxo-1,2-dihydroindol-3-ylidene)-1-phenylbutane-1,3-dione 4e1: This
was purified via column chromatography (SiO2, CHCl3/hexane (1:2)) to give an
orange amorphous solid, 24 mg (27%). 1H NMR (300 MHz, CDCl3) d 2.50 (s, 3H),
6.78 (d, 1H), 7.03 (t, 1H), 7.31 (t, 1H), 7.44–7.52 (m, 2H), 7.56–7.68 (m, 2H), 8.00–
8.12 (m, 3H); 13C NMR (75 MHz, CDCl3) d 30.2, 110.8, 119.9, 123.1, 125.6, 128.7,
129.16, 129.23, 130.4, 132.5, 133.8, 134.3, 136.1, 143.1, 147.4, 168.0, 193.9,
198.6; HRMS (EI+ mode) calcd for C18H13NO3 M+ 291.0896, found 291.0894.
(Z)-2-(2-Oxo-1,2-dihydroindol-3-ylidene)-1-phenylbutane-1,3-dione 4e2: This
was purified via column chromatography (SiO2, CHCl3/hexane (1:2)) to give an
orange amorphous solid, 36 mg (40%). 1H NMR (300 MHz, CDCl3) d 2.64 (s, 3H),
6.78 (m, 2H), 6.86 (d, 1H), 7.18 (t, 1H), 7.44–7.52 (m, 3H), 7.62–7.70 (m, 1H),
8.10–8.20 (m, 2H), 8.71 (br s, 1H); 13C NMR (75 MHz, CDCl3) d 30.8, 111.0, 119.9,
123.0, 124.8, 128.7, 129.6, 130.4, 130.7, 131.5, 133.9, 134.3, 135.5, 142.4, 149.4,
168.3, 192.0, 199.9; m/z (EI+ mode) 291 (M+, 11%), 220 (6), 122 (33), 105 (58), 84
(100); HRMS (EI+ mode) calcd for C18H13NO3 M+ 291.0896, found 291.0894.
(E)- and (Z)-3-Oxo-2-(2-Oxo-1,2-dihydroindol-3-ylidene)butyric acid methyl ester
(mixture E:Z-1.7:1) 4f: This was purified via column chromatography (SiO2,
EtOAc/hexane (1:1)) to give an orange amorphous solid, 46 mg (61%). Z-isomer
(4f1): 1H NMR (300 MHz, CDCl3) d 2.48 (s, 3H), 3.96 (s, 3H), 6.82 (d, 1H), 6.98 (t,
1H), 7.32 (t, 1H), 7.93 (d, 1H), 8.49 (br s, 1H). E-isomer (4f2): 1H NMR (300 MHz,
CDCl3) d 2.56 (s, 3H), 3.90 (s, 3H), 6.86 (d, 1H), 7.03 (t, 1H), 7.32 (t, 1H), 8.21 (d,
1H), 8.57 (br s, 1H).
2-(2-Oxo-1,2-dihydroindol-3-ylidene)malonitrile 4b: This was purified via
column chromatography (SiO2, EtOAc/hexane (1:1)) to give
40 mg (66%), mp 228–229 °C (lit.8d mp 235–238 °C). 1H NMR (300 MHz,
DMSO-d6) d 6.91 (d, 1H), 7.11 (t, 1H), 7.55 (t, 1H), 7.85 (d, 1H), 11.2 (s, 1H); 13
a red solid,
C
NMR (75 MHz, DMSO-d6) d 80.6, 111.56, 111.64, 113.1, 118.8, 122.9, 125.9,
137.8, 146.5, 150.7, 163.8.
2-(2-Oxo-1,2-dihydroindol-3-ylidene)malonic acid dimethyl ester 4c: This was
purified via column chromatography (SiO2, EtOAc/hexane (1:1)) to give an
orange solid, 44 mg (55%), mp 141–142 °C. 1H NMR (300 MHz, CDCl3) d 3.92 (s,
3H), 3.95 (s, 3H), 6.82 (d, 1H), 7.04 (t, 1H), 7.34 (t, 1H), 7.93 (br s, 1H), 8.39 (d,
1H); 13C NMR (75 MHz, CDCl3) d 53.4, 53.5, 110.4, 119.9, 123.3, 129.0, 129.5,
133.7, 135.4, 143.6, 163.5, 166.3, 167.5; m/z (EI+ mode) 261 (M+, 100%), 230
(70), 202 (23), 170 (46), 162 (17), 143 (27), 130 (21), 115 (24), 88 (15); HRMS
(EI+ mode) calcd for C13H11NO5 M+ 261.0637, found 261.0639.
2-(2-Oxo-1,2-dihydroindol-3-ylidene)-1,3-diphenylpropane-1,3-dione 4d: This
was purified via column chromatography (SiO2, EtOAc/hexane (1:2)) to give
an orange amorphous solid, 53 mg (49%), mp 93–95 °C. 1H NMR (300 MHz,
CDCl3) d 6.72 (d, 1H), 6.79 (t, 1H), 6.95 (d, 1H), 7.19 (t, 1H), 7.47–7.67 (m, 5H),
8.09 (d, 1H), 8.18 (d, 2H), 8.28 (d, 2H), 8.77 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 111.1, 119.8, 122.9, 124.7, 128.7, 128.93, 128.97, 129.4, 130.1, 130.3, 131.1,
131.6, 133.8, 134.3, 134.4, 135.4, 135.6, 142.6, 147.9, 167.8, 192.1, 192.2; m/z
13. Morales-Rios, M. S.; Garcia-Velgara, M.; Cervantes-Cuevas, H.; Alvarez-
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