Synthesis of a novel N-nitroalkyl bisindolylmaleimide

Article abstract of DOI:10.1080/00397910701319205

We describe the synthesis of the novel N-nitropropyl bisindolylmaleimide 6. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701319205

This article was downloaded by: [Aston University]
On: 05 October 2014, At: 14:28
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of a Novel N‐Nitroalkyl
Bisindolylmaleimide
Sudipta Roy a & Gordon W. Gribble a
a Department of Chemistry , Dartmouth College , Hanover, New Hampshire,
USA
Published online: 30 Jun 2007.
To cite this article: Sudipta Roy & Gordon W. Gribble (2007) Synthesis of a Novel N‐Nitroalkyl
Bisindolylmaleimide, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:11, 1879-1886, DOI: 10.1080/00397910701319205
To link to this article: http://dx.doi.org/10.1080/00397910701319205
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 37: 1879–1886, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701319205
Synthesis of a Novel N-Nitroalkyl
Bisindolylmaleimide
Sudipta Roy and Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover,
New Hampshire, USA
Abstract: We describe the synthesis of the novel N-nitropropyl bisindolylmaleimide 6.
Keywords: bisindolylmaleimides, indoles, nitroalkyl group
The natural bisindolylmaleimide arcyriarubin A (1) is a highly selective,
potent protein kinase C (PKC) inhibitor (IC50 ¼ 87 nM).[1] Many synthetic
analogues of 1 have been prepared, among which GF109203x (2), Ro
¨
31–7549 (3), Go6983 (4), and Ro 31–8220 (5) exhibit strong pharmacologi-
cal activities (Fig. 1).[2] In our search for novel checkpoint kinase 1 inhibitors,
we have previously synthesized several bisindolylmaleimides and the corre-
sponding indolocarbazoles.[3] During these studies, we found that no
synthesis of N-nitroalkyl-substituted bisindolylmaleimides had been
reported. The nitroalkyl group possesses further challenges because of the
high acidity of the a-hydrogen. Herein, we report the synthesis of the novel
nitropropyl-substituted bisindolylmaleimide 6.
To synthesize 6, we initially adopted a protecting group strategy in which
the phenylsulfonyl protecting group was removed after the base-mediated
coupling reaction to furnish the known anhydride 11 (Scheme 1).[1a]
An attempt to prepare 1-phenylsulfonylindole-3-glyoxyloyl chloride from
Received in the USA October 19, 2006
Address correspondence to Gordon W. Gribble, Department of Chemistry,
Dartmouth College, Hanover, New Hampshire 03755, USA. E-mail: ggribble@
dartmouth.edu
1879

1880
S. Roy and G. W. Gribble
Figure 1. Arcyriarubin A and its synthetic analogues.
Scheme 1.

N-Nitroalkyl Bisindolylmaleimide
1881
1-phenylsulfonylindole by the treatment of oxalyl chloride was unsuccessful
(even with a longer reaction time) because of the strong electron-withdrawing
effect of the phenylsulfonyl group. 1-(Phenylsulfonyl)indole-3-acetic acid (9),
required for the coupling reaction, was prepared from indole-3-acetic acid
using benzenesulfonyl chloride in the presence of excess (2.1 equiv) n-butyl-
lithium at 2708C. The anhydride 11 was converted to known imide 12 by
heating with ammonium acetate,[4] but an attempt to alkylate the indole
nitrogen of 12 with 1,3-dibromopropane furnished a complex mixture of products.
Therefore, we alkylated indole with 1,3-dibromopropane to furnish 3-bro-
mopropylindole (14),[5] which was subjected to the coupling reaction to give
the desired anhydride 15 in 38% yield (Scheme 2). However, attempts to
convert bromo derivative 15 to nitro compound 16 with silver nitrite or
sodium nitrite did not furnish the product or gave undesired products that
could not be identified. Also, we were unsuccessful in converting the
anhydride 15 to the corresponding imide using 1,1,1,3,3,3-hexamethyldisila-
zane (HMDS) and methanol.[6]
Therefore, we performed the bromo to nitro conversion at the early stage
of the synthesis (Scheme 3),[5] and the resulting nitro derivative 17 was
subjected to the coupling reaction. To our satisfaction, the desired
anhydride 16 was prepared, albeit in very low yield perhaps due to the
acidic hydrogens a- to the nitro group. The anhydride 16 was finally
converted to the target molecule 6 in 93% yield. An attempt to alkylate
indole with 1-chloro-3-nitropropane, prepared from 1-bromo-3-chloropro-
pane,[7] in the presence of sodium hydride unexpectedly furnished a small
amount of indole-1-propionitrile N-oxide (18).
Scheme 2.

1882
S. Roy and G. W. Gribble
Scheme 3.
EXPERIMENTAL
Melting points were determined with a Mel-Temp laboratory device apparatus
and are uncorrected. IR spectra were recorded on a Perkin-Elmer 600 series
1
FTIR spectrophotometer. H and 13C NMR spectra were recorded on either
a Varian XL-300 or 500 Fourier transform NMR spectrometer. Both low-
and high-resolution mass spectra were carried out at the Mass Spectrometry
Laboratory, School of Chemical Sciences, University of Illinois at Urbana
Champaign. Anhydrous THF and CH2Cl2 were prepared by a solvent purifi-
cation system. All other solvents (analytical grade), including anhydrous
solvents and reagents, were used as received.
1-(Phenylsulfonyl)indole-3-acetic Acid (9)
To a stirred solution of indole-3-acetic acid (2.63 g, 15 mmol) in THF (80 ml)
at 2708C, 2.5 M n-BuLi in hexane (12.8 mL, 32 mmol) was added
dropwise. The mixture was stirred at the same temperature for 1 h. A
solution of benzenesulfonyl chloride (1.9 mL, 15 mmol) in THF (25 mL)
was added very slowly to the reaction mixture at 2708C. The mixture was
allowed to come to rt and stirred for 16 h. The solvent was removed in
vacuo, and the residue was redissolved in dichloromethane and washed with
1 N HCl. The organic layer was dried (Na2SO4) and concentrated, and the
residue was recrystallized from ethyl acetate–hexanes to furnish the desired
product (3.31 g, 70%) as a brownish solid: mp 171–1738C (dec); IR (thin

N-Nitroalkyl Bisindolylmaleimide
1883
film) 1710, 1447, 1366, 1174, 1121, 746 cm21; 1H NMR (DMSO-d6) d 7.98–
7.93 (m, 3H), 7.75–7.54 (m, 5H), 7.38–7.24 (m, 2H), 3.72 (s, 1H); 13C NMR
(DMSO-d6) d 171.9, 137.1, 134.6, 134.3, 130.5, 129.9, 126.6, 124.9, 123.3,
120.3, 116.6, 113.1, 30.2; LRMS (EI) m/z 315 (Mþ, 100%), 270, 132, 77;
HRMS (EI) calcd. for C16H13NO4S: 315.0565; found: 315.0560.
3-[1-(3-Bromo-propyl)-1H-indol-3-yl]-4-(1-methyl-1H-indol-3-yl)-
furan-2,5-dione (15)
To a stirred solution of 1-(3-bromopropyl)indole (0.71 g, 3 mmol) in
anhydrous ether (30 mL) at 08C, oxalyl chloride (0.43 mg, 3.3 mmol) was
added dropwise. The mixture was stirred at 08C for 30 min. The solvent
was evaporated, and the crude residue was redissolved in dichloromethane
(30 mL) and added to a solution of N-methylindole-3-acetic acid (0.57 mg,
3 mmol) and triethylamine (0.61 mg, 6 mmol) in dichloromethane (12 mL)
over 1 h. The mixture was stirred for 20 h. The crude product was
purified by column chromatography on silica gel (dichloromethane–
methanol ¼ 99:1) to yield the desired product (0.53 mg, 38%) as a red
solid: mp 169–1718C; IR (thin film) 1815, 1749, 1628, 1529, 1254, 1226,
1
740 cm21; H NMR (DMSO-d6) d 8.00 (s, 1H), 7.79 (s, 1H), 7.56 (d, 1H,
J ¼ 8.5 Hz), 7.48 (d, 1H, J ¼ 8.2 Hz), 7.08–7.14 (m, 2H), 7.04 (d, 1H,
J ¼ 7.9 Hz), 6.82 (t, 1H, J ¼ 7.9 Hz), 6.65–6.71 (m, 2H), 4.35 (t, 2H,
J ¼ 6.6 Hz), 3.89 (s, 3H), 3.38 (t, 2H, J ¼ 6.6 Hz), 2.24 (qn, 2H,
J ¼ 6.6 Hz); 13C NMR (DMSO-d6) d 166.5, 166.3, 136.8, 135.8, 134.5,
132.7, 128.4, 126.8, 125.7, 124.9, 122.4, 122.3, 121.5, 121.4, 120.2, 120.1,
110.6, 110.4, 104.7, 103.9, 44.3, 33.1, 32.7, 31.2; LRMS (EI) m/z 463
(Mþ), 418, 390, 382, 279, 269, 167, 149 (100%); HRMS (EI) calcd. for
C24H19BrN2O3: 462.0579; found: 462.0587.
1-(3-Nitropropyl)indole (17)
A mixture of 1-(3-bromopropyl)indole (1.15 g, 4.8 mmol) and silver nitrite
(2.60 g, 16.8 mmol) in ether (50 mL) was stirred in dark for 2 d. The
mixture was filtered through a sintered-glass funnel and washed with ether.
The filtrate was concentrated (at 08C with icecooling) in rotovap to about
15–20 mL. The crude liquid was subjected to column chromatography on
silica gel (pet. ether–ether ¼ 2:1) to furnish the desired product (0.66 g,
68%) as a colorless liquid. 1-(3-Nitropropyl)indole is stable in etheral
solution but slowly decomposes in the dry state even at 0–48C. IR (thin
film) 1551, 1462, 1314, 743 cm21 1H NMR (CDCl3) d 7.71 (d, 1H,
;
J ¼ 7.8 Hz), 7.27–7.37 (m, 2H), 7.17–7.23 (m, 1H), 7.10 (d, 1H,
J ¼ 3.2 Hz), 6.58 (dd, 1H, J ¼ 3.2 Hz, 0.7 Hz), 4.24–4.30 (m, 4H), 2.49

1884
S. Roy and G. W. Gribble
(qn, 2H, J ¼ 6.6 Hz); 13C NMR (CDCl3) d 135.8, 128.9, 127.9, 122.1, 121.4,
119.9, 109.1, 102.2, 72.3, 42.8, 27.7.
3-(1-Methyl-1H-indol-3-yl)-4-[1-(3-nitro-propyl)-1H-indol-3-yl]-
furan-2,5-dione (16)
To a stirred solution of 1-(3-nitropropyl)indole (0.61 mg, 3 mmol) in
anhydrous ether (30 mL) at 08C, oxalyl chloride (0.43 g, 3.3 mmol) was
added dropwise. The mixture was stirred at 08C for 1.5 h. Then solvent was
evaporated; the residue was redissolved in dichloromethane (30 mL) and
added dropwise (throughout 1 h) to a stirred solution of N-methylindole-3-
acetic acid (0.57 g, 3 mmol) and triethylamine (0.61 g, 6 mmol) in dichloro-
methane (12 mL). The mixture was stirred for 23 h. The crude residue was
purified by column chromatography on silica gel (dichloromethane–
methanol ¼ 97:3) to yield the desired product (74 mg, 6%) as a red solid:
1
IR (thin film) 1751, 1612, 1552, 1529, 1467, 1255, 743 cm21; H NMR
(DMSO-d6) d 8.00 (s, 1H), 7.83 (s, 1H), 7.56 (d, 1H, J ¼ 8.1 Hz), 7.49
(d, 1H, J ¼ 8.1 Hz), 7.08–7.15 (m, 2H), 7.02 (d, 1H, J ¼ 8.1 Hz), 6.81
(t, 1H, J ¼ 7.6 Hz), 6.68–6.73 (m, 2H), 4.52 (t, 2H, J ¼ 6.8 Hz), 4.35
(t, 2H, J ¼ 7.1 Hz), 3.89 (s, 3H), 2.35 (qn, 2H, J ¼ 6.8 Hz); LRMS (ESI)
m/z 430 [Mþ þ H], 282 (100%); HRMS (ESI) calcd. for C24H20N3O5:
430.1403 [M þ H]; found: 430.1401.
3-(1-Methyl-1H-indol-3-yl)-4-[1-(3-nitro-propyl)-1H-indol-3-yl]-
pyrrole-2,5-dione (6)
To a solution of anhydride 16 (35 mg, 0.08 mmol) in DMF (1 mL) at rt,
HMDS (132 mg, 0.8 mmol) and methanol (13 mg, 0.4 mmol) were quickly
added. The flask was tightly sealed, and the mixture was stirred for 24 h. It
was poured into water (25 mL) and extracted with ethyl acetate
(2 ꢀ 25 mL) and dried (Na2SO4). The crude residue was purified by column
chromatography (dichloromethane–methanol ¼ 95:5) to yield the desired
product (32 mg, 93%) as a red solid: mp 125–1278C; IR (thin film) 1703,
1
1609, 1551, 1467, 1334, 744 cm21; H NMR (DMSO-d6) d 10.95 (s, 1H),
7.87 (s, 1H), 7.70 (s, 1H), 7.48 (d, 1H, J ¼ 8.2 Hz), 7.41 (d, 1H,
J ¼ 8.2 Hz), 7.00–7.08 (m, 2H), 6.94 (d, 1H, J ¼ 7.9 Hz), 6.73 (t, 1H,
J ¼ 7.9 Hz), 6.61–6.65 (m, 2H), 4.49 (t, 2H, J ¼ 6.9 Hz), 4.32 (t, 2H,
J ¼ 6.9 Hz), 3.86 (s, 3H), 2.34 (qn, 2H, J ¼ 6.9 Hz); 13C NMR (DMSO-d6)
d 173.0, 172.9, 136.6, 135.6, 133.3, 131.6, 128.1, 126.5, 126.2, 125.5,
122.0, 121.8, 121.4, 121.1, 119.8, 119.6, 110.2, 110.0, 105.6, 104.5, 72.6,
42.7, 33.0, 27.2; LRMS (ESI) m/z 451 [Mþ þ Na], 429 [Mþ þ H]; HRMS
(ESI) calcd. for C24H21N4O4: 429.1563 [M þ H]; found 429.1544.

N-Nitroalkyl Bisindolylmaleimide
1885
3-[2,5-Dihydro-4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-3-furanyl]-1-(phenyl-
1
sulfonyl)-1H-indole (10): mp . 2008C (dec); H-NMR (acetone-d6) d 8.12
(m, 2H), 8.08–8.00 (m, 2H), 7.81–7.76 (m, 1H), 7.68–7.63 (m, 2H), 7.41
(d, 1H, J ¼ 8.3Hz), 7.26–7.21 (m, 1H), 7.06–7.01 (m, 2H), 6.90–6.85 (m,
1H), 6.47 (d, 1H, J ¼ 8.1Hz), 6.31–6.26 (m, 1H), 3.96 (s, 3H); 13C-NMR
(acetone-d6) d 167.1, 166.7, 138.5, 138.3, 136.7, 135.7, 135.2, 135.1, 130.9,
129.8, 129.5, 128.0, 126.4, 126.2, 124.3, 123.6, 122.9, 122.1, 121.8, 114.3,
113.5, 111.4, 110.7, 105.3, 33.9.
3-(1H-Indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-2,5-furandione (11): mp
246–2488C; IR (thin film): 3371, 1818, 1742, 1528, 1247, 113, 740cm21
;
1H-NMR (acetone-d6) d 11.06 (brs, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.46 (t,
2H, J ¼ 8.9Hz), 7.10 (dt, 1H, J ¼ 7.6Hz, 0.9Hz), 7.05 (dt, 1H, J ¼ 7.6Hz,
0.9Hz), 6.96 (d, 1H, J ¼ 8.2Hz), 6.91 (d, 1H, J ¼ 7.9Hz), 6.71 (t, 2H,
J ¼ 7.6Hz), 3.95 (s, 3H); 13C-NMR (acetone-d6) d 167.7, 167.6, 138.1,
135.1, 131.1, 131.0, 129.2, 128.8, 126.9, 123.3, 123.2, 122.8, 122.5, 121.1,
120.9, 112.8, 112.7, 111.0, 106.8, 105.7, 33.6; LRMS (EI) m/z 342 (Mþ,
100%), 270, 255, 227, 135, 121, 114; HRMS (El) calcd for C21H14N2O3:
342.100; found: 342.1003.
1-(3-Bromopropyl)indole (14): 1H-NMR (CDCl3) d 7.71-7.73 (m, 1H), 7.45
(d, 1H, J ¼ 8.3Hz), 7.29–7.32 (m, 1H), 7.19–7.22 (m, 2H), 6.58 (d, 1H,
J ¼ 2.9Hz), 4.38 (t, 2H, J ¼ 6.3Hz), 3.35 (t, 2H, J ¼ 6.3Hz), 2.39 (2H, qn,
J ¼ 6.3Hz); 13C-NMR (CDCl3) d 135.9, 128.8, 128.1, 121.8, 121.2, 119.6,
109.4, 101.6, 44.0, 32.8, 30.7.
Indole-1-propionitrile-N-oxide (18): 1H-NMR (CDCl3) d 8.29 (d, 1H,
J ¼ 8.3Hz), 7.64 (d, 1H, J ¼ 7.8Hz), 7.38 (dt, 1H, J ¼ 7.7Hz, 0.7Hz), 7.28
(dt, 1H, J ¼ 7.4Hz, 1.0Hz), 7.10–7.12 (m, 1H), 4.47–4.52 (m, 2H), 3.46
(q, 2H, J ¼ 9.7Hz); 13C-NMR (CDCl3) d 154.2, 135.1, 130.1, 125.5, 124.2,
122.5, 121.1, 115.4, 106.9, 106.8, 68.5, 35.0; LRMS (El) m/z 186 (Mþ,
100%) 117: HRMS (EI) calcd for C11H10N2O: 186.0793, found 186.0799.
ACKNOWLEDGMENTS
This investigation was supported in part by the donors of the Petroleum Research
Fund (PRF), administered by the American Chemical Society, and Wyeth.
REFERENCES
1. (a) Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.;
Hurst, S. A.; Keech, E.; Turner, S. E. Inhibitors of protein kinase C, 1:2,3-Bisar-
ylmaleimides. J. Med. Chem. 1992, 35, 177–184; (b) Fabre, S.;

1886
S. Roy and G. W. Gribble
Prudhomme, M.; Rapp, M. Protein kinase C inhibitors; structure–activity relation-
ships in K252c-related compounds. Bioorg. Med. Chem. 1993, 1, 193–196;
(c) Gribble, G. W.; Berthel, S. J. A survey of indolo[2,3-a]carbazole alkaloids
and related natural products. In Studies in Natural Product Chemistry; Atta-ur-
Rahman, (ed); Elsevier: Amsterdam, 1993; Vol. 12, pp. 365–409.
2. (a) Toullec, D.; Pianetti, P.; Coste, H.; Bellevergue, P.; Grand-Perret, T.;
Ajakane, M.; Baudet, V.; Boissin, P.; Boursier, E.; Loriolle, F.; Lucette
Duhamel, L.; Charon, D.; Kirilovsky, J. The bisindolylmaleimide GF109203X is
a potent and selective inhibitor of protein kinase C. J. Biol. Chem. 1991, 266,
15771–15781; (b) Barth, H.; Hartenstein, J.; Rudolph, C.; Schaechtele, C.;
Betche, H. J.; Osswald, H.; Reck, R. Preparation of 3,4-bis(indol-3-yl)maleimides
as protein kinase C inhibitors. Eur. Pat. Appl. 1990, EP397060, November 14,
1990; (c) Dieter, P.; Fitzke, E. RO31-8220 and RO31-7549 show improved selec-
tivity for protein kinase C over staurosporine in macrophages. Biochem. Biophys.
Res. Commun. 1991, 181, 396–401.
3. (a) Roy, S.; Eastman, A.; Gribble, G. W. Synthesis of bisindolylmaleimides related
to GF109203x and their efficient conversion to the bioactive indolocarbazoles.
Org. Biomol. Chem. 2006, 4, 3228–3244; (b) Roy, S.; Eastman, A.;
Gribble, G. W. Synthesis of N-alkyl substituted bioactive indolocarbazoles
¨
related to Go6976. Tetrahedron 2006, 62, 7838–7845; (c) Roy, S.; Eastman, A.;
Gribble, G. W. Synthesis of 7-keto-Go6976 (ICP-103). Synth. Commun. 2005,
¨
35, 595–601.
4. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. A.; new, efficient method for the
synthesis of bisindolylmaleimides. J. Org. Chem. 1998, 63, 6053–6058.
5. Dehaen, W.; Hassner, A. Annulation of heterocycles via intramolecular nitrile
oxide–heterocycle cycloaddition reaction. J. Org. Chem. 1991, 56, 896–900.
6. Davis, P. D.; Bit, R. A. A mild conversion of maleic anhydrides into maleimides.
Tetrahedron Lett. 1990, 31, 5201–5204.
7. (a) Kai, Y.; Knochel, P.; Kwiatkowski, S.; Dunitz, J. D.; Oth, J. F. M.; Seebach, D.;
Kalinowski, H. O. Structure, synthesis, and properties of some persubstituted 1,2-
dinitroethanes: In quest of nitrocyclopropyl-anion derivatives. Helv. Chim. Acta
1982, 65, 137–161; (b) Kurth, M. J.; Ahlberg-Randall, L. A.; Takenouchi, K.
Solid-phase combinatorial synthesis of polyisoxazolines:
iterative protocol. J. Org. Chem. 1996, 61, 8755–8761.
A two-reaction