Reductive heck reactions of N-methyl-substituted tricyclic imides

Article abstract of DOI:10.3390/molecules15031303

The palladium-catalyzed hydroarylation of N-methyl-substituted tricyclic imides was studied in order to find a new stereoselective access to a series of new exoaryl(hetaryl)-substituted tricyclic N-methylimides.

Full text of DOI:10.3390/molecules15031303

Molecules 2010, 15, 1302-1308; doi:10.3390/molecules15031303
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Reductive Heck Reactions of N-Methyl-substituted Tricyclic
Imides
Gokce Goksu 1, Nuket Ocal 1,* and Dieter E. Kaufmann 2,*
1
Department of Chemistry, Faculty of Art and Sciences, Davutpasa Campus, Yildiz Technical
University, 34210 Esenler-Istanbul, Turkey
2
Institute of Organic Chemistry, Leibnizstr. 6, Clausthal University of Technology, D-38678
Clausthal-Zellerfeld, Germany
* Authors to whom correspondence should be addressed; E-Mails: nocal@yildiz.edu.tr (N.O.);
dieter.kaufmann@tu-clausthal.de (D.E.K.); Tel.: +90-212-3834214; Fax: +90-212-3834106.
Received: 30 January 2010; in revised form: 10 February 2010 / Accepted: 2 March 2010 /
Published: 4 March 2010
Abstract: The palladium-catalyzed hydroarylation of N-methyl-substituted tricyclic imides
was studied in order to find a new stereoselective access to a series of new exo-
aryl(hetaryl)-substituted tricyclic N-methylimides.
Keywords: homogenous catalysis; palladium; C-C coupling; hydroarylation; heterocycles
1. Introduction
The imide moiety is an integral structural part of various important bioactive molecules such as
fumaramidmycin, granulatimide, isogranulatimide and rebeccamycin. These molecules are reported to
exhibit antitumor, anti-inflammatory and antimicrobial activities [1–3]. A literature search reveals that
certain compounds with antitumor activity, and in particular molecules able to interact with DNA, are
characterized by the presence of both an extended π-system and an imide function.
On the other hand, derivatives of the tricyclic anhydride exo-5,6-dehydronorcantharidin (2,
Figure 1) are also pharmacologically active [4]. Norcantharidin shows a comparable activity with
cantharidin (1, Figure 1) which is the major effective ingredient in pharmaceuticals for the treatment of
certain malignant tumors in China. Compound 2 has been widely employed in clinical practice, as it is
less toxic and much easier to synthesize [5,6]. Furthermore, in connection with an additional imide unit

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this type of structure has recently become an intense research topic in heterocyclic chemistry because
of its anti-tumor, anti-virus, analgesic, sedative and fungicidal activities.
Figure 1. Cantharidin (1) and exo-5,6-dehydronorcantharidin (2).
Therefore, we became interested in bioactive cantharidin analogues that represent aryl-modified
bicyclic imide systems. We first synthesized endo-N-phenylbicyclo[2.2.1]hept-5-ene-2,3-
dicarboximide as the starting material for reductive Heck reactions. In the presence of triphenylarsine
as a ligand [7] the palladium-catalyzed hydroarylation of the easily accessible, unsaturated tricyclic
N-phenyl (or phenyl-substituted) imides has been proven to be a stereoselective, versatile and high-
yield approach for the synthesis of the corresponding aryl and heteroaryl derivatives [8,9]. In this
paper, we synthesized various N-methyl derivatives of the unsaturated imides by a hydroarylation
procedure to check the effect on both, the reactivity of the starting materials as well as the bioactivity
of the products.
2. Results and Discussion
Our synthesis started with the Diels-Alder reaction of cyclopentadiene and N-methylmaleimide in
dry benzene under reflux to give N-methylbicyclo[2.2.1]hept-5-ene-2-endo,3-endo-dicarboximide (3)
as colorless crystals in a yield of 93% [10]. The same reaction was successfully applied to the reaction
of furan with N-methylmaleimide to give both diastereomers, N-methyl-7-oxabicyclo[2.2.1]hept-5-
ene-2-endo,3-endo-dicarboximide (4) and N-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2-exo,3-exo-di-
carboximide (5) in good yields after chromatographic separation [11] (Scheme 1).
Scheme 1. Synthesis of 3–5.
Treatment of 3 with 1-iodobenzene, 4-chloro-1-iodobenzene and 2-iodothiophene under reductive
Heck conditions gave the 6, 7 and 8 pure products as exo-isomers after chromatographic separation on
silica gel in isolated yields of 70–94% (Scheme 2).

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Scheme 2. Synthesis of 6–11.
The same reductive Heck arylation conditions were successfully applied to the reaction of 4 with
4-methoxy-1-iodobenzene, 2-chloro-1-iodobenzene and 1-iodonaphthalene to give the new exo-
arylated heterocycles 9, 10 and 11 in good yields after chromatographic separation (Scheme 2). We
also synthesized 12, 13 and 14 from 5 with 2-chloro-5-iodopyridine, 1-iodobenzene and 4-chloro-1-
iodobenzene prepared as new 8-exo-compounds under the same hydroarylation conditions (Scheme 3).
Scheme 3. Synthesis of 12–14.
1
The new structures were assigned by their H-NMR data. The stereochemistry was inferred from
their NMR spectra including diagnostic spin-spin interactions. The exo-position of the C-8 substituent

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was confirmed by the fact that H8 showed no significant interaction with H1. The geminal protons
at C-9 were identified by vicinal coupling to H1. Additionally, H-H COSY spectra showed cross peaks
between H2 and H6 and between H8 and H9, respectively. In addition to the 13C-NMR, DEPT and FTIR
spectral data which were in agreement with the proposed structures, the mass spectra of all new
compounds showed the expected molecular ion peaks. The data show that independently from the
stereochemistry of the starting imide moiety, hydroarylation leads to the formation of the exo-arylated
products, exclusively.
3. Experimental Section
3.1. General
All the reactions were carried out under nitrogen atmosphere unless otherwise indicated. Reactions
were monitored by thin-layer chromatography (TLC). Visualization of the developed chromatograms
were performed either with UV light or KMnO4 stain. Products were purified by silica gel
chromatography with a solvent gradient of ethyl acetate/n-hexane to afford the title compounds. IR
spectra were obtained with a Perkin Elmer FT-IR instrument and absorption frequencies are reported
in cm-1. Melting points were determined with a Gallenkamp digital thermometer. NMR spectra were
determined with a Varian-INOVA-500 MHz NMR. 2D NMR experimental studies were measured
with a Bruker Ac-400 MHz NMR. TMS (tetramethylsilane) was used as an internal standard and
CDCl3 was used as the solvent. Signal multiplicities in the NMR spectra are reported as follows: s-
singlet, brs-broad singlet, d-doublet, dd-doublet of doublets, m-multiplet. Mass spectra were measured
with Agilent 6890N GC-System-5973 IMSD.
3.2. General procedure for reductive Heck reactions
A solution of Pd(OAc)2 (5.6 mg, 0.025 mmol) and AsPh3 (33.7 mg, 0.11 mmol) in anhydrous DMF
(3 mL) was stirred under nitrogen at 65 ºC for 15 min. Then, alkene (1.0 mmol), Et3N (488 μL,
3.5 mmol), aryl(hetaryl) iodide (1.5 mmol) and HCOOH (138 mg, 3 mmol) were added sequentially.
The reaction mixture was stirred for 8–24 h. After cooling to room temperature EtOAc and brine were
added, the organic layer was separated, dried over MgSO4, filtered, and the solvent evaporated. The
residue was purified by column chromatography (SiO2).
N-Methyl-exo-8-phenylbicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide (6). Colorless solid, m.p.
108–110 ºC, yield: 70%. IR (ATR) υ: 3029, 2968, 2891, 1763, 1686, 1601, 1491, 1472, 1449, 1427,
1
1376, 1273, 1258, 1181, 1118, 979, 770, 746 cm-1; H-NMR δ: 1.50 (d, J = 10.7 Hz, 1H,
H10a), 1.68 (ddd, J = 15.6, 10.7, 1.9 Hz, 1H, H10s), 1.77–1.83 (m, 2H, H9x and H9n), 2.68 (dd, J = 8.7,
5.8 Hz, 1H, H8n), 2.80–2.84 (m, 2H, H1 and H7), 2.95 (s, 3H, N-CH3), 3.08 (ddd, J = 14.6, 10.7, 1.9
Hz, 1H, H2), 3.14 (dd, J = 8.7, 4.8 Hz, 1H, H6), 7.08–7.13 (m, 3H, Har), 7.19–7.23 (m, 2H, Har) ppm;

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13C-NMR δ: 24.65, 32.76, 39.58, 39.82, 42.09, 45.93, 48.76, 49.34, 126.40, 127.26, 128.66, 144.64,
178.34, 178.36 ppm; GC-MS m/z: 255 (M+), 143, 113, 66.
N-Methyl-exo-8-(4-chlorophenyl)bicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide (7). Colorless
solid, m.p. 120–123 ºC, yield: 84%. IR (ATR) υ: 2970, 2906, 1768, 1687, 1492, 1454, 1427, 1379,
1
1275, 1259, 1182, 1138, 1126, 1091, 986, 830, 812, 798 cm-1; H-NMR δ: 1.50 (d, J = 9.7 Hz, 1H,
H10a), 1.65–1.77 (m, 3H, H10s, H9x and H9n), 2.63–2.67 (m, 1H, H8n), 2.77 (d, J = 4.8 Hz, 1H,
H1), 2.82 (brs, 1H, H7), 2.95 (s, 3H, N-CH3), 3.08 (ddd, J = 9.7, 5.8, 2.8 Hz, 1H, H2), 3.14 (dd, J = 9.7,
13
5.8 Hz, 1H, H6), 7.04 (d, J = 8.7 Hz, 2H, Har), 7.17 (d, J = 8.7 Hz, 2H, Har) ppm; C-NMR δ: 24.68,
32.85, 39.52, 39.78, 41.59, 45.88, 48.65, 49.24, 128.60, 128.74, 132.20, 143.12, 178.15, 178.21 ppm;
GC-MS m/z: 289 (M+), 177, 152, 138, 113, 66.
N-Methyl-exo-8-(2-thienyl)bicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide (8). Colorless solid,
m.p. 93–96 ºC, yield: 94%. IR (ATR) υ: 3068, 2972, 2886, 1762, 1688, 1470, 1430, 1378, 1310, 1272,
1
1255, 1181, 1119, 1079, 980, 937, 796, 742 cm-1; H-NMR δ: 1.54 (d, J = 10.7 Hz, 1H, H10a), 1.76
(brd, J = 5.8 Hz, 2H, H9x and H9n), 1.89 (d, J = 10.7 Hz, 1H, H10s), 2.81 (brd, J = 4.3 Hz, 2H, H1 and
H7), 2.87–2.90 (m, 1H, H8n), 2.94 (s, 3H, N-CH3), 3.07 (dd, J = 8.7, 4.8 Hz, 1H, H2), 3.12 (dd, J = 8.7,
4.8 Hz, 1H, H6), 6.71 (d, J = 3.9 Hz, 1H, Har), 6.84 (dd, J = 4.8, 3.4 Hz, 1H, Har), 7.06 (dd, J = 4.8, 0.9
Hz, 1H, Har) ppm; 13C-NMR δ: 24.68, 35.26, 38.27, 39.49, 39.99, 47.26, 48.48, 48.93, 123.56, 123.64,
126.98, 149.61, 178.01, 178.07 ppm; GC-MS m/z: 261 (M+), 149, 113, 66.
N-Methyl-exo-8-(4-methoxyphenyl)-10-oxabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide
(9).
Colorless solid, m.p. 151–153 ºC, yield: 91%. IR (ATR) υ: 3041, 2960, 2903, 1766, 1689, 1611, 1512,
1
1463, 1427, 1374, 1274, 1244, 1180, 1132, 1032, 996, 948, 892, 829 cm-1; H-NMR δ: 1.83 (dt,
J = 13.6, 4.8 Hz, 1H, H9x), 2.03 (dd, J = 13.6, 8.7 Hz, 1H, H9n), 2.80 (dd, J = 8.7, 4.8 Hz, 1H, H8n),
2.97 (s, 3H, N-CH3), 3.40–3.44 (m, 2H, H2 and H6), 3.70 (s, 3H, -OCH3), 4.65 (brs, 1H, H7), 4.96 (brs,
13
1H, H1), 6.74 (d, J = 8.7 Hz, 2H, Har), 7.08 (d, J = 8.7 Hz, 2H, Har) ppm; C-NMR δ: 25.07, 37.49,
43.96, 51.59, 51.81, 55.48, 78.11, 84.20, 114.18, 128.48, 136.62, 158.72, 175.63, 175.72 ppm; GC-MS
m/z: 287 (M+), 259, 147, 68.
N-Methyl-exo-8-(2-chlorophenyl)-10-oxabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide
(10).
Colorless solid, m.p. 122–123 ºC, yield: 65%. IR (ATR) υ: 3019, 2973, 2948, 1775, 1693, 1471, 1432,
1
1379, 1311, 1274, 1129, 994, 954, 835 cm-1; H-NMR δ: 1.76-1.80 (m, 1H, H9x), 2.12 (dd, J = 13.6,
8.7 Hz, 1H, H9n), 2.99 (s, 3H, N-CH3), 3.42 (dd, J = 8.7, 4.8 Hz, 1H, H8n), 3.45–3.47 (m, 2H, H2
and H6), 4.80 (brd, J = 4.8 Hz, 1H, H1), 4.98 (brs, 1H, H7), 7.08–7.16 (m, 2H, Har), 7.26 (d, J = 8.7 Hz,
1H, Har), 7.32 (d, J = 8.7 Hz, 1H, Har) ppm; 13C-NMR δ: 23.85, 35.24, 39.43, 50.38, 50.54, 77.10,
81.65, 126.28, 126.44, 126.92, 128.32, 132.45, 140.07, 173.90, 174.37 ppm; GC-MS m/z: 291 (M+),
256, 228, 151, 112, 68.
N-Methyl-exo-8-(1-naphthyl)-10-oxabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide
(11).
Colorless solid, m.p. 170–172 ºC, yield: 62%. IR (ATR) υ: 2987, 2964, 1770, 1690, 1597, 1508, 1428,
1
1375, 1314, 1271, 1136, 1065, 1001, 954, 894, 802, 786 cm-1; H-NMR δ: 2.06–2.16 (m, 2H, H9x
and H9n), 3.05 (s, 3H, N-CH3), 3.48–3.56 (m, 2H, H2 and H6), 3.72 (dd, J = 8.7, 4.8 Hz, H8n), 4.83 (d,

Molecules 2010, 15
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J = 5.8 Hz, 1H, H7), 5.04 (t, J = 5.8 Hz, 1H, H1), 7.36–7.38 (m, 2H, Har), 7.40–7.44 (m, 1H, Har),
7.48–7.51 (m, 1H, Har), 7.66 (d, J = 6.1, 2.9 Hz, 1H, Har), 7.78 (d, J = 8.7 Hz, 1H, Har), 7.86 (d, J = 8.7
Hz, 1H, Har) ppm; 13C-NMR δ: 25.20, 35.22, 39,75, 51.82, 51.83, 78.36, 83.26, 122.92, 123.39,
125.66, 125.93, 126.77, 127.71, 129.23, 131.57, 134.10, 138.74, 175.73, 176.04 ppm; GC-MS m/z:
307 (M+), 167, 152, 112, 68.
N-Methyl-exo-8-(6-chloro-3-pyridinyl)-10-oxabicyclo[2.2.1]heptane-3-exo,5-exo-dicarboximide (12).
Colorless solid, m.p. 202–204 ºC, yield: 41%. IR (ATR) υ: 3060, 2993, 1770, 1688, 1566, 1454, 1433,
1
1381, 1282, 1266, 1130, 1028, 1003, 887, 828, 784 cm-1; H-NMR δ: 1.80 (dt, J = 13.1, 4.8 Hz,
1H, H9x), 2.20 (dd, J = 13.1, 8.7 Hz, 1H, H9n), 2.91 (s, 3H, N-CH3), 2.95 (d, J = 6.8 Hz, 1H,
H2), 2.98 (d, J = 4.8 Hz, 1H, H8n), 3.00 (d, J = 6.8 Hz, 1H, H6), 4.68 (s, 1H, H7), 4.98 (d, J = 5.3
Hz, 1H, H1), 7.22 (s, 1H, Har), 7.53 (dd, J = 8.7, 2.4 Hz, 1H, Har), 8.18 (d, J = 2.4 Hz, 1H, Har) ppm;
13C-NMR δ: 25.38, 40.29, 44.35, 49.86, 50.12, 79.21, 84.51, 124.72, 137.51, 138.74, 148.74, 150.42,
176.43, 176.74 ppm; GC-MS m/z: 292 (M+), 180, 153, 117, 68.
N-Methyl-exo-8-phenyl-10-oxabicyclo[2.2.1]heptane-3-exo,5-exo-dicarboximide (13). Colorless solid,
m.p. 137–138 ºC, yield: 79%. IR (ATR) υ: 3062, 2956, 1768, 1683, 1479, 1431, 1386, 1288, 1136,
1008, 986, 888, 837, 763, 745 cm-1; 1H-NMR δ: 1.89 (dt, J = 12.6, 4.8 Hz, 1H, H9x), 2.15 (dd, J = 12.6,
8.7 Hz, 1H, H9n), 2.90 (s, 3H, N-CH3), 2.91-2.98 (m, 3H, H8n, H2 and H6), 4.72 (s, 1H, H7), 4.93 (d,
13
J = 4.8 Hz, 1H, H1), 7.13–7.17 (m, 3H, Har), 7.19–7.23 (m, 2H, Har) ppm; C-NMR δ: 25.29, 40.29,
47.59, 50.01, 50.43, 79.28, 84.92, 127.06, 127.33, 128.90, 144.30, 176.94, 177.25 ppm; GC-MS m/z:
257 (M+), 157, 117, 68.
N-Methyl-exo-8-(4-chlorophenyl)-10-oxabicyclo[2.2.1]heptane-3-exo,5-exo-dicarboximide
(14).
Colorless solid, m.p. 174–175 ºC, yield: 82%. IR (ATR) υ: 2991, 1770, 1692, 1491, 1432, 1376, 1283,
1
1183, 1131, 1089, 1000, 979, 883, 823, 808, 779 cm-1; H-NMR δ: 1.82 (dt, J = 12.6, 4.8 Hz,
1H, H9x), 2.16 (dd, J = 12.6, 8.7 Hz, 1H, H9n), 2.90 (s, 3H, N-CH3), 2.92 (d, J = 6.8 Hz, 1H,
H2), 2.94 (d, J = 4.8 Hz, 1H, H8n), 2.96 (d, J = 6.8 Hz, 1H, H6), 4.68 (s, 1H, H7), 4.94 (d, J = 4.8 Hz,
1H, H1), 7.10 (d, J = 8.7 Hz, 2H, Har), 7.18 (d, J = 8.7 Hz, 2H, Har) ppm; 13C-NMR δ: 25.32, 40.35,
46.99, 49.95, 50.30, 79.22, 84.80, 128.70, 129.01, 132.91, 142.80, 176.78, 177.06 ppm; GC-MS m/z:
291 (M+), 191, 151, 112, 68.
4. Conclusions
In summary, in the presence of triphenylarsine as a ligand the palladium-catalyzed hydroarylation
of the readily accessible N-substituted tricyclic imides 3, 4 and 5 was shown to be a stereoselective,
versatile and high yield approach to the synthesis of aryl and heteroaryl derivatives of tricyclic imides
6–14. The above approach has been proved very useful for the construction of novel heterocycles of
potential pharmacological interest.
Acknowledgements
We gratefully acknowledge financial support of this work by the Yildiz Technical University
scientific research projects coordination department (Project No. 28-01-02-04).

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