Domino-Heck reactions of carba- and oxabicyclic, unsaturated dicarboximides: Synthesis of aryl-substituted, bridged perhydroisoindole derivatives

Article abstract of DOI:10.1002/hlca.200800388

The C-C coupling of the two bicyclic, unsaturated dicarboximides 5 and 6 with aryl and heteroaryl halides gave, under reductive Heck conditions, the C-aryl-N-phenyl-substituted oxabicyclic imides 7a - c and 8a - c (Scheme 3). Domino-Heck C-C coupling reac

Full text of DOI:10.1002/hlca.200800388

1
092
Helvetica Chimica Acta – Vol. 92 (2009)
Domino-Heck Reactions of Carba- and Oxabicyclic, Unsaturated
Dicarboximides: Synthesis of Aryl-Substituted, Bridged Perhydroisoindole
Derivatives
a
a
a
b
by Cumali Celik ), Irem Kulu ), Nuket Ocal* ), and Dieter E. Kaufmann* )
a) Yildiz Technical University, Faculty of Art and Sciences, Department of Chemistry, Davutpasa
Campus, 34210 Istanbul, Turkey (phone: þ 90-212-3834214; e-mail: nocal@yildiz.edu.tr)
b
)
Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstr. 6,
D-38678 Clausthal-Zellerfeld
The CꢀC coupling of the two bicyclic, unsaturated dicarboximides 5 and 6 with aryl and heteroaryl
halides gave, under reductive Heck conditions, the C-aryl-N-phenyl-substituted oxabicyclic imides 7a – c
and 8a – c (Scheme 3). Domino-Heck CꢀC coupling reactions of 5, 6, and 1b with aryl or heteroaryl
iodides and phenyl- or (trimethylsilyl)acetylene also proved feasible giving 8, 9, and 10a – c, respectively
(
Scheme 4). Reduction of 1b with LiAlH (!11) followed by Heck arylation and reduction of 5 with
4
NaBH (!13) followed by Heck arylation open a new access to the bridged perhydroisoindole
4
derivatives 12a,b and 14a,b with prospective pharmaceutical activity (Schemes 5 and 6).
Introduction. – Due to its broad synthetic potential as a stereoselective CꢀC
coupling method, the Heck reaction has been the subject of several synthetic and
mechanistic studies over the last 30 years [1 – 5]. Originally developed to arylate acyclic
alkenes, the reaction scope has been extended to cyclic compounds later, too. Rigid bi-
and multicyclic systems make the catalytic oxidative Heck-coupling reaction impos-
sible. To circumvent this problem, domino-Heck reactions were introduced with a
hydroarylation reaction as its simplest variant [6 – 8], leading to a reductive CꢀC
coupling reaction. Kaufmann and co-workers have been carrying out new examples of
reductive Heck reactions using bicyclic systems aiming at the synthesis of new
biologically active compounds [9 – 15].
In our previous works, we have accomplished Pd-catalyzed domino-Heck applica-
tions of bi- and tricyclic precursors of epibatidine analogs [16]. We then focused on
reductive Heck reactions of polyfunctional tricyclic molecules with a strained C¼C
bond and an N-(acylamino)imide group [17].
Later, we became interested in the synthesis of bioactive norcantharidin analogues
3
and 4b that represent aryl-modified bicyclic imide systems, too. We had first
synthesized N-phenylbicyclo[2.2.1]hept-5-ene-2-endo,3-endo-dicarboximide (1a) and
N-phenyl-7-oxabicyclo[2.2.1]hept-5-ene-2-exo,3-exo-dicarboximide (1b) as starting
compounds according to [18][19]. We then investigated their hydroarylation reactions
with aryl- and heteroaryl iodides (ArI) in the presence of Ph As giving 2a,b and
3
subsequent reduction reactions by LiAlH to open a new access to perhydroisoindole
4
derivatives 4a,b [20] (Scheme 1). In reductive arylation reactions, Ph As has proved to
3
be superior to Ph P and carbenes as ligands in both selectivity and yield [21].
3
ꢀ
2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 92 (2009)
1093
Scheme 1
Results and Discussion. – We now have prepared N-(4-methoxyphenyl)-7-
1
oxabicyclo[2.2.1]hept-5-ene-2-exo,3-exo-dicarboximide ) (5) and the 4-chlorophenyl
derivative 6 as the starting compounds in good yields (70 and 72%, resp.) [22][23]
(
Scheme 2).
Scheme 2
Treatment of 5 with iodobenzene, 2-iodothiophene, and 2-chloro-5-iodopyridine
under reductive Heck conditions gave the pure products 7a – c after chromatographic
separation on silica gel as single diastereoisomers in isolated yields of 48 – 75%
1)
Trivial atom numbering; for systematic names, see Exper. Part.

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094
Helvetica Chimica Acta – Vol. 92 (2009)
(
Scheme 3). The configuration was inferred from their NMR spectra including
1
diagnostic spin – spin interactions. The exo-position of the C(5) ) substituent was
confirmed by the fact that HꢀC(5) showed no significant interaction with HꢀC(1).
The geminal H-atoms at C(6) were identified by vicinal coupling to HꢀC(1). The Table
1
shows selected H-NMR data of the hydroarylation products 7a – c.
Scheme 3
1
1
Table. Selected H-NMR Data (d in ppm) of Compounds 7a – c )
7a
7b
7c
HꢀC(2)
HꢀC(3)
HꢀC(1)
HꢀC(4)
3.13 (d)
3.17 (d)
5.13 (d)
4.90 (s)
3.11 (d)
3.18 (d)
5.14 (d)
4.91 (s)
3.15 (d)
3.20 (d)
5.16 (d)
4.85 (s)
The same reductive Heck-arylation conditions were successfully applied to the
reaction of 6 with 4-chloro-1-iodobenzene, 1-iodonaphthalene, and 1-iodo-4-methoxy-
benzene to give the new exo-arylated heterocycles 8a – c in good yields after
chromatographic separation (Scheme 3). Again, a characteristic coupling pattern
1
between the bridgehead protons and HꢀC(5) and HꢀC(6) appeared in the H-NMR
1
1
spectra. Additionally, H, H-COSY plots showed cross-peaks between HꢀC(2) and
HꢀC(3) and between HꢀC(5) and HꢀC(6), respectively.
Research in the field of domino reactions is attracting considerable attention in
synthetic organic chemistry since it enables the rapid assembly of complex molecules in
one-pot processes [24]. Very elegant examples of Pd-catalyzed cascade processes

Helvetica Chimica Acta – Vol. 92 (2009)
1095
where a single catalytic cycle entails several sequential bond transformations have
recently been reported [25][26]. In this work, we also would like to describe our results
in the investigations on the Pd-catalyzed domino-Heck-type reactions of 5, 6, and 1b
[
20].
The use of phenylacetylene or (trimethylsilyl)acetylene under domino-Heck
conditions [16][17] provided alkynyl-substituted tricyclic imides 8, 9, and 10a – c
1
1
(
Scheme 4). The structures were assigned by their H, H-COSY and HSQC data.
Scheme 4
13
In addition to the C-NMR and IR spectral data which were in agreement with the
proposed structures, the mass spectra of all new compounds showed the expected
molecular-ion peaks.
The structurally related perhydroisoindoles are selective sigma receptor antagonists
and have a low potential for movement-disorder side effects associated with typical
antipsychotic agents [27][28]. Therefore, we have first reduced N-phenyl-7-oxabicy-
clo[2.2.1]hept-5-ene-2-exo,3-exo-dicarboximide (1b) with LiAlH to obtain 11, fol-
4
lowed by the synthesis of some perhydroisoindoles [20]. As part of our continuing
interest in new perhydroisoindole derivatives, we now prepared 12a and 12b from 11 by
the same Heck-arylation procedure (Scheme 5).
We also tried to reduce compound 5 with an excess of LiAlH in Et O at
4
2
temperatures ranging from 25 to ꢀ 408. After regular workup, the crude product was
purified by column chromatography to obtain exclusively 1-(4-methoxyphenyl)-1H-
pyrrole as the unexpected main product. Therefore, we subsequently reduced 5 with
NaBH in EtOH at ꢀ 218. Regular workup (HCl; column chromatography) gave
4
compound 13 in 84% yield; its spectroscopic data and crystal structure have recently
been reported [29]. Reductive arylation of 13 with 1-iodonaphthalene under Heck

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 5
conditions gave the pure regioisomers 14a and 14b after column chromatography in
yields of 50 and 37%, respectively (Scheme 6). The configuration of the new
1
1
1
compounds was inferred from their H-NMR and H, H-COSY data. First evidence
for the detection of both regioisomers was the observation that HꢀC(7) at d 4.88
1
appeared as a d in the H-NMR spectrum of 14a, while it appeared as a s at d 4.89 for
1
1
1
4b. In the H, H-COSY plot of 14a, interaction between H ꢀC(8) and HꢀC(7) was
exo
clearly seen, but the spectrum of 14b did not show the same coupling due to the 8
-
exo
substituent. The HSQC and MS data were also in agreement with the proposed
structures.
Scheme 6
Conclusions. – In the presence of Ph As as a ligand, the Pd-catalyzed hydro-
3
arylation of the easily accessible tricyclic N-phenyl derivatives of the unsaturated
imides 5 and 6 was proven to be a stereoselective, versatile, and high-yield approach to
the synthesis of aryl and heteroaryl derivatives of heterotricyclic systems. Domino-

Helvetica Chimica Acta – Vol. 92 (2009)
1097
Heck CꢀC coupling reactions with aryl or heteroaryl halides were shown to be feasible
in the presence of (trimethylsilyl)acetylene or phenylacetylene. Our results also
demonstrated that the reductive access to aryl-substituted bridged perhydroisoindole
derivatives will be useful for the construction of novel heterocycles of potential
pharmacological interest.
We gratefully acknowledge financial support of this work by the Yildiz Technical University Scientific
Research Projects Coordination Department (Project No. 26-01-02-04).
Experimental Part
General. All reactions were conducted under N2 and carried out in a Schlenk system. M.p.:
Gallenkamp-melting-point apparatus; uncorrected. Column chromatography (CC): silica gel (SiO ) 60.
2
TLC: SiO -precoated (0.2 mm layer) Al sheets (Merck). IR Spectra: Perkin-Elmer FT-IR spectrometer;
2
ꢀ1
KBr pellets; in cm . NMR Spectra: Bruker-Digital-FT-NMR-Avance (400 MHz) and Varian Inova
500 MHz) spectrometers; CDCl solns.; d in ppm rel. to Me Si as internal standard, J in Hz. MS: Varian-
(
3
4
Saturn-2100T/GC3900 GC/MS spectrometer; FAB ionization; in m/z. Elemental analyses: Thermo-
Flash-EA-1112 elemental analyzer for C, H, N, and S.
Reductive Heck Reactions of 5 and 6: General Procedure. A soln. of [Pd(OAc) ] (5.6 mg,
2
0
.025 mmol) and Ph As (33.7 mg, 0.11 mmol) in anh. DMF or DMSO (3 ml) was stirred under N at 658
3
2
for 15 min. Then, 5 (271 mg, 1 mmol) or 6 (275.5 mg, 1 mmol), Et N (488 ml, 3.5 mmol), the appropriate
3
aryl or heteroaryl iodide (1.5 mmol), and HCOOH (138 mg, 3 mmol) were added. The mixture was
stirred for 8 – 24 h. After cooling to r.t., AcOEt and brine were added. The org. layer was dried (MgSO ),
4
the solvent evaporated, and the residue purified by CC.
N-(4-Methoxyphenyl)-5-exo-phenyl-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-dicarboximide (¼ rel-
(
7
1
3aR,4S,5R,7R,7aS)-Hexahydro-2-(4-methoxyphenyl)-5-phenyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;
a). CC (AcOEt/hexane 3 :2): 7a (63%). Colorless crystals. M.p. 2418. IR: 3085, 3012, 2922, 1709, 1605,
1
512, 1437, 1396, 1254, 1198, 1024, 880, 772, 737. H-NMR (400 MHz): 1.99 – 2.04 (m, HexoꢀC(6)); 2.28
(
dd, J ¼ 8.97, 3.91, H ꢀC(6)); 3.07 (dd, J ¼ 4.88, 3.91, H ꢀC(5)); 3.13 (d, J ¼ 7.02, HꢀC(2)); 3.17 (d,
endo
endo
J ¼ 7.02, HꢀC(3)); 3.81 (s, MeO); 4.90 (s, HꢀC(4)); 5.13 (d, J ¼ 4.86, HꢀC(1)); 6.96 (d, J ¼ 9.28, 2 arom.
13
H); 7.17 (d, J ¼ 8.79, 2 arom. H); 7.23 – 7.32 (m, 5 arom. H). C-NMR (100 MHz): 40.3; 47.7; 50.0; 50.4;
þ.
5
1
3
5.7; 79.8; 85.5; 114.8; 124.6; 127.1; 127.3; 127.9; 128.9; 144.2; 159.9; 176.3; 176.6. MS: 349 (M ), 320, 203,
88, 134, 106, 91, 78. Anal. calc. for C H NO (349.38): C 72.19, H 5.48, N 4.01; found: C 72.23, H 5.47, N
21
19
4
.99.
N-(4-Methoxyphenyl)-5-exo-(2-thienyl)-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-dicarboximide
¼ rel-(3aR,4R,5S,7R,7aS)-Hexahydro-2-(4-methoxyphenyl)-5-(2-thienyl)-4,7-epoxy-1H-isoindole-
,3(2H)-dione; 7b). CC (AcOEt/hexane 1:1): 7b (48%). Colorless crystals. M.p. 1818. IR: 3073, 3011,
925, 1706, 1606, 1589, 1482, 1437, 1394, 1254, 1195, 1025, 827, 709, 693. 1H-NMR: 2.04 – 2.12 (m,
(
1
2
HexoꢀC(6)); 2.29 (dd, J ¼ 8.97, 3.91, H ꢀC(6)); 3.11 (d, J ¼ 7.02, HꢀC(2)); 3.18 (d, J ¼ 7.02, HꢀC(3));
endo
3
.44 (dd, J ¼ 4.88, 3.91, HendoꢀC(5)); 3.82 (s, MeO); 4.91 (s, HꢀC(4)); 5.14 (d, J ¼ 4.86, HꢀC(1)); 6.84 –
13
6
.88 (m, 1 arom. H); 6.92 – 6.99 (m, 3 arom. H); 7.15 – 7.18 (m, 3 arom. H). C-NMR: 40.78; 43.21; 49.66;
þ.
4
9.76; 55.71; 79.7; 85.6; 114.8; 124.2; 124.4; 124.6; 127.0; 127.9; 147.3; 159.9; 176.4; 176.2. MS: 355 (M ),
3
27, 203, 188, 162, 149, 134, 106, 92. Anal. calc. for C H NO S (355.41): C 64.21, H 4.82, N 3.94, S 9.02;
19
17
4
found: C 64.22, H 4.81, N 3.90, S 8.99.
5
-exo-(6-Chloropyridin-3-yl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-dicar-
boximide (¼ rel-(3aR,4S,5R,7R,7aS)-5-(6-Chloropyridin-3-yl)hexahydro-2-(4-methoxyphenyl)-4,7-ep-
oxy-1H-isoindole-1,3(2H)-dione; 7c). CC (AcOEt/hexane 3 :2): 7c (75%). Colorless crystals. M.p.
1
1
928. IR: 3010, 2973, 2840, 1708, 1608, 1584, 1564, 1457, 1444, 1392, 1252, 1192, 1106, 827. H-NMR
(
400 MHz): 1.88 – 1.94 (m, HexoꢀC(6)); 2.33 (dd, J ¼ 8.97, 3.91, H ꢀC(6)); 3.10 (dd, J ¼ 4.88, 3.91,
endo
HendoꢀC(5)); 3.15 (d, J ¼ 7.02, HꢀC(2)); 3.20 (d, J ¼ 7.02, HꢀC(3)); 3.81 (s, MeO); 4.85 (s, HꢀC(4));
5
.16 (d, J ¼ 4.86, HꢀC(1)); 6.97 (d, J ¼ 9.20, 2 arom. H); 7.16 (d, J ¼ 8.80, 2 arom. H); 7.28 (d, J ¼ 8.79, 1
13
arom. H); 7.62 (dd, J ¼ 2.40, 6.00, 1 arom. H); 8.27 (d, J ¼ 2.40, 1 arom. H). C-NMR (100 MHz): 40.1;

1
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Helvetica Chimica Acta – Vol. 92 (2009)
4.1; 49.5; 49.8; 55.5; 79.4; 84.7; 114.5; 124.1; 124.5; 127.6; 137.3; 138.5; 148.5; 150.2; 159.7; 175.7; 176.0.
þ.
MS: 382 (M ), 354, 179, 150, 135, 106, 91. Anal. calc. for C H ClN O (384.81): C 62.42, H 4.45, N 7.28;
20
17
2
4
found: C 62.56, H 4.46, N 7.29.
N,5-exo-Bis(4-chlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-dicarboximide
(¼ rel-
(
3aR,4S,5R,7R,7aS)-2,5-Bis(4-chlorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione; 8a). CC
(
1
AcOEt/hexane 3 :2): 8a (46%). Colorless crystals. M.p. 2198. IR: 3091, 3001, 2959, 1702, 1494, 1409, 1377,
1
180, 1095, 824, 810. H-NMR (400 MHz): 1.92 – 1.98 (m, HexoꢀC(6)); 2.29 (dd, J ¼ 8.97, 3.91,
HendoꢀC(6)); 3.05 (dd, J ¼ 4.88, 3.91, H ꢀC(5)); 3.17 (dd, J ¼ 7.02, 12.48, HꢀC(2), HꢀC(3)); 4.86
endo
(
s, HꢀC(4)); 5.13 (d, J ¼ 4.86, HꢀC(1)); 7.18 – 7.29 (m, 6 arom. H); 7.43 (d, J ¼ 8.58, 2 arom. H).
1
3
C-NMR (125 MHz): 39.1; 45.8; 48.7; 49.1; 78.6; 84.1; 126.7; 127.5; 127.8; 128.4; 129.2; 131.8; 141.4; 174.4,
þ.
1
74.7. MS: 387 (M ), 359, 207, 178, 153, 90. Anal. calc. for C H Cl NO (388.24): C 61.87, H 3.89, N 3.61;
20
15
2
3
found: C 61.87, H 3.90, N 3.63.
N-(4-Chlorophenyl)-5-exo-(naphthalen-1-yl)-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-dicarboximide
¼ rel-(3aR,4S,5R,7R,7aS)-2-(4-Chlorophenyl)hexahydro-5-(naphthalen-1-yl)-4,7-epoxy-1H-isoindole-
(
1
,3(2H)-dione; 8b). CC (AcOEt/hexane 3 :2): 8b (56%). Colorless crystals. M.p. 2288. IR: 3083, 3031,
1
2
990, 2945, 1703, 1598, 1492, 1382, 1202, 1182, 1093, 828 802, 778. H-NMR (400 MHz): 2.01 – 2.07 (m,
HexoꢀC(6)); 2.46 (dd, J ¼ 8.97, 3.91, H ꢀC(6)); 3.27 (d, J ¼ 7.02, HꢀC(2)); 3.35 (d, J ¼ 7.02, HꢀC(3));
endo
3
.88 (dd, J ¼ 4.88, 3.91, H ꢀC(5)); 5.17 (d, J ¼ 4.86, HꢀC(1)); 5.22 (s, HꢀC(4)); 7.22 – 7.27 (m, 1 arom.
endo
H); 7.44 – 7.58 (m, 7 arom. H); 7.75 (d, J ¼ 8.70, 1 arom. H); 7.89 (d, J ¼ 9.36, 1 arom. H); 8.01 (d, J ¼ 8.19,
13
1
1
9
arom. H). C-NMR (100 MHz): 39.9; 42.4; 49.3; 50.5; 80.1; 84.3; 122.9; 123.1; 125.9; 126.0; 126.5; 127.6;
þ.
28.0; 129.4; 129.6; 130.5; 131.3; 134.3; 134.9; 139.4; 175.8; 176.1. MS: 403 (M ), 375, 207, 193, 179, 153,
0. Anal. calc. for C H ClNO (403.86): C 71.38, H 4.49, N 3.47; found: C 71.27, H 4.38, N 3.45.
24
18
3
N-(4-Chlorophenyl)-5-exo-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-dicarboximide
¼ rel-(3aR,4S,5R,7R,7aS)-2-(4-Chlorophenyl)hexahydro-5-(4-methoxyphenyl)-4,7-epoxy-1H-isoin-
dole-1,3(2H)-dione; 8c). CC (AcOEt/hexane 3 :2): 8c (59%). Colorless crystals. M.p. 1698. IR: 3097,
072, 2989, 2836, 1704, 1611, 1582, 1513, 1495, 1406, 1380, 1254, 1176, 1092, 832, 812. 1H-NMR
(
3
(
400 MHz): 1.95 – 2.01 (m, HexoꢀC(6)); 2.27 (dd, J ¼ 8.97, 3.91, H ꢀC(6)); 3.04 (dd, J ¼ 4.88, 3.91,
endo
HendoꢀC(5)); 3.14 (d, J ¼ 7.02, HꢀC(2)); 3.19 (d, J ¼ 7.02, HꢀC(3)); 3.79 (s, MeO); 4.86 (s, HꢀC(4));
5
.12 (d, J ¼ 4.86, HꢀC(1)); 6.84 (d, J ¼ 8.58, 2 arom. H); 7.18 (d, J ¼ 8.58, 2 arom. H); 7.23 (d, J ¼ 8.58, 2
13
arom. H); 7.43 (d, J ¼ 8.58, 2 arom. H). C-NMR (100 MHz): 40.4; 46.9; 50.0; 50.4; 55.5; 79.8; 85.7; 114.3;
þ.
1
27.9; 128.3; 129.6; 130.5; 134.8; 136.4; 158.8; 175.8; 176.1. MS: 383 (M ), 290, 207, 147, 153, 91, 77. Anal.
calc. for C H ClNO (383.82): C 65.71, H 4.73, N 3.65; found: C 65.70, H 4.73, N 3.62.
21
18
4
Domino-Heck Reactions of 5, 6, and 1b: General Procedure. A soln. of [Pd(OAc) ] (5.6 mg,
2
2
5 mmol) and Ph As (55 mmol) in anh. DMF (3 ml) was stirred at 408 for 15 min. Then, 5 (or 6 or 1b)
3
(
1 mmol), the aryl compound (1.5 mmol), Et N (488 ml, 3.50 mmol), and (trimethylsilyl)acetylene or
3
phenylacetylene (3 mmol) were rapidly added in one portion. The mixture was kept at 408 for 24 h. After
cooling to r.t., brine (50 ml) was added, the mixture extracted with AcOEt and dried (MgSO ), the
4
solvent evaporated, and the residue purified by CC.
5
-(4-Chlorophenyl)-N-(4-methoxyphenyl)-6-exo-(phenylethynyl)-7-oxabicyclo[2.2.1]heptane-2-
exo,3-exo-dicarboximide (¼ rel-(3aR,4S,5R,6S,7R,7aS)-5-(4-Chlorophenyl)hexahydro-2-(4-methoxy-
phenyl-6-(2-phenylethynyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione; 8). CC (AcOEt/hexane 3 :1): 8
(
1
47%). Colorless crystals. M.p. 2438. IR: 3046, 3011, 2993, 2838, 1778, 1708, 1608, 1512, 1491, 1442,
396, 1251, 1191, 1035, 756, 692, 677. H-NMR (400 MHz): 3.26 (d, J ¼ 7.02, HꢀC(2)); 3.29 (d, J ¼ 7.02,
1
HꢀC(3)); 3.43 (d, J ¼ 8.80, HendoꢀC(6)); 3.54 (d, J ¼ 8.80, HendoꢀC(5)); 3.86 (s, MeO); 5.13 (s, HꢀC(4));
13
5
.20 (s, HꢀC(1)); 6.96 – 7.03 (m, 4 arom. H); 7.21 – 7.27 (m, 5 arom. H); 7.35 (s, 4 arom. H). C-NMR
(
100 MHz): 42.8; 49.3; 49.6; 52.1; 55.6; 84.5; 85.0; 86.9; 87.0; 114.6; 122.6; 124.2; 127.7; 128.1; 128.2; 128.2;
þ.
1
30.2; 131.3; 133.0; 135.9; 138.2; 159.8; 175.5; 175.6. MS: 483 (M ), 279, 203, 188, 150, 135, 106, 90. Anal.
calc. for C H ClNO (483.94): C 71.97, H 4.58, N 2.89; found: C 61.87, H 3.90, N 3.63.
29
22
4
N-(4-Chlorophenyl)-5-exo-phenyl-6-exo-[2-(trimethylsilyl)ethynyl]-7-oxabicyclo[2.2.1]heptane-2-
exo,3-exo-dicarboximide (¼ rel-(3aR,4S,5R,6S,7R,7aS)-2-(4-Chlorophenyl)hexahydro-5-phenyl-6-[2-
(
trimethylsilyl)ethynyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione; 9). CC (AcOEt/hexane 3 :1): 9 (46%).
Colorless crystals. M.p. 1558. IR: 3066, 3029, 2960, 2898, 2165, 1773, 1708, 1603, 1493, 1456, 1392, 1249,
1
1
192, 1092, 757, 729, 699. H-NMR (400 MHz): 0.08 (s, 3 Me); 3.24 (s, HꢀC(2), HꢀC(3)); 3.33 (d, J ¼

Helvetica Chimica Acta – Vol. 92 (2009)
1099
8
.91, HendoꢀC(6)); 3.37 (d, J ¼ 8.91, H ꢀC(5)); 5.14 (d, J ¼ 2.80, HꢀC(1), HꢀC(4)); 7.26 – 7.33 (m, 7
endo
13
arom. H); 7.41 (d, J ¼ 8.80, 2 arom. H). C-NMR (100 MHz): ꢀ 0.5; 43.0; 49.4; 49.7; 52.4; 84.6; 85.2;
9
1.4; 103.1; 127.1; 127.7; 128.0; 128.9; 129.5; 130.1; 134.8; 139.3; 175.1; 175.2. MS: 399, 242, 179, 153, 91, 74.
-exo-(4-Chlorophenyl)-N-phenyl-exo-[2-(6-trimethylsilyl)ethynyl]-7-oxabicyclo[2.2.1]heptane-2-
5
exo,3-exo-dicarboximide (¼ rel-(3aR,4S,5R,6S,7R,7aS)-5-(4-Chlorophenyl)hexahydro-2-phenyl-6-[2-
(
trimethylsilyl)ethynyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione; 10a). CC (AcOEt/hexane 1:3): 10a
(
1
56%). Colorless crystals. M.p. 2268. IR: 3034, 3015, 2961, 2900, 2161, 1781, 1705, 1598, 1495, 1457,
1
393, 1248, 1188, 843, 738, 705. H-NMR (500 MHz): 0.00 (s, 3 Me); 3.28 (s, HꢀC(2), HꢀC(3)); 3.37 (d,
J ¼ 8.91, H ꢀC(6)); 3.39 (d, J ¼ 8.91, H ꢀC(5)); 5.15 (s, HꢀC(4)); 5.18 (s, HꢀC(1)); 7.31 – 7.36 (m, 5
endo
endo
13
arom. H); 7.49 (d, J ¼ 8.80, 2 arom. H) 7.55 (d, J ¼ 8.80, 2 arom. H). C-NMR (125 MHz): 1.4; 45.0; 51.3;
5
4
1.6; 53.8; 86.5; 86.9; 93.8; 104.7; 129.9; 130.9; 131.1; 131.2; 132.2; 133.8; 134.9; 139.9; 177.0; 177.2. MS:
þ.
49 (M ), 413, 242, 179, 153, 91, 74.
5-exo-(4-Methoxyphenyl)-N-phenyl-6-exo-[2-(trimethylsilyl)ethynyl]-7-oxabicyclo[2.2.1]heptane-2-
exo,3-exo-dicarboximide (¼ rel-(3aR,4S,5R,6S,7R,7aS)-Hexahydro-5-(4-methoxyphenyl)-2-phenyl-6-[2-
(
trimethylsilyl)ethynyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione; 10b). CC (AcOEt/hexane 1:1): 10b
(
1
43%). Colorless crystals. M.p. 1768. IR: 3000, 2996, 2958, 2835, 2185, 1778, 1712, 1613, 1513, 1497,
458, 1387, 1248, 1196, 1179, 845, 710, 695. 1H-NMR (500 MHz): 0.00 (s, 3 Me); 3.26 (s, HꢀC(2),
HꢀC(3)); 3.35 (d, J ¼ 8.80, H ꢀC(6)); 3.39 (d, J ¼ 8.80, H ꢀC(5)); 3.88 (s, MeO); 5.14 (s, HꢀC(4));
endo
endo
5
.17 (s, HꢀC(1)); 6.90 – 6.93 (m, 2 arom. H); 7.30 – 7.36 (m, 3 arom. H); 7.47 – 7.57 (m, 4 arom. H).
13
C-NMR (125 MHz): 0.0; 43.6; 49.8; 50.2; 52.2; 55.7; 85.0; 85.8; 91.7; 103.9; 113.8; 126.9; 129.3; 129.7;
þ.
1
30.4; 132.1; 132.2; 159.2; 175.8; 175.9. MS: 445 (M ), 430, 414, 242, 179, 153, 91, 74.
5-exo-(4-Chlorophenyl)-N-phenyl-6-exo-(2-phenylethynyl)-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-
dicarboximide (¼ rel-(3aR,4S,5R,6S,7R,7aS)-5-(4-Chlorophenyl)hexahydro-2-phenyl-6-(2-phenylethyn-
yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione; 10c). CC (AcOEt/hexane 1:3): 10c (48%). Colorless crystals.
M.p. 2548. IR: 3048, 3018, 2981, 2915, 2835, 2185, 1777, 1703, 1597, 1491, 1456, 1389, 1185, 791, 755, 743.
1
H-NMR (500 MHz): 3.25 (d, J ¼ 7.32, HꢀC(2)); 3.27 (d, J ¼ 7.32, HꢀC(3)); 3.41 (d, J ¼ 8.80,
H
ꢀC(6)); 3.50 (d, J ¼ 8.80, H ꢀC(5)); 5.11 (s, HꢀC(4)); 5.17 (s, HꢀC(1)); 6.92 – 6.95 (m, 2 arom.
endo
endo
13
H); 7.17 – 7.28 (m, 8 arom. H); 7.39 – 7.49 (m, 4 arom. H). C-NMR (125 MHz): 43.1; 49.6; 49.9; 52.3;
8
1
4
4.8; 85.2; 87.0; 87.3; 122.9; 126.7; 128.3; 128.3; 128.4; 129.2; 129.5; 130.4; 131.5; 131.8; 133.3; 138.4; 175.4;
þ.
75.5. MS: 453 (M ), 438, 422, 279, 188, 135, 106, 51. Anal. calc. for C H ClNO (453.92): C 74.09, H
28
20
3
.44, N 3.09; found: C 73.97, H 4.49, N 3.01.
8
-ꢂexoꢃ-(4-Methoxyphenyl)-4-phenyl-10-oxa-4-azatricyclo[5.2.1.02,6]decane (¼ rel-(3aR,4R,5S,7S,
7
1
1
2
3
aS)-Octahydro-5-(4-methoxyphenyl)-2-phenyl-4,7-epoxy-1H-isoindole; 12a). CC (AcOEt/hexane
:3): 12a (48%). Colorless crystals. M.p. 1678. IR: 3052, 2999, 2978, 2967, 2886, 2829, 1596, 1507, 1470,
370, 1246, 1175, 1031, 829, 752, 693. H-NMR (500 MHz): 1.75 (ddd, J ¼ 12.20, 10.25, 4.88, HꢀC(9));
1
.08 (dd, J ¼ 8.78, 12.20, HꢀC(9)); 2.67 – 2.74 (m, HꢀC(2), HꢀC(6)); 2.85 – 2.98 (m, 1 CH N, HꢀC(8));
2
.66 – 3.72 (m, 1 CH N); 3.77 (s, MeO); 4.26 (s, HꢀC(7)); 4.52 (d, J ¼ 5.36, HꢀC(1)); 6.62 (d, J ¼ 8.79, 2
2
13
arom. H); 6.70 (d, J ¼ 7.32, 1 arom. H); 6.81 (d, J ¼ 8.79, 2 arom. H); 7.18 – 7.23 (m, 4 arom. H). C-NMR
(
125 MHz): 40.4; 46.9; 47.9; 48.4; 53.6; 53.8; 55.3; 80.8; 87.2; 113.6; 113.9; 116.9; 128.2; 129.0; 138.3; 148.4;
þ.
1
4
58.1. MS: 321 (M ), 306, 244, 214, 138, 106, 77. Anal. calc. for C H NO (321.41): C 78.47, H 7.21, N
21
23
2
.36; found: C 78.54, H 7.16, N 4.38.
8
-ꢂexoꢃ-(Naphthalen-1-yl)-4-phenyl-10-oxa-4-azatricyclo[5.2.1.02,6]decane (¼ rel-(3aR,4R,5S,7S,
7
1
1
8
aS)-Octahydro-5-(naphthalen-1-yl)-2-phenyl-4,7-epoxy-1H-isoindole; 12b). CC (AcOEt/hexane 1:8):
2b (54%). Colorless crystals. M.p. 2118. IR: 3041, 2982, 2952, 2899, 2815, 1596, 1504, 1475, 1365, 1332,
1
214, 1174, 786, 755, 693. H-NMR (500 MHz): 1.85 (ddd, J ¼ 12.20, 10.25, 4.88, HꢀC(9)); 2.27 (dd, J ¼
.78, 12.20, HꢀC(9)); 2.81 – 2.92 (m, HꢀC(2), HꢀC(6)); 2.99 – 3.03 (m, CH N); 3.70 – 3.78 (m, CH N,
2
2
HꢀC(8)); 4.58 (d, J ¼ 5.36, HꢀC(1)); 4.61 (s, HꢀC(7)); 6.65 (d, J ¼ 7.80, 2 arom. H); 6.73 (d, J ¼ 7.32,
1
arom. H); 7.23 (d, J ¼ 7.30, 2 arom. H); 7.42 – 7.54 (m, 3 arom. H); 7.58 (d, J ¼ 6.84, 1 arom. H); 7.71 (d,
13
J ¼ 8.30, 1 arom. H); 7.85 (d, J ¼ 7.80, 1 arom. H); 8.07 (d, J ¼ 8.30, 1 arom. H). C-NMR (125 MHz):
3
1
8
9.5; 42.0; 48.2; 48.6; 53.7; 53.8; 55.3; 81.1; 85.7; 113.6; 116.9; 123.0; 123.1; 125.4; 125.9; 126.6; 129.0;
þ.
29.1; 131.4; 133.9; 141.1. 148.4. MS: 341 (M ), 214, 152, 97, 77. Anal. calc. for C24
H
23NO (341.45): C
4.42, H 6.79, N 4.10; found: C 84.52, H 6.78, N 4.11.

1
100
Helvetica Chimica Acta – Vol. 92 (2009)
5
-Hydroxy-4-(4-methoxyphenyl)-9-ꢂexoꢃ-(naphthalen-1-yl)-10-oxa-4-azatricyclo[5.2.1.02,6]decan-3-
one (¼ rel-(3aR,4S,6S,7R,7aS)-Octahydro-3-hydroxy-2-(4-methoxyphenyl)-6-(naphthalen-1-yl)-4,7-ep-
oxy-1H-indol-1-one; 14a). CC (AcOEt/hexane 3 :2): 14a (38%). Colorless crystals. M.p. 1998. IR:
3
391, 3011, 2995, 2956, 2833, 1674, 1655, 1611, 1516, 1445, 1416, 1337, 1255, 1181, 1079, 828, 802, 778.
1
H-NMR (400 MHz, (D )DMSO): 1.62 – 1.68 (m, H ꢀC(8)); 2.38 (dd, J ¼ 9.19, 2.73, H
ꢀC(8));
6
ꢀexoꢁ
ꢀendoꢁ
3
.34 (d, HꢀC(2), HꢀC(6) with DMSO); 3.75 (s, MeO); 3.94 (dd, J ¼ 4.88, 3.91, HꢀendoꢁꢀC(9)); 4.69 (s,
HꢀC(1)); 4.88 (d, J ¼ 4.86, HꢀC(7)); 5.33 (d, J ¼ 8.41, HꢀC(5)); 6.45 (d, J ¼ 8.60, OH); 6.94 (d, J ¼ 8.90,
2
arom. H); 7.42 (d, J ¼ 8.90, 2 arom. H); 7.45 – 7.59 (m, 4 arom. H); 7.76 (d, J ¼ 8.80, 1 arom. H); 7.92 (d,
13
J ¼ 9.19, 1 arom. H); 8.20 (d, J ¼ 8.21, 1 arom. H). C-NMR (100 MHz, (D )DMSO): 39.5; 41.0; 49.5;
6
5
1
3
1.8; 55.2; 80.5; 83.2; 87.6; 113.7; 123.0; 123.5; 125.0; 125.6; 126.0; 126.4; 128.6; 130.5; 131.0; 133.4; 140.9;
þ.
56.9; 172.2. MS: 400 (M ), 205, 190, 189, 154, 67. Anal. calc. for C H NO (401.45): C 74.79, H 5.77, N
25
23
4
.49; found: C 74.78, H 5.78, N 3.53.
5
-Hydroxy-4-(4-methoxyphenyl)-8-ꢂexoꢃ-(naphthalen-1-yl)-10-oxa-4-azatricyclo[5.2.1.02,6]decan-3-
one (¼ rel-(3aR,4S,5R,7R,7aS)-Octahydro-3-hydroxy-2-(4-methoxyphenyl)-5-(naphthalen-1-yl)-4,7-ep-
oxy-1H-indol-1-one; 14b). CC (AcOEt/hexane 3 :2): 14b (50%). Colorless crystals. M.p. 2078. IR:
3
245, 3011, 2991, 2973, 2937, 2845, 1655, 1595, 1510, 1458, 1446, 1394, 1252, 1179, 1074, 806, 765, 737.
1
H-NMR (400 MHz, (D )DMSO): 1.67 – 1.72 (m, H ꢀC(9)); 2.43 (dd, J ¼ 9.19, 2.73, H
ꢀC(9));
6
ꢀexoꢁ
ꢀendoꢁ
2
H
.67 (d, J ¼ 7.82, HꢀC(6)); 3.14 (d, J ¼ 7.62, HꢀC(2)); 3.75 (s, MeO); 3.87 (dd, J ¼ 9.19, 2.73,
ꢀC(8)); 4.76 (d, J ¼ 4.86, HꢀC(1)); 4.89 (s, HꢀC(7)); 5.35 (d, J ¼ 8.41, HꢀC(5)); 6.44 (d, J ¼ 8.60,
ꢀendoꢁ
OH); 6.95 (d, J ¼ 8.80, 2 arom. H); 7.42 (d, J ¼ 8.80, 2 arom. H); 7.45 – 7.60 (m, 4 arom. H); 7.78 (d, J ¼
13
7
.62, 1 arom. H); 7.93 (d, J ¼ 7.62, 1 arom. H); 8.20 (d, J ¼ 8.21, 1 arom. H). C-NMR (100 MHz,
(
D )DMSO): 39.4; 41.6; 50.1; 52.4; 55.7; 79.2; 85.3; 88.0; 114.2; 124.1; 125.5; 126.5; 126.8; 129.1; 131.0;
6
þ.
1
31.5; 133.9; 141.4; 157.3; 172.8. MS: 400 (M ), 206, 190, 189, 154, 67. Anal. calc. for C H NO (401.45):
25
23
4
C 74.79, H 5.77, N 3.49; found: C 74.78, H 5.77, N 3.51.
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Received October 25, 2008