Effect of ring size on the Exo/Endo selectivity of a thermal double cycloaddition of fused pyran-2-ones

Article abstract of DOI:10.1021/jo9011199

(Chemical Equation Presented) A study of an unusual effect of the size of the ring fused to 2H-pyran-2-ones on the exo/endo selectivity of a thermal double cycloaddition of N-substituted maleimides or maleic anhydride yielding bicyclo[2.2.2]octene derivat

Full text of DOI:10.1021/jo9011199

pubs.acs.org/joc
applied, benz[e]isoindoles2d have been prepared. However,
Effect of Ring Size on the Exo/Endo Selectivity
of a Thermal Double Cycloaddition of Fused
Pyran-2-ones
so far all of these bicyclo[2.2.2]octenes obtained in thermal
cycloadditions were of the type containing a plane of sym-
metry (exo,exo).3 Such symmetrical exo,exo products arise
through the following pathway: in the first cycloaddition
step (which can take place either as an exo or endo4 process)
two enantiomeric pairs of different CO2-bridged adducts 3
are produced. The next step involves the retro-Diels-Alder
elimination of CO2 (which includes the loss of one asymme-
try element) and yields just a single enantiomeric pair of the
cyclohexadiene intermediate 4. In the second cycloaddition
step (again either exo or endo, but in this case additionally
also anti or syn5) 4 can be transformed via four enantiomeric
pairs of transition states into the following possible products:
an enantiomeric pair of unsymmetrical products (exo,endo)
and two different symmetrical products (i.e., exo,exo 5 and
endo,endo), each of the latter two being a meso compound
(Scheme 1, not taking into account the dynamic asymmetry
caused by the fused cycloalkene ring). Nevertheless, we were
curious to see whether it would be possible to modify the
starting fused pyran-2-ones in such a way that the second
attack would take place differently, leading to products
without a plane of symmetry. With this goal in mind, we
embarked on a comparative investigation of the cycoaddi-
tions of a set of pyran-2-ones 16 with fused rings of different
sizes (6- to 8-membered rings) anticipating that an eight-
membered ring, with one of its preferred boat conforma-
tions,7 should provide the appropriate steric effects.
Initially, we carried out the reactions under conventional
heating conditions in refluxing toluene; however, in some
cases higher temperatures were needed, and so we applied
decalin (bp 189-191 °C) or tetralin (bp 207 °C). We found
that this was an appropriate way to obtain the products 5,6
(Schemes 1 and 2, Table 1, entries 1-7, 11, and 13), but
unfortunately the reaction times were rather long and the
yields a little low, due to isolation complications.
The structural elucidation of the prepared bicyclo[2.2.2]-
octenes 5,6 indeed showed that when starting from 1A,B the
cycloadducts obtained with all the investigated dienophiles
have a symmetric exo,exo structure 5A,B. Only when starting
from 1C, where the ring fused to the pyran-2-one was eight
membered, did the cycloadditions with 2a-c proceed via a
different stereocourse, providing the other type of bicyclo
products, i.e., those with the asymmetric exo,endo structure 6.
To improve our control of the reaction parameters, in
particular the temperature, and to simplify the isolation
ꢀ
Kristof Kranjc,* Franc Perdih, and Marijan Kocevar*
ꢀ
Faculty of Chemistry and Chemical Technology, University of
ꢀ ꢀ
Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia
kristof.kranjc@fkkt.uni-lj.si; marijan.kocevar@fkkt.uni-lj.si
Received May 27, 2009
A study of an unusual effect of the size of the ring fused to
2H-pyran-2-ones on the exo/endo selectivity of a thermal
double cycloaddition of N-substituted maleimides or
maleic anhydride yielding bicyclo[2.2.2]octene deriva-
tives is presented. With subtle variations of starting
compounds and reaction conditions exclusively exo,exo
or exo,endo products can be prepared.
The Diels-Alder reaction, as a special case of cycloaddi-
tions, is a well-established method for constructing new C-C
bonds.1 In a continuation of investigations on such reactions
with a variety of 2H-pyran-2-ones and their fused derivatives
containing a protected 3-amino group their potential use as
dienes was demonstrated.2 In such reactions maleic anhy-
dride2c and N-substituted maleimides2d-g proved to be of
special interest, yielding symmetrical, double cycloadducts
containing the bicyclo[2.2.2]octene core or, alternatively,
when a suitable dehydrogenation agent (e.g., Rh/C) was
*To whom correspondence should be addressed. Fax: þ386 (0) 1 2419220.
Phone: þ386 (0) 1 2419260.
(1) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
(3) (a) Kende, A. S.; Lan, J.; Arad, D. Tetrahedron Lett. 2002, 43, 5237–
ꢀ
ꢁ
G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (b) Marko, I. E.; Evans, G. R.;
Seres, P.; Chelle, I.; Janousek, Z. Pure Appl. Chem. 1996, 68, 113–122.
5239. (b) Hren, J.; Polanc, S.; Kocevar, M. ARKIVOC 2008, i, 209–231.
ꢁ
(4) Endo addition involves the tendency for dienophile substituents to be
so oriented in the favored transition state that they lie directly above the
residual unsaturation of the diene (see: Martin, J. G.; Hill, R. K. Chem. Rev.
1961, 61, 537–562).
(5) Syn being defined as an attack from the same side of the diene system
as the previously incorporated dienophile ring is located. Conversely, anti
means from the other side.
(2) (a) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetra-
hedron 1992, 48, 9111–9171.(b) Woodard, B. T.; Posner, G. H. In Advances
in Cycloaddition; Harmata, M., Ed.; JAI: Greenwich, CT, 1999; Vol. 5, pp 47-83.
(c) Kranjc, K.; Leban, I.; Polanc, S.; Kocevar, M. Heterocycles 2002, 58, 183–
190. (d) Kranjc, K.; Polanc, S.; Kocevar, M. Org. Lett. 2003, 5, 2833–2836. (e)
ꢀ
ꢀ
ꢀ
Kranjc, K.; Kocevar, M.; Iosif, F.; Coman, S. M.; Parvulescu, V. I.; Genin, E.;
^
ꢂ
(6) For the synthesis of the starting compounds 1, see: Pozgan, F.;
Genet, J.-P.; Michelet, V. Synlett 2006, 1075–1079. (f) Tolmachova, N. A.; Gerus,
I. I.; Vdovenko, S. I.; Essers, M.; Frohlich, R.; Haufe, G. Eur. J. Org. Chem. 2006,
€
ꢀ
ꢀ
Kranjc, K.; Kepe, V.; Polanc, S.; Kocevar, M. ARKIVOC 2007, 8, 97–111.
4704–4709. (g) Kranjc, K.; Kocevar, M. Heterocycles 2007, 73, 481–491.
(7) (a) Anet, F. A. L. Top. Curr. Chem. 1974, 45, 169–220. (b) Romines,
K. R.; Morris, J. K.; Howe, W. J.; Tomich, P. K.; Horng, M.-M.; Chong,
K.-T.; Hinshaw, R. R.; Anderson, D. J.; Strohbach, J. W.; Turner, S. R.;
Mizsak, S. A. J. Med. Chem. 1996, 39, 4125–4130.
ꢀ
(h) Kranjc, K.; Kocevar, M. Bull. Chem. Soc. Jpn. 2007, 80, 2001–2007.
ꢀ
ꢀ
(i) Kranjc, K.; Kocevar, M. Tetrahedron 2008, 64, 45–52. (j) Kranjc, K.; Kocevar,
M. Synlett 2008, 2613–2616.
DOI: 10.1021/jo9011199
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 6303–6306 6303
2009 American Chemical Society

Kranjc et al.
JOCNote
SCHEME 1. General Pathway of Cycloadditions Yielding the Sy-
mmetrical Exo,Exo Products 5
TABLE 1. Reaction Conditions and Yields for the Synthesis of 5-7
starting compounds
entry
1
n
2
X
product structure t/h yield (%)a
5Aa exo,exo
0.5b 67
exo,exo 9c
62
exo,exo
2.5c 61
exo,exo 3c
1
2
3
4
5
6
7
8
9
1A
1A
1A
1A
1B
1B
1C
1C
1C
1
1
1
1
2
2
3
3
3
3
3
3
3
3
3
3
2a NPh
2b NMe 5Ab
2c
2d NH
2b NMe 5Bb
2d NH
2a NPh
2a NPh
2a NPh
2a NPh
2b NMe 6Cb
2b NMe 6Cb
2c
2c
2e
2e
NEt
5Ac2d
5Ad
65
exo,exo
exo,exo
2.5c 78
3.25c 75
5Bd
6Ca
exo,endo 4b
77
6Ca:5Ca
6Ca:5Ca
6Ca
0.1d,e 1:0.35
0.5d,e 1:0.35
10 1C
11 1C
12 1C
13 1C
14 1C
15 1C
16 1C
exo,endo 1.5e,f 90
exo,endo 6b
exo,endo 1.5f,g 86
exo,endo 4b
82
exo,endo 1.5f,g 92
exo,exo
0.5h 68
1i
89
71
NEt
NEt
O
6Cc
6Cc
5Ce
7Ce
O
SCHEME 2. Cycloaddition on Pyran-2-One with a Fused Eight-
Membered Ring Yielding Either the Exo,Endo (6) or Exo,Exo (5)
Products
c
aYield of isolated products. bReflux in decalin. Reflux in toluene.
dMicrowave irradiation in a closed vessel (10 mL) at 100 °C. eWith the
addition of 100 mg (1.1 mmol) of toluene. fThe same as d, only at 180 °C.
gAt 180 °C and with the addition of 100 mg (1.35 mmol) of butan-1-ol.
hReflux in tetralin. iThe same as d, only at 200 °C.
FIGURE 1. Two different forms of the intermediate 4Ca-c (each
exists as a pair of enantiomers).
for the preparation of 6Cb and 6Cc (Table 1, entries 12
and 14). Additionally, irradiation of the pure adduct 5Ca (of
the exo,exo structure) at 220 °C for 3 h yielded, with a
complete conversion, the exo,endo product 6Ca (accompa-
nied by a small amount of the aromatized product 7Ca).
The number of intermediates and transition states in the
cycloaddition pathway starting from 1C is doubled in com-
parison with the case described above for 1A,B, because 1C
contains an eight-membered ring, adding an element of
dynamic asymmetry. Therefore, the first cycloaddition step
can produce four enantiomeric pairs of the CO2-bridged
systems 3C, which are, after the elimination of CO2, trans-
formed into two enantiomeric pairs of the cyclohexadiene
intermediates 4C (termed T- and C-type,9 Figure 1). It is
worth pointing out that with the flipping of the eight-
membered ring some of these isomers can interconvert.
The second cycloaddition step can subsequently take place
via eight enantiomeric pairs of transition states. It is impor-
tant to note that the endo-anti attack is the only possible
pathway leading to a symmetric exo,exo product. This
attack, of course, can happen either on the T-4C or C-4C;
however, on the basis of sterical hindrances evident in such
an attack on the T-4C it is, energetically speaking, exceed-
ingly demanding. The most probable possibility for obtain-
ing the exo,exo product 5C is therefore via C-4C, whereas
procedure as a consequence of circumventing the use of high-
boiling-point solvents, we decided to investigate some of
these transformations as neat reactions under microwave-
irradiation conditions.8 As the model reaction, a mixture of
the starting pyran-2-one 1C and N-phenylmaleimide (2a) in
the molar ratio 1:2.2 together with a minor amount of
toluene (100 mg) indeed provided the desired exo,endo
adduct 6Ca; however, after a short irradiation time (1-
30 min) at 100 °C there was also an appreciable amount
(30-40%) of another product detected in the crude reaction
mixture (Scheme 2, Table 1, entries 8 and 9). We surmised
that this secondary product might be the symmetrical
exo,exo adduct 5Ca (as was proved in subsequent experi-
ments, see below). To obtain the pure adduct 6Ca and to
circumvent the appearance of the product 5Ca it was neces-
sary to irradiate the reaction mixture of 1C and 2a for a
longer time (90 min) and at a higher temperature (180 °C)
(Table 1, entry 10). Analogous conditions were appropriate
(8) (a) Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Weinheim, Germany, 2002. (b) Hayes, B. L. Microwave Synthesis: Chemistry
€
at the Speed of Light; CEM: Matthews, NC, 2002. (c) Lidstrom, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–9283. (d) de la Hoz, A.;
Díaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 164–178. (e) Martelanc,
M.; Kranjc, K.; Polanc, S.; Kocevar, M. Green Chem. 2005, 7, 737–741.
(f) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563–2591. (g) Polshetti-
war, V.; Varma, R. S. Chem. Soc. Rev. 2008, 37, 1546–1557. (h) Kappe, C. O.;
Dallinger, D. Mol. Diversity 2009, 13, 71–193.
ꢀ
(9) The C-form (cisoid) of the intermediate 4C is defined as the one where
the ring of dienophile is on the same side of the diene system as the
cyclooctene ring is bent to. In the T-form (transoid) one ring is on the
opposite side. See Figure 1.
6304 J. Org. Chem. Vol. 74, No. 16, 2009

Kranjc et al.
JOCNote
SCHEME 3. Preparation of the Aromatized Cycloadduct 7Ce
T-4C reacts via another, energetically favorable possibility
(probably via endo-syn attack), into the unsymmetrical exo,
endo product 6C. It is appropriate to assume that 6C is
thermodynamically more stable than 5C (by approximately
5.6 kcal/mol, according to AM1 and PM3);10 5C therefore
represents the kinetically favored product, thus corroborat-
ing the experimental results (Table 1, entries 8-10). How-
ever, in the case when six- or seven-membered rings are fused
to the pyran-2-one (i.e., 1A and 1B) the thermodynamically
more stable products according to AM1 and PM3 calcula-
tions are the symmetrical exo,exo 5A and 5B (and not exo,
endo 6A and 6B as in the previous case) by approximately 4.9
and 3.2 kcal/mol, respectively.
The cycloadditions of maleic anhydride (2e) with 1A,B,
having a six- or seven-membered ring fused to pyran-2-one,
were already investigated, and were found to yield the
symmetrical exo,exo adducts (5Ae and 5Be).2c On the other
hand, we expected that with the eight-membered fused
pyran-2-one 1C the asymmetric exo,endo adduct would be
obtained (6Ce). However, it turned out that in this case we
obtained exclusively the symmetrical exo,exo product 5Ce
(Scheme 2, Table 1, entry 15).
The adduct 5Ce can be easily transformed with aniline
under microwave irradiation (1.25 h, 160 °C) into the
derivative 5Ca, having significantly different spectroscopic
properties than 6Ca, and thus evidently being its stereoiso-
mer. Product 5Ca, obtained in this way, was used as a
comparison with the side product of the microwave-irra-
diated reaction between 1C and 2a (Table 1, entries 8 and 9),
thus unequivocally proving that the side product in these
cases was indeed the symmetrical exo,exo adduct 5Ca.11
On the other hand, when a neat mixture of 1C and maleic
anhydride (2e) was irradiated with microwaves at a higher
temperature and for a longer time (Scheme 3, Table 1, entry
16), the product obtained was the aromatized cycloocta[e][2]-
benzofuran 7Ce and not the exo,endo double adduct 6Ce, as
one might expect. Obviously, under such severe conditions
the aromatization12 of 4Ce becomes the preferred path.
Unfortunately, all our attempts so far to produce an exo,
endo product 6Ce have proved to be futile.
integrated as 2 H at 2.92-3.59 (9b-H/10-H, 10b-H/11-H,
and 11b-H/12-H for six-, seven-, and eight-membered rings,
respectively) and 4.10-4.57 (3a-H/14-H, 3a-H/15-H, and 3a-
H/16-H for six-, seven-, and eight-membered rings, respec-
tively), were observed, belonging to the four aliphatic pro-
tons of the bicyclo[2.2.2]octene skeleton,13 thus implying the
symmetric structure. For the exo,endo structures 6, on the
other hand, for the same aliphatic protons of the bicyclo-
[2.2.2]octene skeleton four sets of doublets (each integrated
as 1 H) were observed at 2.69-3.18 and 3.37-4.66 for 3a-H/
11b-H and 12-H/16-H, respectively, clearly showing that
these are no longer symmetric. The coupling constant for
the two sets of protons is also markedly different: for the set
of protons 3a-H/11b-H (which are endo to the double bond)
it is 7.4-8.0 Hz, whereas for the other set of protons 12-H/
16-H (which are exo to the double bond) it is 9.9-10.4 Hz. It
is of interest to note that 5Ce gives a symmetric spectrum
(exactly like the other products 5), proving that the dynamics
on the NMR time scale of the eight-membered ring in
solution at room temperature is fast. The loss of symmetry
between the two types of products (5 vs. 6) can also be
concluded after an analysis of the 13C NMR spectra. The
definitive answer regarding the correct stereo structure of the
presented bicyclo[2.2.2]octenes, however, was obtained from
the X-ray diffraction studies (see Figures 1 and 2 in the
Supporting Information), which clearly confirmed the con-
clusions drawn from the NMR studies.
The presented results are very interesting, as it was not
possible to anticipate (at least not from previous literature
reports) that the interplay between the size of the ring (1A,B
vs. 1C), the type and size of the substituent on the cyclic
dienophile 2 (NR1 vs. O), and the stabilities of products would
have such a strong effect on the stereo outcome of these
thermal cycloadditions. Similar exo,endo products were so
far obtained only under photochemical conditions;14 how-
ever, an effect of the structure of the starting compounds on
the stereo outcome of the cycloaddition was not reported;
only the effects of various reaction conditions were presented.
In our future research we will try to elucidate in detail the
reasons for this unusual phenomenon and, with appropri-
ate calculation methods, provide a further insight into our
simple, qualitative explanation described above. In this way
we might be able to anticipate additional reactions of this
type.
The difference between the two types of structures, 5 and 6,
could be relatively easily inferred from the 1H and 13C NMR
spectra. For the exo,exo structures 5, in the 1H NMR
spectrum two sets of doublets (J = 8.0-8.6 Hz), each
(10) Frisch, M. J.; et al. et al. Gaussian 03, Revision B.03; Gaussian, Inc.,
Wallingford, CT, 2004.
(11) According to AM1 and PM3 calculations, exo,endo adduct 6Ce is
thermodinamcally more stable than exo,exo adduct 5Ce by approximately 5
kcal/mol. Therefore, this process seems to take place under kinetic control
yielding the adduct via the endo,anti attack.
(12) Aromatization takes place via the transfer of hydrogen to the 2e,
thus forming succinic anhydride (for a related case forming substituted
succinimides from maleimides, as observed previously, see ref 2d).
(13) Numbering sequences for compounds 5Aa, 5Bb, and 6Ca are the
following:
Experimental Section15
Microwave-Assisted Synthesis of the Products 6 and 7. A
mixture of the starting fused pyran-2-one 1 (1 mmol) and
(14) (a) Obata, T.; Shimo, T.; Yoshimoto, S.; Somekawa, K.;
Kawaminami, M. Chem. Lett. 1999, 181–182. (b) Shimo, T.; Matsushita,
M.; Omar, H. I.; Somekawa, K. Tetrahedron 2005, 61, 8059–8064.
(15) For the other general experimental details and characterization data
for all synthesized compounds, see the Supporting Information.
J. Org. Chem. Vol. 74, No. 16, 2009 6305

Kranjc et al.
JOCNote
dienophile 2 (2.2 mmol) with the addition of a liquid additive
(100 mg; toluene (1.1 mmol) or butan-1-ol (1.35 mmol)) or
alternatively without (in the case of synthesis of 7) was irradiated
in the focused microwave equipment for the specified time
(Table 1). The final temperature was set to 180 °C (or 200 °C
in the case of 7), the power to 150 W (or 100 W in the case of 7),
and the ramp time to 5 min. Thereafter, the reaction mixture was
cooled to room temperature and the volatile components were
removed in vacuo, the remaining solid was treated with a
minimal amount of EtOH/H2O (1 mL) and then it was cooled
in a refrigerator. The precipitated product was filtered off and
washed with EtOH/H2O.
131.8, 134.3, 147.5, 167.4, 175.1, 175.2, 176.1, 176.3 (1 signal is
hidden); MS-EI m/z 475 (Mþ, 1%), 105 (100). Anal. Calcd for
C27H29N3O5: C, 68.19; H, 6.15; N, 8.84. Found: C, 67.98; H,
6.33; N, 8.80.
N-[rel-(3aR,11bS,12S,16R)-2,14-Diethyl-2,3,3a,6,7,8,9,10,
11,11b,13,14,15,16-tetradecahydro-1,3,13,15-tetraoxo-12H-
4,11a[30,40]-endo-pyrrolocyclooct[e]isoindol-4(1H)-yl]benzamide
(6Cc): yield 461 mg (92%), mp 233-236 °C (EtOH); IR (KBr) ν
1766, 1699, 1667, 1523 cm-1 1H NMR (300 MHz, CDCl3)
;
δ (ppm) 1.05 (t, J=7.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H), 1.40 (m,
2H), 1.53 (m, 2H), 1.65 (m, 2H), 1.88 (m, 1H), 2.03 (m, 1H),
2.19 (m, 2H), 2.39 (m, 1H), 2.72 (m, 1H), 2.69 (d, J=8.0 Hz,
1H), 2.76 (d, J=8.0 Hz, 1H), 3.37 (d, J=10.2 Hz, 1H), 3.45 (q,
J=7.2 Hz, 2H), 3.54 (q, J=7.2 Hz, 2H), 4.42 (d, J=10.2 Hz,
N-[rel-(3aR,11bS,12S,16R)-2,3,3a,6,7,8,9,10,11,11b,13,14,15,
16-Tetradecahydro-1,3,13,15-tetraoxo-2,14-diphenyl-12H-4,11a[30,
40]-endo-pyrrolocyclooct[e]isoindol-4(1H)-yl]benzamide (6Ca):13
yield 540 mg (90%), mp 254-256 °C (EtOH); IR (KBr) ν 1774,
1H), 6.07 (s, 1H), 7.51 (m, 3H), 7.94 (m, 2H), 8.02 (s, 1H); 13
C
NMR (75.5 MHz, CDCl3) δ (ppm) 12.9, 13.0, 25.7, 26.2, 26.3,
29.0, 30.8, 31.6, 33.7, 33.9, 42.8, 44.1, 44.6, 44.8, 47.1, 57.5,
127.2, 128.7, 130.8, 131.8, 134.4, 147.4, 167.4, 174.9, 175.0,
175.8, 176.1; MS-EI m/z 503 (Mþ, 3%), 105 (100). Anal. Calcd
for C29H33N3O5: C, 69.17; H, 6.60; N, 8.34. Found: C, 69.12;
H, 6.41; N, 8.47.
1
1715, 1665, 1533 cm-1; H NMR (300 MHz, CDCl3) δ (ppm)
1.45 (m, 1H), 1.59 (m, 4H), 1.74 (m, 1H), 1.92 (m, 1H), 2.07 (m,
1H), 2.41 (m, 3H), 2.85 (m, 1H), 3.10 (d, J=7.9 Hz, 1H), 3.18 (d,
J=7.9 Hz, 1H), 3.63 (d, J=10.4 Hz, 1H), 4.66 (d, J=10.4 Hz,
1H), 6.29 (s, 1H), 7.12 (m, 2H), 7.28 (m, 2H), 7.44 (m, 9H), 7.90
(m, 2H), 8.05 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
25.7, 26.2, 26.3, 28.9, 31.0, 31.6, 43.1, 44.2, 44.7, 45.0, 47.5, 57.7,
126.1, 126.2, 127.1, 128.6, 128.9, 129.2, 129.3, 131.0, 131.1,
131.3, 131.8, 134.2, 147.8, 167.5, 174.0, 174.1, 174.9, 175.4 (1
signal is hidden); MS-EI m/z 599 (Mþ, 1%), 105 (100). Anal.
Calcd for C37H33N3O5: C, 74.11; H, 5.55; N, 7.01. Found: C,
73.90; H, 5.47; N, 7.04.
Acknowledgment. We thank the Ministry of Higher Edu-
cation, Science and Technology of the Republic of Slovenia
and the Slovenian Research Agency for financial support
ꢂ
(P1-0230-0103 and P1-0175). Dr. B. Kralj and Dr. D. Zigon
ꢂ
(Center for Mass Spectroscopy, “Jozef Stefan” Institute,
Ljubljana, Slovenia) are gratefully acknowledged for the
mass measurements.
N-[rel-(3aR,11bS,12S,16R)-2,3,3a,6,7,8,9,10,11,11b,13,14,15,
16-Tetradecahydro-2,14-dimethyl-1,3,13,15-tetraoxo-12H-4,11a-
[30,40]-endo-pyrrolocyclooct[e]isoindol-4(1H)-yl]benzamide (6Cb):
yield 410 mg (86%), mp 285-286 °C (EtOH); IR (KBr) ν
1767, 1699, 1668, 1528 cm-1; 1H NMR (300 MHz, DMSO-d6)
δ (ppm) 1.29 (m, 2H), 1.48 (m, 3H), 1.68 (m, 2H), 1.97 (m, 2H),
2.19 (m, 2H), 2.78 (m, 1H), 2.74 (s, 3H), 2.78 (d, J=7.6, 1H), 2.82
(s, 3H), 3.06 (d, J=7.6, 1H), 3.42 (d, J=9.9, 1H), 3.98 (d, J=9.9,
Supporting Information Available: Typical experimental
procedures, characterization data, copies of 1H and 13C NMR
spectra for all synthesized compounds (5Aa, 5Ab, 5Ad, 5Bb,
5Bd, 6Ca, 6Cb, 6Cc, 5Ce, 5Ca, and 7Ce), the results of semi-
empirical calculations (together with the atom coordinates), and
crystal data with ORTEP drawings for compounds 5Ac and
6Cc, as well as the corresponding CIF files. This material is
available free of charge via the Internet at http://pubs.acs.org.
1H), 6.00 (s, 1H), 7.59 (m, 3H), 7.88 (m, 2H), 8.34 (s, 1H); 13
C
NMR (75.5 MHz, CDCl3) δ (ppm) 24.9, 25.0, 25.7, 26.2, 26.3,
29.1, 30.5, 31.5, 42.8, 44.4, 44.9, 47.7, 57.4, 127.1, 128.7, 130.6,
6306 J. Org. Chem. Vol. 74, No. 16, 2009