Cis-3,5-cyclohexadiene-1,2-diol derivatives: Facial selectivity in their Diels-Alder reactions with ethylenic, acetylenic and azo dienophiles

Article abstract of DOI:10.1039/b607938e

The Diels-Alder reactions of maleimide with the acetonide derivative (6a) of cis-3,5-cyclohexadiene-1,2-diol (1a) in various solvents showed facial selectivities ranging from 1: 1 to 1: 9. The same derivative 6a reacted in benzene with ethylenic dienophil

Full text of DOI:10.1039/b607938e

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cis-3,5-Cyclohexadiene-1,2-diol derivatives: facial selectivity in their
Diels–Alder reactions with ethylenic, acetylenic and azo dienophiles
Sunny M. Ogbomoa and D. Jean Burnell*a,b
Received 5th June 2006, Accepted 5th September 2006
First published as an Advance Article on the web 20th September 2006
DOI: 10.1039/b607938e
The Diels–Alder reactions of maleimide with the acetonide derivative (6a) of cis-3,5-cyclohexadiene-1,2-
diol (1a) in various solvents showed facial selectivities ranging from 1 : 1 to 1 : 9. The same derivative 6a
reacted in benzene with ethylenic dienophiles with generally modest facial selectivity, but acetylenic
dienophiles added exclusively anti to the oxygen functions of 6a. Dimerization of cyclic acetals 6a and 7
was mainly, but for 6a not exclusively, by anti addition with respect to both the diene and the dienophile
partners. Reactions of azo dienophiles with derivatives of 1a were predominantly by anti addition, but
the diol itself (1a) gave the syn adduct as the major product.
as the dienophile.11 What was most remarkable was that additions
Introduction
were very largely syn to the oxygen functions with 1a and with
the noncyclic derivatives 2, 3 and 4a (from 88 : 12 with 4a up
to exclusively syn with 2). This was corroborated recently by the
reaction of 1a with a bromophenyl analog of N-phenylmaleimide,9
and, under high pressure, cyclic enones added to 1b (X = CH3)
to provide the syn-addition products with isolated yields of
approximately 70%.4,7,8 The reactions of 4-phenyl-1,2,4-triazoline-
3,5-dione (PTAD) with 1b (X = carbon and halogen) took place
with at least 97% syn selectivity.12 Thus, the oxygen functions of
1a/b appear to impart a significant bias toward syn addition,
just as syn addition is the preferred mode of reaction of some
5-heteroatom-substituted 1,3-cyclopentadienes.13–15 However, the
structure of the adduct of a bromophenyl analog of PTAD with
4b (X = CH3) was determined by X-ray crystallography, and this
was the anti adduct.16
cis-3,5-Cyclohexadiene-1,2-diol 1a and its optically active variants
1b (Fig. 1) are available directly from aromatic precursors by the
action of mutant strains of Pseudomonas putida.1,2 These cis-diols
are now well established as compact, multifunctional starting
materials,3 and there are many recent examples of their use in
synthesis.4–10
The facial selectivities in the additions of N-phenylmaleimide
to the cyclic derivatives 6a, 7 and 8 ranged from 60 : 40, slightly
favoring syn addition with 5 and 6a, to 4 : 96, strongly favoring
anti addition with 8.11 It was postulated that these cyclic derivatives
present steric interactions in the syn-transition state that cannot
be avoided by conformational mobility of the protecting groups,
so the cyclic protecting groups in 6a, 7 and 8 overcome the
inherent tendency for syn addition. The result is that the anti-
addition product either equals the amount of the syn adduct, or
predominates.
The acetonide (6a/b) has been the derivative of 1a/b that has
been utilized far more than any other. Experiments with 6a and
6b (X = alkyl, 7-norbornadienyl, CF3, and halogens) and N-
phenyl- and N-ethylmaleimide resulted in additions with low facial
selectivities,11,17–20 with the ratios being somewhat dependent on
the solvent.19,20 However, for the reactions of 6b (X = carbon)
with maleic anhydride, a dienophile that with 5-alkyl- and 5-
halogen-substituted 1,3-cyclopentadienes was closely related to
the maleimides in terms of reactivity and facial selectivity,14,21
only anti-addition products were reported,22,23 and the additions
of substituted maleic anhydride derivatives to 6a gave the anti-
addition products in roughly 75% yield.5 Quinones are also
closely related to maleimides in terms of their Diels–Alder
behavior,14,21 so it is curious that the reactions of benzoquinone
Fig. 1 The diene 1a with its 3-substituted analogue 1b and derivatives.
It is not surprising that the diols and their derivatives have served
as Diels–Alder dienes in many instances. We assessed the facial
selectivities of 1a and a number of diol-protected derivatives 2–8
in Diels–Alder reactions in chloroform with N-phenylmaleimide
aDepartment of Chemistry, Memorial University of Newfoundland, St.
John’s, Newfoundland and Labrador, Canada A1B 3X7
bDepartment of Chemistry, Dalhousie University, Halifax, Nova Scotia,
Canada B3H 4J3. E-mail: Jean.Burnell@dal.ca; Fax: +1 902 494 1310;
Tel: +1 902 494 1664
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and naphthoquinone with 6b (X = Cl, Br) gave only the anti
adducts, although the yields were reported to be modest.23–25
All other reactions of 6b (X = carbon, halogens) with carbon-
based dienophiles provided anti-addition products only.6,8,17–20,24,26
Reactions of 6a and 6b (X = CF3, 7-norbornadieneyl, halogen)
with PTAD and with nitroso compounds gave the anti adducts
exclusively.17,18,20,24,26,27 Also, addition of singlet oxygen to 6b (X =
Cl) was only via anti addition.28
The epoxide compound 9 has some similarity to 1a, and
its Diels–Alder reaction with N-phenylmaleimide took place
exclusively anti to the oxygen.29 The same facial preference was
reported for the addition of PTAD to 9.30 Calculations pointed to
steric hindrance as the controlling factor.31
In spite of the number of examples of Diels–Alder reactions of
1a and 1b in the literature, explanations for the facial selectivities
are still lacking. The major drawback of using the published data
for the development of hypotheses is that in most instances it
appears that only the major adduct was isolated and characterized.
Yields of less than 70% are not uncommon—some are even less
than 50%—and so it is not known if the reactions of 1a/b are
really highly facially selective with some important dienophiles.
Therefore we undertook a reexamination of the facial selectivity
in the Diels–Alder reactions of diol 1a and some of its derivatives.
First, the acetonide 6a was reacted with a series of carbon-based
dienophiles to determine if the maleimides are truly different from
other dienophiles in that only they have been reported to have low
facial selectivities. Second, 1a and a number of derivatives were
reacted with azo-dienophiles in order to confirm whether large
differences exist in facial selectivity between 1a and the derivatives.
Our results are presented here.
Results and discussion
The acetonide 6a with carbon-based dienophiles
The acetonide 6a was prepared from 10 by acetonization and
double-elimination with base. The diol 10 had been synthesized
from 1,4-cyclohexadiene (Scheme 1) by a previously described
method.11
Scheme 1 Preparation of acetonide 6a.
Fig. 2 Adducts derived from diene 6a and various ethylenic and acetylenic
dienophiles.
The reactant pair of diene 6a and maleimide provided an
opportunity to assess the influence of the solvent on facial
selectivity, because both addends might be expected to associate
significantly with polar solvents. To the best of our knowledge,
only three similar studies have been reported.11,19,32 The reactions
of 6a with maleimide were carried out at room temperature in a
variety of solvents (Table 1). In every instance two adducts (11
and 12, in Fig. 2) were obtained, in combined yields of over
80%. As in all of the work described here, the relative amounts
of the adducts were determined by careful integration of the well-
dispersed signals for the olefinic hydrogens in the 1H NMR spectra
of the reaction mixtures. (In this, and most subsequent reactions,
the adducts were separable by flash chromatography, and the
stereochemistry of each adduct was determined by measurement
of NOE enhancements.)
The results in Table 1 show a much greater range of fa-
cial selectivities than the previous studies, from essentially
no facial selectivity up to a 1 : 9 ratio. Whereas the three
previous studies all used oxygen-substituted dienes (1a,11 6a19
and 5-[(hydroxyimino)methyl]-1,2,3,4,5-pentamethylcyclopenta-
diene32), in this work the dienophile bore an acidic hydrogen (in
contrast with N-ethyl- and N-phenylmaleimide11,19,32). The anti-
addition product was generally more favored by a high solvent
dielectric. (In Table 1, the solvents from benzene to water are given
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Table 1 Ratios of the syn adduct (11) to the anti adduct (12) from the
Diels–Alder reactions of maleimide with the acetonide diene 6a in different
solvents
facially selective than maleimide, producing (endo) adducts in a
ratio of 1 : 4 in favor of the anti adduct. In addition to the two
endo adducts, the reaction with 3-buten-2-one yielded a small
proportion of the anti-exo adduct 28. It was surprising that
vinylene carbonate, which reacted sluggishly with 6a, produced
adducts in a ratio of 4 : 1 in favor of the syn adduct. The reason
for this difference in facial preference is not obvious.
Overall, none of these ethylenic dienophiles gave only one
adduct with 6a. The many results for 6b suggest that it reacts with
much higher facial selectivity than does 6a. A possible explanation
is that an interaction between the annular substituent and the
closer oxygen of 6b makes the difference in transition state energies
of the syn and anti transition states larger with 6b than with 6a.
The torsional angle from the annular substituent to the closer
oxygen of 6b is very close to 60◦. In the syn transition state, this
angle would be compressed, whereas in the anti transition state
this angle would become larger. While angular changes at the
transition states would be similar with 6a, the size of a hydrogen
on 6a, versus the substituent on 6b, would make the consequence
of the angular change less pronounced.
Tetracyanoethylene presents sterically hindering carbon sub-
stituents in both the endo and exo regions of the Diels–Alder
transition state. Thus, it would be reasonable to expect a significant
barrier to syn addition with this dienophile,14,21 and, indeed, only
its anti adduct 31 was observed. On the other hand, there is no
steric reason to anticipate a significant barrier to syn addition
with an acetylenic dienophile. With 5-alkyl-1,3-cyclopentadienes
dimethyl acetylenedicarboxylate showed more syn adduct than did
ethylenic dienophiles,21 and Paquette’s dodecahedrane synthesis
relied on an initial syn addition of acetylenedicarboxylate to 9,10-
dihydrofulvalene.33 Nevertheless, both dimethyl acetylenedicar-
boxylate and ethyl propiolate reacted with 6a to provide only
the anti adducts 32 and 33. Unsymmetrical dienes 1b (X =
CF3, 7-norbornadieneyl, F) had shown the same selectivity.17,18,20
It can be conjectured that the reluctance of the alkyne to add
syn to the oxygen functions stems from a repulsive interaction
in the syn transition state between the p-bond of the alkyne
that is orthogonal to the plane of the developing r-bonds and
the lone pair(s) of the oxygen(s) on the diene. There is some
computational evidence that a second factor can attenuate syn
addition. A comparison of computed (HF/6-31G(d)) transition
Total yield (11 Ratio of the syn adduct (11)
Solvent
and 12) (%)
to the anti adduct (12)
No solvent
Benzene
Chloroform
Diethyl ether
Dichloromethane
Pyridine
99
83
99
90
99
97
94
99
97
89
81
85
27 : 73
42 : 58
46 : 54
45 : 55
39 : 61
29 : 71
27 : 73
21 : 79
14 : 86
10 : 90
14 : 86
19 : 81
32 : 68
Methanol
Acetonitrile
Dimethyl sulfoxide
Water
1 M LiCl in water
1 M LiClO4 in water
5 M LiClO4 in diethyl ether 92
in the order of increasing dielectric constant.) Addition of salts
(LiCl and LiClO4) to the water resulted in slightly reduced facial
selectivities. The facial selectivity in a solution of LiClO4 in diethyl
ether was better than in just diethyl ether. Thus, synthetically it
would be advisable to use a solvent of high dielectric to maximize
the yield of an anti adduct.
The facial selectivities of the reactions of N-methyl-, N-ethyl,
and N-phenylmaleimide with 6a (leading to products 13–18) were
similar to that of maleimide, i.e., low, when all the reactions
were conducted in benzene (Table 2). The facial selectivity in
the reaction of the unsymmetrical diol 1b (X = CF3) with N-
ethylmaleimide was consistent with the reactions of 1a: the ratio
was 48 : 53 slightly favoring the anti adduct.18
Reactions of 6a with a number of additional carbon-based,
ethylenic dienophiles were conducted in benzene (Table 2).
Like maleimide, maleic anhydride, p-benzoquinone, and dimethyl
maleate reacted with low facial selectivities, at best approximately 1
: 2, in favor of the anti adducts. The two adducts from the reaction
of the quinone behaved very differently during purification on
silica. The syn adduct 21 was isolated in a straightforward way,
1
but the anti adduct 22, while evident by H NMR in the crude
product mixture, was obtained as the aromatized compound 23.
The unsymmetrical dienophile 3-buten-2-one was modestly more
Table 2 Proportions of syn adduct and anti adduct from the Diels–Alder reactions of carbon-based dienophiles with the acetonide diene 6a in benzene
Proportions (%) of the syn
Dienophile
syn Adduct
anti Adduct
and the anti adducts
Maleimide
11
13
15
17
19
21
24
26
29
—
—
—
12
14
16
18
20
22
25
27
30
31
32
33
42 : 58
47 : 53
39 : 61
52 : 48b
40 : 60c
32 : 68
32 : 68
21 : 79e
81 : 19
0 : 100
0 : 100
0 : 100
N-Methylmaleimide
N-Ethylmaleimidea
N-Phenylmaleimidea
Maleic anhydride
p-Benzoquinone
Dimethyl maleate
3-Buten-2-oned
Vinylene carbonate
Tetracyanoethylene
Dimethyl acetylenedicarboxylate
Ethyl propiolate
a Data from ref. 19. b Ratio 60 : 40 for the reaction in chloroform, ref. 11. c The adducts were not isolated. d Reaction in toluene. e Only the endo adducts
are given in the Table. The ratio of 25 : 26 : 27 was 21 : 79 : 14.
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Table 3 Proportions of syn adduct and anti adduct from the Diels–Alder
reactions of 4-phenyl-1,2,4-triazoline-3,5-dione with 1a and derivatives in
acetone
states for syn and anti additions of acetylene and of maleimide
to 5-methyl-1,3-cyclopentadiene indicates that more syn addition
should occur with acetylene (29% syn with acetylene versus 13%
syn with maleimide).15 This is in accord with a simple steric
rationalization. However, the corresponding comparisons with 5-
chloro- and5-bromo-1,3-cyclopentadiene revealthatmuch less syn
addition should take place with acetylene compared to maleimide
(for the chloro-diene, 14% syn with acetylene versus 88% syn with
maleimide; and for the bromo-diene, 0.7% syn with acetylene
versus 33% syn with maleimide).15 These results are not consistent
with a simple steric argument, but do indicate another, very
significant mechanism of inhibition of the syn addition. In the
case of 6a/b, the geometry of this interaction is different from that
in a 5-substituted 1,3-cyclopentadiene, and 6a/b has two, not just
one, lone-pair-bearing plane-nonsymmetric atoms.
Proportions (%) of syn
and anti adducts
Diene
syn Adduct
anti Adduct
1a
2
38
—
41
—
—
—
39
40
42
43
44
45
76 : 24
0 : 100
12 : 88
0 : 100
0 : 100
0 : 100
4a
6a
7
8
produced from 6a indicates that 6a is more facially selective as a
dienophile than as a diene.
Azo dienophiles with 1a and derivatives
Dimerization
A survey of additions of 1a and derivatives 2, 4a, 6a, 7 and
8 with PTAD was carried out. The results are summarized in
Table 3. The stereochemistry of the adducts could be determined
by measurement of NOE enhancements, in most instances. This
was not the case for 42 (Fig. 4), but acetylation of 39, the minor
adduct from 1a, produced 42, the major adduct from 4a.
Dimerization of 1a or its derivatives would be a special case of the
addition of a carbon-based dienophile, one in which the dienophile
is also plane-nonsymmetric. Dienes 1a and 1b do not appear to
dimerize spontaneously, but dimerization of 6b (X = CF3,17 Br,34,35
Cl,35 vinyl,36 CN,37 SiHMe238) is well known, and trans-benzylidene
8 (and the p-NO2-phenyl variant) also dimerizes readily giving 34
(Fig. 3).11 In every instance, the only dimer isolated was the result
of anti addition of both the diene and the dienophile partners.
That only one dimer was produced from 8 was in accord with
the high facial selectivity witnessed in the reaction of 8 with N-
phenylmaleimide.11 Prolonged storage of the cis-benzylidene 7,
which was initially thought not to dimerize,11 also produced one
dimer 35. This was once again the result of anti addition of both
the diene and the dienophile partners.
Fig. 4 Adducts derived from PTAD and DEAD.
Fig. 3 Dimeric products from acetonides.
The computational study with 5-substituted 1,3-cyclopen-
tadienes15 had revealed inhibition of syn addition of 4-phenyl-
1,2,4-triazoline-3,5-dione (PTAD) to a diene with a lone-pair-
bearing substituent. It was suggested that this interaction was
a filled-orbital repulsion. The data in Table 3 suggest that such
an interaction might exist with the derivatives of 1a as well.
Whereas PTAD should be less sterically demanding than N-
phenylmaleimide, the proportions of anti adduct with PTAD were
much higher. What was again observed was that the simpler dienes
1a and 4a seemed to react with less facial selectivity than the
substituted dienes 1b (X = wide variety of substituents), which
had reacted with PTAD to give over 97% of the syn adduct,12 and
4b (X = CH3), for which only the anti adduct had been reported.16
In comparison with 7 and 8, 6a had shown less facial selectivity
with N-phenylmaleimide.11 Diene 6a was less facially selective in
dimerization, also. When 6a was kept under nitrogen at room
temperature for 28 days, the result was conversion to two dimers
36 and 37, in a ratio of 1 : 6. Measurement of NOE enhancements
revealed that the minor isomer was the result of syn addition of the
diene and anti addition of the dienophile (36). The major isomer
was the result of anti addition of both the diene and the dienophile
partners (37). Compound 37 was the same as the product of
debromination of the dimer of 6b (X = Br).35 It is not clear why
6a shows less facial selectivity in its dimerization than does 6b,
but that only two of the four possible endo-addition dimers were
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It is tempting to ascribe the syn selectivity of 1a/b to hydrogen
bonding between the addends.
pure adducts (11–14, 24, 25, 29, 30, 31 and 33) were heated under
reflux for 12 to 16 h. In no case was there evidence, by TLC or by
1H NMR, of equilibration to a mixture of adducts.
The only products detected from the Diels–Alder reactions of
PTAD with dienes 6a, 7 and 8 were the anti adducts 43, 44
and 45. The same facial selectivity was observed when diethyl
azodicarboxylate (DEAD) was employed as an azo dienophile
with 6a, 7 and 8. There are many examples of additions of hetero-
dienophiles to 6b, and, in every instance, only the anti adducts
were reported.17,18,20,24,26,27
Diels–Alder reaction of 6a with maleimide
A solution of 6a (124 mg, 0.817 mmol) and maleimide (158 mg,
1.63 mmol) in benzene (4.0 ml) at RT for 16 h gave 11 (182 mg,
45% after recrystallization from benzene) and 12 (152 mg, 38%
after recrystallization from benzene) as colourless crystals.
For
(3aa,4a,4ab,7ab,8a,8aa)-4a,7a,8,8a-tetrahydro-2,2-di-
Conclusions
methyl-4,8-etheno-4H-1,3-dioxolo[4,5-f ]isoindole-5,7(3aH,6H)-
dione 11: mp 172–174 ◦C; mmax/cm−1 1754; dH (CDCl3) 8.40 (1
H, very br, N-H), 6.20 (2 H, m, 9-H and 10-H), 4.15 (2 H, dd, J
1.6 and 2.2, 3a-H and 8a-H), 3.39 (2 H, m, 4-H and 8-H), 3.36
(2 H, narrow m, 4a-H and 7a-H), 1.49 (3 H, s, 2-Meb) and 1.35
(3 H, s, 2-Mea); saturation at d 6.20 led to NOEs at d 4.15 (1%)
and 3.39 (9%), saturation at d 4.15 led to NOEs at d 6.20 (1.5%),
3.39 (14%) and 1.35 (2%), saturation at d 3.39 led to NOEs at d
6.20 (8%) and 4.15 (7%), saturation at d 3.36 led to NOE at d
1.49 (1%), saturation at d 1.49 led to NOE at d 3.36 (5%) and
saturation at d 1.35 led to NOE at d 4.15 (8%); dC (CDCl3) 179.7
(C-5 and C-7), 131.6 (C-9 and C-10), 112.5 (C-2), 73.7 (C-3a and
C-8a), 39.0 (C-4a and C-7a), 36.5 (C-4 and C-8), 26.3 (2-Meb)
The reactions of 6a with maleimide in various solvents showed
a significant range of facial selectivities, from essentially 1 : 1 up
to 1 : 9. Different ethylenic dienophiles added to 6a (in benzene)
with modest facial selectivities, in contrast with reportedly high
selectivities for the substituted dienes 6b. Acetylenic dienophiles
added to 6a exclusively anti. There was also a marked tendency
for azo dienophiles (PTAD and DEAD) to add anti to the oxygen
functions of the diene, although the reaction of PTAD and 1a gave
mainly the syn adduct.
Experimental
and 24.2 (2-Mea); m/z 250 (5%, M+ + 1), 234.0775 (64, M+
CH3, C12H12NO4 requires 234.0766), 192 (51), 191 (63), 163 (40),
162 (35), 146 (36), 135 (48), 120 (64), 119 (32), 118 (48), 117 (39),
100 (74), 92 (78), 91 (82), 85 (53), 78 (49), 65 (55) and 43 (100).
−
General
Melting points are uncorrected. NMR spectra are at 300 MHz for
1H and 74.5 MHz for 13C. Shifts are relative to internal tetramethyl-
silane. Nuclear Overhauser effect (NOE) measurements were made
using difference spectra. Assignments are based on 2-D homo-
and heterocorrelation experiments, APT spectra (for 13C) and the
NOE measurements. 13C NMR shifts that are not assigned may
be followed in parentheses by the number of attached hydrogens.
Mass spectra were obtained by electron impact ionization at 70 eV.
“Chromatography” refers to flash chromatography on silica gel;
elution was with hexanes containing an increasing proportion of
ethyl acetate.
Diene 1a was obtained from the Aldrich Chemical Co. Dienes
2,11 4a,11 6a,11,39,40 7,11 and 811 were prepared by literature methods
from 10.39,40 Diels–Alder reactions were conducted at RT except
in those cases in which no product was evident by TLC after
a few hours at RT. Solvents were evaporated, and the ratios of
the adducts were obtained by careful integration of the 1H NMR
spectra. In most instances, the adducts could be separated by
chromatography.
For
(3aa,4b,4aa,7aa,8b,8aa)-4a,7a,8,8a-tetrahydro-2,2-di-
methyl-4,8-etheno-4H-1,3-dioxolo[4,5-f ]isoindole-5,7(3aH,6H)-
dione 12: mp 233–234 ◦C; mmax/cm−1 1701; dH (CDCl3) 8.27 (1 H,
very br, N-H), 6.13 (2 H, m, 9-H and 10-H), 4.28 (2 H, narrow
m, 3a-H and 8a-H), 3.44 (2 H, br m, 4-H and 8-H), 2.81 (2 H,
t, J 1.4, 4a-H and 7a-H), 1.34 (3 H, s, 2-Meb) and 1.29 (3 H, s,
2-Mea); saturation at d 6.13 led to NOE at d 3.44 (7%), saturation
at d 4.28 led to NOEs at d 3.44 (9%), 2.81 (13%) and 1.29
(2%), saturation at d 3.44 led to NOEs at d 6.13 (8%), 4.28 (4%)
and 2.81 (5%), saturation at d 2.81 led to NOEs at d 4.28 (11%) and
3.44 (8%), saturation at d 1.34 led to NOE at d 6.13 (1.5%)
and saturation at d 1.29 led to NOE at d 4.28 (7%); dC (CDCl3)
177.3 (C-5 and C-7), 129.7 (C-9 and C-10), 109.8 (C-2), 77.2
(C-3a and C-8a), 41.7 (C-4a and C-7a), 36.3 (C-4 and C-8), 25.3
(2-Meb) and 24.9 (2-Mea); m/z 250 (0.7%, M+ + 1), 234.0773
(30, M+ − CH3, C12H12NO4 requires 234.0766), 192 (17), 191 (23),
163 (14), 162 (12), 146 (12), 135 (15), 120 (23), 100 (32), 92 (55),
91 (72) and 43 (100).
Diels–Alder reactions of acetonide 6a with carbon-based
dienophiles
Diels–Alder reaction of 6a with N-methylmaleimide
Solutions of 6a and the dienophile in benzene were maintained
at RT for a few hours. If TLC revealed some reaction progress,
the mixture was stirred at RT until reaction was complete (by
TLC). If TLC showed no reaction progress, the solution was
heated at reflux until reaction was complete (by TLC). (Under
these conditions cis-stilbene and styrene failed to undergo any
Diels–Alder addition to 6a.) After removal of the solvent the
crude reaction mixture was analysed by H NMR in order to
obtain the proportions of the adducts by integration. Adducts
were then purified by chromatography. Benzene solutions of some
A solution of 6a (108 mg, 0.712 mmol) and N-methylmaleimide
(79 mg, 0.71 mmol) in benzene (1.0 ml), stirred at RT for 17 h,
yielded 13 (74 mg, 40%) and 14 (71 mg, 38%) as colourless crystals.
For (3aa,4a,4ab,7ab,8a,8aa)-4a,7a,8,8a-tetrahydro-2,2,6-tri-
methyl-4,8-etheno-4H-1,3-dioxolo[4,5-f ]isoindole-5,7(3aH,6H)-
dione 13: mp 218–220 ◦C; mmax/cm−1 1689; dH (CDCl3) 6.12 (2 H,
dd, J 3.0 and 4.5, 9-H and 10-H), 4.15 (2 H, dd, J 1.7 and 2.2,
3a-H and 8a-H), 3.41 (2 H, m, 4-H and 8-H), 3.32 (2 H, narrow m,
4a-H and 7a-H), 2.91 (3 H, s, N–Me), 1.48 (3 H, s, 2-Meb) and 1.35
(3 H, s, 2-Mea); saturation at d 4.15 led to NOEs at d 6.12 (2%),
1
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3.41 (10%) and 1.35 (2%) and saturation at d 1.48 led to NOE at d
3.32 (5%); dC (CDCl3) 179.4 (C-5 and C-7), 131.5 (C-9 and C-10),
112.4 (C-2), 73.9 (C-3a and C-8a), 37.7 (C-4a and C-7a), 36.6
(C-4 and C-8), 26.3 (2-Meb), 24.7 (N–Me) and 24.2 (2-Mea); m/z
264 (2%, M+ + 1), 248.0913 (35, M+ − CH3, C13H14NO4 requires
248.0922), 206 (51), 205 (47), 204 (16), 177 (32), 176 (25), 160
(21), 146 (37), 120 (43), 119 (21), 118 (22), 100 (73), 92 (100), 91
(100), 85 (39), 78 (28), 77 (22), 65 (33) and 43 (100).
For (3aa,4b,4aa,7aa,8b,8aa)-4a,7a,8,8a-tetrahydro-2,2,6-tri-
methyl-4,8-etheno-4H-1,3-dioxolo[4,5-f ]isoindole-5,7(3aH,6H)-
dione 14: mp 190–192 ◦C; mmax/cm−1 1691; dH (CDCl3) 6.05 (2 H,
dd, J 3.1 and 4.4, 9-H and 10-H), 4.30 (2 H, narrow m, 3a-H and
8a-H), 3.46 (2 H, m, 4-H and 8-H), 2.92 (3 H, s, N–Me), 2.76 (2 H,
narrow m, 4a-H and 7a-H), 1.33 (3 H, s, 2-Meb) and 1.29 (3 H, s,
2-Mea); saturation at d 4.30 led to NOEs at d 3.46 (9%), 2.76
(14%) and 1.29 (2%) and saturation at d 1.33 led to NOE at d
6.05 (2%); dC (CDCl3) 177.4 (C-5 and C-7), 129.6 (C-9 and C-10),
109.7 (C-2), 77.3 (C-3a and C-8a), 40.4, 36.4, 25.3 and 24.9 (3C);
m/z 264 (1%, M+ + 1), 248.0922 (41, M+ − CH3, C13H14NO4
requires 248.0922), 206 (45), 205 (41), 204 (16), 177 (32), 176 (22),
160 (20), 146 (33), 120 (41), 118 (22), 100 (54), 92 (100), 91 (96),
85 (37), 78 (29), 65 (25) and 43 (93).
For
(3aa,4a,4ab,8ab,9a,9aa)-3a,4,9,9a-tetrahydro-2,2-di-
methyl-4,9-etheno-1,3-dioxolo[4,5-b]naphthalene-5,8(4aH,8aH)-
dione 21: mp 122–123 ◦C; mmax/cm−1 1703; dH (CDCl3) 6.69 (2 H,
s, 6-H and 7-H), 6.17 (2H, dd, J 2.9 and 4.4, 10-H and 11-H), 4.10
(2 H, apparent t, J 1.9, 3a-H and 9a-H), 3.51 (4 H, apparent br s,
4-H, 4a-H, 8a-H and 9-H), 1.51 (3 H, s, 2-Meb) and 1.36 (3 H,
s, 2-Mea); saturation at d 6.17 led to NOEs at d 4.10 (1%) and 3.51
(2%), saturation at d 4.10 led to NOEs at d 6.17 (2%) and
3.51 (4%), saturation at d 1.51 led to NOE at d 3.51 (3%) and
saturation at d 1.36 led to NOE at d 4.10 (8%); dC (CDCl3) 199.4
(C-5 and C-8), 141.8 (C-6 and C-7), 132.8 (C-10 and C-11), 122.2
(C-2), 73.9 (C-3a and C-9a), 42.0, 39.2, 26.5 (2-Meb) and 24.3
(2-Mea); m/z 260 (7%, M+), 245.0815 (50, M+ − CH3, C14H13O4
requires 245.0812), 231 (8), 203 (11), 202 (13), 185 (18), 173 (23),
157 (13), 145 (16), 129 (17), 120 (29), 100 (46), 91 (44), 82 (54), 54
(33) and 43 (100).
For
(3aa,4b,4aa,8aa,9b,9aa)-3a,4,9,9a-tetrahydro-2,2-di-
methyl-4,9-etheno-1,3-dioxolo[4,5-b]naphthalene-5,8(4aH,8aH)-
dione 22: dH (CDCl3) (data from the adduct mixture before
chromatography) 6.70 (2 H, s, 6-H and 7-H), 6.10 (2 H, dd, J 3.0
and 4.5, 10-H and 11-H), 4.33 (2 H, narrow m, 3a-H and 9aH),
3.53 (2 H, m, 4-H and 9-H), 2.82 (2 H, narrow m, 4a-H and
8a-H), 1.32 (3 H, s, 2-Me) and 1.29 (3 H, s, 2-Me).
For
(3aa,4b,4aa,8aa,9b,9aa)-3a,4,9,9a-tetrahydro-2,2-di-
Diels–Alder reaction of 6a with maleic anhydride
methyl-4,9-etheno-1,3-dioxolo[4,5-b]naphthalene-5,8-diol 23: mp
151–152 ◦C; dH (CDCl3) 6.68 (2 H, s, 6-H and 7-H), 6.41 (2 H, dd,
J 3.0 and 4.3, 10-H and 11-H), 4.57 (2 H, m, 4-H and 9-H), 4.27 (2
H, t, J 1.7, 3a-H and 9a-H), 1.37 (3 H, s, 2-Meb) and 1.25 (3 H, s,
2-Mea); saturation at d 6.41 led to NOE at d 4.57 (7%), saturation
at d 4.57 led to NOEs at d 6.41 (7%) and 4.27 (4%), saturation at
d 4.27 led to NOEs at d 4.57 (10%) and 1.25 (1.5%), saturation at
d 1.37 led to NOE at d 6.41 (3%) and saturation at d 1.25 led to
NOE at d 4.27 (9%); dC (CDCl3) 146.9, 135.9, 131.5, 113.7, 78.4,
39.4, 25.7 and 25.5 (two aromatic signals are likely overlapped);
m/z 260.1031 (10%, M+, C15H16O4 requires 260.1047), 245 (27),
231 (19), 203 (13), 202 (29), 185 (24), 173 (36), 145 (18), 129 (15),
120 (47), 100 (90), 91 (57), 85 (22), 82 (88), 77 (16), 65 (22), 54
(51) and 43 (100).
A solution of 6a (124 mg, 0.817 mmol) and maleic anhydride
(159 mg, 162 mmol) in benzene (4.0 ml) was stirred at RT for
1
16 h. After a H NMR spectrum was taken, the product was
passed through a very short silica gel column in order to remove
less polar impurities. A mixture of adducts (334 mg, 83%) was
obtained. Attempts to separate the adducts by chromatography led
to hydrolysis. Assignment of the structures was based on similarity
1
of the NMR spectra to other adduct mixtures. In the H NMR
spectra, the olefinic signal was always slightly downfield in the syn
adduct, the carbinolic signal was always slightly downfield in the
anti adduct, and the signal for the hydrogens a to the carbonyls
was always at least 0.5 ppm downfield for the syn adduct.
For
(3aa,4a,4ab,7ab,8a,8aa)-3a,4,4a,7a,8,8a-hexahydro-2,2-
dimethyl-4,8-ethenofuro[3,4-f ]-1,3-benzodioxole-5,7-dione 19: dH
(CDCl3) (data from the adduct mixture) 6.20 (2 H, dd, J 2.9 and
4.3), 4.15 (2 H, narrow m), 3.40 (2 H, m), 3.38 (2 H, narrow m),
1.49 (3 H, s) and 1.35 (3 H, s).
Diels–Alder reaction of 6a with dimethyl maleate
A solution of 6a (120 mg, 0.794 mmol) and dimethyl maleate
(229 mg, 1.58 mmol) in benzene (1.0 ml) was stirred at RT for
5 days. TLC still showed much unreacted 6a, but the mixture was
concentrated, and flash chromatography provided 24 (25 mg, 11%)
and 25 (83 mg, 35%) as colourless solids.
For
(3aa,4b,4aa,7aa,8b,8aa)-3a,4,4a,7a,8,8a-hexahydro-2,2-
dimethyl-4,8-ethenofuro[3,4-f ]-1,3-benzodioxole-5,7-dione 20: dH
(CDCl3) (data from the adduct mixture) 6.13 (2 H, dd, J 3.0 and
4.5), 4.28 (2 H, narrow m), 3.44 (2 H, m), 2.82 (2 H, apparent t, J
1.4), 1.34 (3 H, s) and 1.29 (3 H, s).
For dimethyl (3aR,4S,7R,7aS,8S,9R)-3a,4,7,7a-tetrahydro-2,2-
dimethyl-4,7-ethano-1,3-benzodioxole-8,9-dicarboxylate 24: mp
134–135 ◦C; mmax/cm−1 1738 and 1732; dH (CDCl3) 6.29 (2 H,
dd, J 3.0 and 4.8, 5-H and 6-H), 4.05 (2 H, br t, J ≈ 2.1, 3a-H
and 7a-H), 3.61 (6 H, s, 2 × OCH3), 3.54 (2 H, br s, 8-H and 9-H),
3.14 (2 H, br m, 4-H and 7-H), 1.53 (3 H, s, 2-Meendo) and 1.34
(3 H, s, 2-Meexo); saturation at d 6.29 led to NOEs at d 4.05 (1%)
and 3.14 (4%), saturation at d 4.05 led to NOEs at d 6.29 (1%),
3.14 (5%) and 1.34 (1.5%), saturation at d 3.54 led to NOEs at d
3.14 (3%) and 1.53 (0.8%), saturation at d 1.53 led to NOE at d
3.54 (3%) and saturation at d 1.34 led to NOE at d 4.05 (5%); dC
(CDCl3) 173.6, 131.6, 112.0, 74.0, 51.7, 40.0, 37.4, 26.3 and 24.3;
m/z 296.1258 (4%, M+, C15H20O6 requires 296.1258), 281 (16), 265
Diels–Alder reaction of 6a with p-benzoquinone
A solution of 6a (358 mg, 2.34 mmol) and p-benzoquinone
(385 mg, 3.53 mmol) in benzene (2.0 ml) was stirred at RT for
72 h. Chromatography (20% EtOAc in hexanes) could not separate
the adducts cleanly. Compound 21 (84 mg, 9%) was obtained
as colourless crystals following recrystallization four times from
EtOAc–hexanes and hexanes. The other adduct was isolated as
the aromatized compound 23 (511 mg, 56%) after recrystallization
three times from EtOAc–hexanes and hexanes.
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(23), 238 (51), 207 (16), 206 (22), 179 (28), 178 (20), 147 (100), 119
(37), 100 (58), 91 (56), 59 (37) and 43 (57).
For (3aR*,4S*,7S*,7aS*,8R*)-8-acetyl-3a,4,7,7a-tetrahydro-
2,2-dimethyl-4,7-ethano-1,3-benzodioxole 28: dH (CDCl3) (data
from a mixture with 26) 6.13–6.26 (2 H, m), 4.17 (1 H, br dd,
J 3.0 and 7.2), 4.1 (1 H, overlapped), 3.8 (1 H, overlapped, 7-H),
2.94 (1 H, m, 4-H), 2.53 (1 H, ddd, J 2.7, 5.5 and 10.8, 8-H), 2.23
(3 H, s, COCH3), 1.86 (1 H, ddd, J 2.1, 5.5 and 13.5, 9-H), 1.37 (1
H, overlapped, 9-H), 1.32 (3 H, s, 2-Me) and 1.23 (3 H, s, 2-Me).
For dimethyl (3aR,4R,7S,7aS,8R,9S)-3a,4,7,7a-tetrahydro-2,2-
dimethyl-4,7-ethano-1,3-benzodioxole-8,9-dicarboxylate 25: mp
196–197 ◦C: mmax/cm−1 1742 and 1725; dH (CDCl3) 6.20 (2 H, dd, J
3.3 and 4.5, 5-H and 6-H), 4.22 (2 H, narrow m, 3a-H and 7a-H),
3.63 (6 H, s, 2 × OCH3), 3.21 (2 H, br m, 4-H and 7-H), 2.86 (2 H,
br s, 8-H and 9-H), 1.34 (3 H, s, 2-Meendo) and 1.28 (3 H, s, 2-Meexo);
saturation at d 6.20 led to NOE at d 3.21 (8%), saturation at d 4.22
led to NOEs at d 3.21 (10%), 2.86 (15%) and 1.28 (2%), saturation
at d 3.21 led to NOEs at d 6.20 (10%), 4.22 (5%) and 2.86 (4%),
saturation at d 2.86 led to NOEs at d 4.22 (15%) and 3.21 (9%),
saturation at d 1.34 led to NOE at d 6.20 (2%) and saturation at d
1.28 led to NOE at d 4.22 (7%); dC (CDCl3) 172.3 (2 × CO2), 129.4
(C-5 and C-6), 109.2 (C-2), 77.5 (C-3a and C-7a), 52.0 (2 × OCH3),
42.9 (C-8 and C-9), 39.5 (C-4 and C-7), 25.3 (2-Meendo) and 25.0
(2-Meexo); m/z 296.1249 (4%, M+, C15H20O6 requires 296.1258),
281 (27), 265 (20), 238 (16), 207 (20), 206 (29), 179 (27), 178 (17),
147 (100), 119 (33), 100 (32), 91 (56), 85 (28), 59 (42) and 43 (62).
Diels–Alder reaction of 6a with vinylene carbonate
A solution of 6a (152 mg, 1.00 mmol) and vinylene carbonate
(0.12 ml, 2.0 mmol) in benzene (8 ml), heated under reflux for
8 days, gave 29 (182 mg, 38%) and 30 (43 mg, 9%) as colourless
solids after recrystallization from hexane.
For (3aa,4b,4ab,7ab,8b,8aa)-3a,4,4a,7a,8,8a-hexahydro-6,6-
dimethyl-4,8-ethenobenzo[1,2-d:4,5-dꢀ]bis[1,3]dioxol-2-one 29:
mp 167–169 ◦C; mmax/cm−1 1796; dH (CDCl3) 6.23 (2 H, dd, J 3.0
and 4.5, 9-H and 10-H), 5.17 (2 H, br s, 3a-H and 8a-H), 4.21 (2 H,
t, J 2.1, 4a-H and 7a-H), 3.47 (2 H, m, 4-H and 8-H), 1.46 (3 H, s,
6-Mea) and 1.30 (3 H, s, 6-Meb); saturation at d 6.23 led to NOEs
at d 4.21 (1%) and 3.47 (5%), saturation at d 5.17 led to NOEs at
d 3.47 (5%) and 1.46 (0.7%), saturation at d 4.21 led to NOEs at d
6.23 (2%), 3.47 (8%) and 1.30 (1.5%), saturation at d 3.47 led to
NOEs at d 6.23 (7%), 5.17 (5%) and 4.21 (5%), saturation at d 1.46
led to NOE at d 5.17 (6%) and saturation at d 1.30 led to NOE at
d 4.21 (9%); dC (CDCl3) 155.0 (C-2), 130.5 (C-9 and C-10), 112.1
(C-6), 74.3 (C-3a and C-8a), 73.7 (C-4a and C-7a), 38.4 (C-4
and C-8), 25.8 (6-Mea) and 23.2 (6-Meb); m/z 239 (1%, M+ + 1),
223.0604 (45, M+ − CH3, C11H11O5 requires 223.0605), 180 (43),
119 (14), 107 (42), 95 (27), 94 (68), 91 (27), 79 (46), 77 (29), 66
(21) and 43 (100).
Diels–Alder reaction of 6a with 3-buten-2-one
A solution of 6a (126 mg, 0.833 mmol), a large excess (1.0 ml) of 3-
buten-2-one, and hydroquinone (10 mg) in toluene (5.0 ml), heated
at reflux for 72 h, provided 27 (119 mg, 64%) after recrystallization
from hexane, and a fraction (17 mg, 9%) containing a mixture of
26 and 28.
For (3aR*,4R*,7R*,7aS*,8R*)-8-acetyl-3a,4,7,7a-tetrahydro-
2,2-dimethyl-4,7-ethano-1,3-benzodioxole 26: dH (CDCl3) (data
from a mixture with 28) 6.22 (1 H, overlapped), 6.06 (1 H, br
t, J 7.2), 4.00–4.11 (2 H, m), 3.8 (2 H, m, overlapped), 2.84 (1 H,
m), 2.13 (3 H, s), 2.13 (1 H, m, overlapped), 1.54 (3 H, s, 2-Me),
1.53 (1 H, m, overlapped) and 1.35 (3 H, s, 2-Me).
For (3aR*,4S*,7S*,7aS*,8S*)-8-acetyl-3a,4,7,7a-tetrahydro-
2,2-dimethyl-4,7-ethano-1,3-benzodioxole 27: mp 61–62 ◦C;
mmax/cm−1 1710; dH (CDCl3) 6.17 (1 H, t, J 7.5, 5-H), 5.97 (1 H, t,
J 7.5, 6-H), 4.28 (1 H, dd, J 3.1 and 7.2, 7a-H), 4.22 (1 H, dd, J
3.2 and 7.2, 3a-H), 3.23 (1 H, m, 7-H), 2.92 (1 H, m, 4-H), 2.48 (1
H, ddd, J 2.0, 5.1 and 9.8, 8-H), 2.16 (3 H, s, COMe), 1.81 (1 H,
ddd, J 3.3, 5.1 and 13.4, 9-Hendo), 1.46 (1 H, ddd, J 2.3, 9.8 and
13.4, 9-Hexo), 1.34 (3 H, s, 2-Meendo) and 1.29 (3 H, s, 2-Meexo);
saturation at d 6.17 led to NOEs at d 5.97 (3%) and 2.92 (2%), satu-
ration at d 5.97 led to NOEs at d 6.17 (4%) and 3.23 (3%),
saturation at d 4.28 led to NOEs at d 3.23 (4%), 2.48 (8%) and
1.29 (0.6%), saturation at d 4.22 led to NOEs at d 2.92 (3%), 1.46
(4%) and 1.29 (approx. 0.5%), saturation at d 3.23 led to NOEs
at d 5.97 (5%); 4.28 (3%), 2.48 (2%) and 2.16 (1%), saturation
at d 2.92 led to NOEs at d 6.17 (5%), 4.22 (3%), 1.81 (3%) and
1.46 (1.5%), saturation at d 2.48 led to NOEs at d 4.28 (7%), 4.22
(1%), 3.23 (3%) and 1.46 (4%), saturation at d 1.81 led to NOEs
at d 2.92 (5%) and 1.46 (9%), saturation at d 1.46 led to NOEs at
d 4.22 (5%), 2.92 (2%), 2.48 (5%) and 1.81 (14%), saturation at d
1.34 led to NOEs at d 6.17 (1%) and 5.97 (1.5%) and saturation at
d 1.29 led to NOEs at d 4.28 (7%) and 4.22 (6%); dC (CDCl3) 207.5
(CO), 132.4 (C-5), 127.8 (C-6), 108.6 (C-2), 78.3 (C-3a and C-7a),
46.9 (C-8), 37.1 (C-7), 34.5 (C-4), 28.4 (COMe), 25.4 (2-Meendo),
24.9 (2-Meexo) and 22.9 (C-9); m/z 222.1247 (1%, M+, C13H18O3
requires 222.1256), 207 (13), 164 (20), 147 (7), 121 (62), 104 (19),
103 (37), 100 (26), 91 (22), 85 (20), 77 (23) and 43 (100).
For
(3aa,4b,4aa,7aa,8b,8aa)-3a,4,4a,7a,8,8a-hexahydro-6,6-
dimethyl-4,8-ethenobenzo[1,2-d:4,5-dꢀ]bis[1,3]dioxol-2-one 30:
mp 205–207 ◦C; mmax/cm−1 1772; dH (CDCl3) 6.16 (2 H, dd, J 3.3
and 4.2, 9-H and 10-H), 4.67 (2 H, br s, 3a-H and 8a-H), 4.20 (2
H, br s, 4a-H and 7a-H), 3.47 (2 H, m, 4-H and 8-H), 1.35 (3 H,
s, 6-Meb) and 1.27 (3 H, s, 6-Mea); saturation at d 6.16 led to NOE
at d 3.47 (5%), saturation at d 4.67 led to NOEs at d 4.20 (10%)
and 3.47 (7%), saturation at d 4.20 led to NOEs at d 4.67 (13%),
3.47 (7%) and 1.27 (2%), saturation at d 3.47 led to NOEs at d
6.16 (6%), 4.67 (3%) and 4.20 (3%), saturation at d 1.35 led to
NOE at d 6.16 (2%) and saturation at d 1.27 led to NOE at d 4.20
(7%); dC (CDCl3) 154.5, 128.4, 110.1, 74.5, 74.0, 38.8, 25.0 and
24.6; m/z 239 (0.5, M+ + 1), 223.0606 (53, M+ − CH3, C11H11O5
requires 223.0605), 180 (9), 119 (14), 118 (29), 107 (48), 95 (25),
94 (43), 91 (26), 79 (35), 77 (23), 59 (40) and 43 (100).
Diels–Alder reaction of 6a with tetracyanoethylene
A solution of 6a (122 mg, 0.802 mmol) and tetracyanoethylene
(102 mg, 0.802 mmol) in benzene (2.0 ml), heated under reflux for
24 h, yielded 31 (141 mg, 63%) as a pale brown solid.
For (3aa,4a,7a,7aa)-8,8,9,9-tetracyano-3a,4,7,7a-tetrahydro-
2,2-dimethyl-4,7-ethano-1,3-benzodioxole 31: mp 218–220 ◦C;
mmax/cm−1 2233 (weak); dH (CDCl3/CD2Cl2/CD3COCD3)
6.52/6.53/6.63 (2 H, dd, J 3.0 and 4.7, 5-H and 6-H),
4.76/4.79/4.87 (2 H, br s, 4-H and 7-H), 3.85/3.92/4.34 (2 H, m,
4-H and 7-H), 1.34/1.32/1.40 (3 H, s, 2-Me) and 1.34/1.32/1.33 (3
H, s, 2-Me); in CDCl3 solution, saturation at d 6.52 led to NOE at d
3844 | Org. Biomol. Chem., 2006, 4, 3838–3848
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3.85 (7%), saturation at d 4.76 led to NOEs at d 3.85 (11%)
and 1.34 (0.7%); saturation at d 3.85 led to NOEs at d 6.52 (7%) and
4.76 (4%) and saturation at d 1.34 led to NOEs at d 6.52 (1.5%)
and 4.76 (9%); dC (CDCl3/CD2Cl2/CD3COCD3) 130.7/131.1/
132.0, 111.6/111.8/112.8, 110.7/111.4/111.7, 109.9/110.6/111.6,
72.3/72.8/73.5, 42.8/43.1/43.4, 25.0/25.1/25.4 and 25.0/
25.1/25.2; m/z 280 (0.7%, M+), 265.0730 (30, M+ − CH3,
C14H9N4O2 requires 265.0725), 100 (17), 95 (57), 85 (12), 59 (48),
58 (17) and 43 (100); analysis: found C, 64.08; H, 4.29; N, 20.04%;
C15H12N4O2 requires C, 64.26; H, 4.32; N, 20.00%.
Dimerization of 7
Diene 7 dimerized to 35 spontaneously during storage, forming
colourless crystals.
For (2a,3ab,5aa,6b,6aa,8b,9aa,10b,10aa,10bb)-3a,5a,6,6a,9a,
10,10a,10b-octahydro-2,8-diphenyl-6,10-ethenonaphtho[1,2-d:6,
7-dꢀ]bis[1,3]dioxole 35: mp 152–154 ◦C; mmax/cm−1 3057, 1522,
1445 and 1055; dH (CDCl3) 7.48–7.24 (10 H, m), 6.17 (2 H, m,
11-H and 12-H), 5.84 (1 H, s, 2-H), 5.68 (2 H, broadened AB, 4-H
and 5-H), 5.61 (1 H, s, 8-H), 4.39–4.31 (3 H, m, 3a-H, 6a-H and
9a-H), 4.30 (1 H, br d, J 5.7, 10b-H), 3.14 (1 H, m, 10-H), 3.07
(1 H, m, 6-H) and 2.44 (2 H, broadened AB, 5a-H and 10a-H);
saturation at d 6.17 led to NOEs at d 3.14 (4%) and 3.07 (4%),
saturation at d 5.84 led to NOEs at d 7.48–7.42 (2%) and 4.30
(7%), saturation at d 5.61 led to NOEs at d 7.48–7.42 (3%) and a
multiplet at 4.38 (3%), saturation at d 4.30 led to NOEs at d 5.84
(12%) and 3.14 (13%), saturation at d 3.14 led to NOEs at d 6.17
(4%), 4.30 (12%) and 2.44 (2%), saturation at d 3.07 led to NOEs
at d 6.17 (4%), 5.68 (5%) and 2.44 (2%) and saturation at d 2.44
led to NOEs at d 5.68 (3%), double-doublets at 4.38 and 4.33
(9%), 3.14 (4%) and 3.07 (5%); dC (CDCl3) 137.9, 136.1, 132.9
(C-11 or C-12), 129.7, 129.2 (C-11 or C-12), 129.1 (C-4 or C-5),
128.3 (4C), 127.4, 127.1, 126.4 (C-4 or C-5), 103.5 (C-2), 103.1
(C-8), 79.7 (C-10b), 79.0 (2C), 70.6, 40.8 (C-6 and C-10), 34.5 and
33.5; m/z 400 (1.6%, M+), 399 (4), 171 (14), 170 (28), 159 (37),
145 (27), 144 (25), 141 (20), 129 (22), 120 (31), 105 (100), 94 (40),
91 (72), 78 (31), 77 (55) and 66 (30); analysis: found C, 78.11; H,
5.99%; C26H24O4 requires C, 77.98; H, 6.04%.
Diels–Alder reaction of 6a with dimethyl acetylenedicarboxylate
A solution of 6a (118 mmol, 0.782 mmol) and dimethyl
acetylenedicarboxylate (111 mg, 0.782 mmol) in benzene (2.0 ml)
was stirred at RT for 17 h. This provided 32 (198 mg, 86%) as
colourless crystals after recrystallization from hexane.
For dimethyl (3aa,4b,7b,7aa)-4,7-dihydro-2,2-dimethyl-4,7-
etheno-1,3-benzodioxole-5,6-dicarboxylate 32: mp 93–94 ◦C;
mmax/cm−1 1732 and 1714; dH (CDCl3) 6.39 (2 H, dd, J 3.1 and
4.4, 8-H and 9-H), 4.39 (2 H, narrow m, 3a-H and 7a-H), 4.23 (2
H, m, 4-H and 7-H), 3.79 (6 H, s, 2 × CO2Me), 1.34 (3 H, s, 2-
Meb) and 1.26 (3 H, s, 2-Mea); saturation at d 6.39 led to NOEs at
d 4.23 (11%) and 1.34 (0.2%), saturation at d 4.39 led to NOEs
at d 4.23 (7%) and 1.26 (1.5%), saturation at d 4.23 led to NOEs
at d 6.39 (9%) and 4.39 (5%), saturation at d 1.34 led to NOE at d
6.39 (2%) and saturation at d 1.26 led to NOE at d 4.39 (9%); dC
=
(CDCl3) 165.8 (2 × C O), 141.3 (C-5 and C-6), 131.2 (C-8 and
C-9), 113.6 (C-2), 78.1 (C-3a and C-7a), 52.4 (2 × OMe), 44.2 (C-4
and C-7), 25.7 (2-Meb) and 25.5 (2-Mea); m/z no M+, 279 (4%),
207 (4), 205 (3), 163 (20), 100 (85), 85 (100) and 43 (22); analysis:
found C, 61.33; H, 6.20%; C15H18O6 requires C, 61.22; H, 6.16%.
Dimerization of 6a
A sample of 6a (214 mg, 1.41 mmol) was kept at RT for 28 d. Flash
chromatography (10% EtOAc in hexanes) gave 36 (41 mg, 19%)
and 37 (129 mg, 60%) as colourless solids.
For (3aa,5ab,6a,6aa,9aa,10a,10ab,10ba)-3a,5a,6,6a,9a,10,10a,
10b-octahydro-2,2,8,8-tetramethyl-6,10-ethenonaphtho[1,2-d:6,
7-dꢀ]bis[1,3]dioxole 36: mp 92–93 ◦C; mmax/cm−1 2985, 2935, 1375,
1238, 1207 and 1061; dH (CDCl3) 6.07 (2 H, narrow m, 11-H and
12-H), 5.56 (1 H, ddd, J 1.3, 3.4 and 10.3, 5-H), 5.49 (1 H, br d, J
10.3, 4-H), 4.19 (1 H, m, 3a-H), 4.06 (3 H, m, 6a-H, 9a-H and 10b-
H), 3.01 (1 H, br d, J 9.0, 5a-H), 2.96 (1 H, br d, J 9.0, 10a-H), 2.80
(2 H, m, 6-H and 10-H), 1.55 (3 H, s, 8-Meb), 1.38 (3 H, s, 2-Meb),
1.35 (3 H, s, 8-Mea) and 1.33 (3 H, s, 2-Mea); saturation at d 6.07
led to NOEs at d 4.19 (3%), 4.06 (0.6%) and 2.80 (5%), saturation
at d 5.56 led to NOEs at d 2.96 (3%) and 2.80 (1%), saturation
at d 5.49 led to NOEs at d 4.19 (2%) and 3.01 (4%), saturation at
d 4.19 led to NOEs at d 6.07 (2%) and 5.49 (4%), saturation at d
4.06 led to NOEs at d 6.07 (2%), 2.96 (4%), 2.80 (11%) and 1.35
(1.5%), saturation at d 2.80 led to NOEs at d 6.07 (7%), 5.56 (4%),
4.06 (8%), 3.01 (4%) and 2.96 (3%) and saturation at d 1.55 led to
NOEs at d 3.01 (5%), 2.96 (5%) and 1.35 (1%); dC (CDCl3) 134.6
(C-12), 131.1 (C-11), 130.3 (C-5), 126.8 (C-4), 111.9 (C-8), 107.4
(C-2), 77.9 (C-10b), 75.2 (C-6a or C-9a), 74.7 (C-6a or C-9a), 71.2
(C-3a), 40.8 (C-6 or C10), 40.3 (C-6 or C10), 30.5 (C-5a and C-
10a), 28.4 (2-Meb), 26.8 (2-Mea), 26.3 (8-Meb) and 24.4 (8-Mea);
m/z no M+, 289 (15%), 275 (2), 231 (3), 188 (40), 171 (85), 159
(30), 153 (19), 145 (20), 143 (26), 129 (26), 100 (50), 91 (34) and
43 (100); analysis: found C, 70.98; H, 7.91%; C18H24O4 requires C,
71.03; H, 7.95%.
Diels–Alder reaction of 6a with ethyl propiolate
A solution of 6a (62 mg, 0.46 mmol) and ethyl propiolate (43 mg,
0.40 mmol) in benzene (0.5 ml) was stirred at RT for 3 days. Adduct
33 (63 mg, 61%) was obtained as a sweet-smelling oil.
For ethyl (3aR*,4R*,7S*,7aS*)-4,7-dihydro-2,2-dimethyl-4,7-
etheno-1,3-benzodioxole-5-carboxylate 33: mmax/cm−1 1713, 1634
and 1598; dH (CDCl3) 7.21 (1 H, dd, J 1.7 and 6.4, 6-H), 6.40
(1 H, br ddd, J 1.6, 6.0 and 6.8, 9-H), 6.30 (1 H, ddd, J 1.7, 6.0
and 6.7, 8-H), 4.39 (1 H, m, 4-H), 4.26 (2 H, m, 3a-H and 7a-H),
4.19 (2 H, dq, J 0.6 and 7.1, OCH2CH3), 4.00 (1 H, m, 7-H), 1.35
(3 H, s, 2-Meendo), 1.29 (3 H, t, J 7.1, OCH2CH3) and 1.26 (3 H, s,
2-Meexo); saturation at d 7.21 led to NOEs at d 4.26 (0.6%) and 4.00
(5%), saturation at d 6.40 led to NOE at d 4.39 (4%), saturation
at d 6.30 led to NOE at d 4.00 (3%), saturation at d 4.39 led to
NOE at d 6.40 (4%), saturation at d 4.26 led to NOEs at d 7.21
(3%), 4.39 (5%), 4.00 (1.5%) and 1.26 (2%), saturation at d 4.00
led to NOEs at d 7.21 (8%) and 6.30 (5%), saturation at d 1.35 led
to NOEs at d 6.40 (1.5%) and 6.30 (1.5%) and saturation at d 1.26
led to NOE at d 4.26 (8%); dC (CDCl3) 164.4 (0), 144.1 (1), 138.7
(0), 132.4 (1), 130.7 (1), 113.2 (0), 78.3 (1), 78.1 (1), 60.7 (2), 43.1
(1), 41.6 (1), 25.8 (3), 25.5 (3) and 14.2 (3); m/z no M+, 235.0957
(3%, M+ − CH3, C13H15O4 requires 235.0969), 163 (10), 147 (5),
135 (7), 105 (25), 100 (96), 91 (10), 85 (100), 77 (16), 60 (14) and
43 (30).
This journal is
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Org. Biomol. Chem., 2006, 4, 3838–3848 | 3845
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For (3aa,5ab,6a,6ab,9ab,10a,10ab,10ba)-3a,5a,6,6a,9a,10,10a,
10b-octahydro-2,2,8,8-tetramethyl-6,10-ethenonaph◦tho[1,2-d:6,7-
dꢀ]bis[1,3]dioxole 37: mp 149–151 ◦C (lit.35 150–151 C); mmax/cm−1
2987, 2930, 2911, 2884, 1456, 1365, 1236, 1046 and 886; dH
(CDCl3) 5.99 (2 H, narrow m, 11-H and 12-H), 5.60 (1 H, dd,
J 3.8 and 10.3, 5-H), 5.51 (1 H, d, J 10.3, 4-H), 4.30 (2 H, m,
6a-H and 9a-H), 4.20–4.14 (2 H, m, 3a-H and 10b-H), 2.87 (2
H, m, 6-H and 10-H), 2.36 (1 H, br d, J 9.1, 5a-H), 2.23 (1 H, d,
J 9.1, 10a-H), 1.36 (3 H, s, 2-Meb), 1.34 (3 H, s, 2-Mea), 1.32 (3
H, s, 8-Mea) and 1.29 (3 H, s, 8-Meb); saturation at d 5.99 led to
NOEs at d 4.17 (4%), 2.87 (5%) and 1.32 (0.3%), saturation at d
5.60 led to NOEs at d 2.87 (2%) and 2.36 (2%), saturation at d
5.51 led to NOE at d 4.17 (2%), saturation at d 4.30 led to NOEs
at d 2.87 (3%), 2.36 (5%) 2.23 (10%) and 1.29 (1%), saturation
at d 4.17 led to NOEs at d 5.99 (2%), 5.51 (4%), 2.87 (6%), 2.23
(3%) and 1.34 (0.7%), saturation at d 2.87 led to NOEs at d 5.99
(7%), 5.60 (6%), 4.30 (4%), 4.17 (10%), 2.36 (3%) and 2.23 (3%),
saturation at d 2.36 led to NOEs at d 5.60 (4%), 4.30 (4%) and
2.87 (2%), saturation at d 2.23 led to NOEs at d 4.30 (4%), 4.17
(1.5%) and 2.87 (0.7%), saturation at d 1.36 led to NOE at d 5.51
(4%), saturation at d 1.34 led to NOE at d 4.17 (9%), saturation at
d 1.32 led to NOE at d 5.99 (2%) and saturation at d 1.29 led to
NOE at d 4.30 (6%); dC (CDCl3) 132.4 (C-12), 129.3 (C-5), 128.8
(C-11), 126.6 (C-4), 108.6 (C-8), 107.6 (C-2), 78.6 (C-6a or C-9a),
78.3 (C-6a or C-9a), 77.6 (C-10b), 70.9 (C-3a), 41.0 (C-6 or C-10),
40.7 (C-6 or C-10), 34.3 (C-10a), 33.1 (C-5a), 28.3 (2-Meb), 26.8
(2-Mea), 25.4 (8-Mea) and 25.0 (8-Meb); m/z no M+, 289 (12%),
246 (8), 230 (7), 188 (49), 171 (20), 158 (26), 145 (19), 143 (18),
131 (20), 129 (22), 119 (22), 100 (30), 95 (72), 91 (36) and 43 (100);
analysis: found C, 71.00; H, 7.84%; C18H24O4 requires C, 71.03;
H, 7.95%.
(likely overlapping the quaternary aromatic signal), 130.1, 129.5,
127.4, 63.6 and 57.4; m/z 287.0893 (3%, M+, C14H13N3O4 requires
287.0905), 258 (8), 228 (16), 227 (83), 119 (42), 91 (12) and
80 (100).
For (5R,8S,10R,11S)-5,8-dihydro-10,11-dihydroxy-2-phenyl-
5,8-ethano-1H -[1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione
39: dH (CDCl3) 7.50–7.35 (5 H, m), 6.56 (2 H, br t, J 3.6), 5.04
(2 H, m), 4.44 (2 H, m) and 2.76 (2 H, OH).
Diels–Alder of 2 with PTAD
PTAD (60 mg, 0.33 mmol) and 2 (85 mg, 0.33 mmol) provided 40
(103 mg, 72%) as colourless crystals.
For (5R,8S,10R,11S)-5,8-dihydro-2-phenyl-10,11-bis(trimethyl-
silyloxy)-5,8-ethano-1H-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-
dione 40: mp 62–63 ◦C; mmax/cm−1 1718; dH (CDCl3) 7.48–7.36 (5 H,
m), 6.55 (2 H, dd, J 3.2 and 4.0, 6-H and 7-H), 4.81 (2 H, m,
5-H and 8-H), 4.34 (2 H, narrow m, 10-H and 11-H) and 0.21
(18 H, s, 2 × OTMS); saturation at d 6.55 led to NOE at d 4.81
(10%), saturation at d 4.81 led to NOEs at d 6.55 (10%) and 4.34
(8%), saturation at d 4.34 led to NOEs at d 4.81 (16%) and 0.21
(0.7%) and saturation at d 0.21 led to NOEs at d 6.55 (1.5%), 4.81
(5%) and 4.34 (5%); dC (CDCl3) 155.6, 130.1, 129.6 (C-6 and C-7),
129.2, 128.4, 125.5, 68.4 (C-10 and C-11), 54.5 (C-5 and C-8) and
0.23 (2 × OTMS); m/z no M+, 416 (3%), 300 (1), 297 (1), 227
(100), 204 (25), 147 (16), 119 (17), 80 (43) and 73 (61); analysis:
found C, 55.70; H, 6.66; N, 9.74%; C20H29N3O4Si2 requires C,
55.66; H, 6.71; N, 9.74%.
Diels–Alder reaction of 4a with PTAD
PTAD (145 mg, 0.830 mmol) and 4a (163 mg, 0.830 mmol)
provided 41 (39 mg, 13%) and 42 (238 mg, 77%) as colourless
crystals.
Diels–Alder reactions with 4-phenyl-1,2,4-triazoline-3,5-dione
(PTAD)
For
(5R,8S,10S,11R)-10,11-bis(acetyloxy)-5,8-dihydro-2-
phenyl-5,8-ethano-1H-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-
dione 41: mp 224–225 ◦C; mmax/cm−1 1744 (m) and 1707; dH
(CDCl3) 7.51–7.36 (5 H, m), 6.60 (2 H, apparent dd, J 3.1 and
4.2, 6-H and 7-H), 5.10 (2 H, m, 5-H and 8-H), 5.04 (2 H, narrow
m, C-10 and C-11), 2.15 (6 H, s, 2 × OAc); saturation at d 6.60
led to NOEs at d 5.10 (10%) and 5.04 (1.5%), saturation at d 5.10
led to NOEs at d 6.60 (9%) and 5.04 (7%) and saturation at d 5.04
led to NOEs at d 6.60 (2%) and 5.10 (12%); dC (CDCl3) 169.8,
155.4, 131.1, 130.1, 129.2, 128.5, 125.6, 63.4, 53.1 and 20.6; m/z
371 (3%, M+), 329 (3), 269 (9), 228 (22), 227 (100), 119 (25), 80
(56) and 43 (71); analysis: found C, 58.27; H, 4.61; N, 11.34%;
C18H17N3O6 requires C, 58.20; H, 4.62; N, 11.32%.
A solution of PTAD in acetone was added dropwise to an
equimolar amount of the diene in acetone. The initial carmine
colour of the PTAD faded as the solution was stirred at RT
for 16–18 h. The solution was concentrated under vacuum, and
1
the residue was analysed by H NMR spectroscopy in order to
obtain the proportions of the adducts in Table 3. The adducts
were isolated by chromatography (20–30% EtOAc in hexanes).
Yields are for the isolated adducts.
Diels–Alder reaction of 1a with PTAD
PTAD (171 mg, 0.98 mmol) and 1a (109 mg, 0.89 mmol) provided
38 (193 mg, 68%), as colourless crystals, and some impure 39
(19 mg, 7% if pure).
For
(5R,8S,10R,11S)-10,11-bis(acetyloxy)-5,8-dihydro-2-
phenyl-5,8-ethano-1H◦-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-
dione 42: mp 219–220 C: mmax/cm−1 1749 and 1717; dH (CDCl3)
7.48–7.36 (5 H, m), 6.58 (2 H, dd, J 3.1 and 4.0, 6-H and 7-H),
5.46 (2 H, narrow m, 10-H and 11-H), 5.10 (2 H, m, 5-H and
8-H), 2.05 (6 H, s, 2 × OAc); saturation at d 6.58 led to NOE at d
5.10 (11%), saturation at d 5.46 led to NOEs at d 5.10 (16%) and
2.05 (0.5%), saturation at d 5.10 led to NOEs at d 6.58 (8%) and
5.46 (8%) and saturation at d 2.05 led to NOEs at d 6.58 (1.5%),
5.46 (1.5%) and 5.10 (1%); dC (CDCl3) 169.2, 155.4, 130.9, 129.5
(C-6 and C-7), 129.1, 128.4, 125.3, 67.0 (C-10 and C-11), 51.4
(C-5 and C-8) and 20.2 (2 × OAc); m/z 371 (1%, M+), 329 (1),
311 (1), 269 (12), 228 (15), 227 (76), 119 (28), 80 (62) and 43 (100);
For (5R,8S,10S,11R)-5,8-dihydro-10,11-dihydroxy-2-phenyl-
5,8-ethano-1H -[1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione
38: mp 226–228 ◦C; mmax/cm−1 1779 (m) and 1738; dH
(CDCl3/CD3OD) 7.50–7.38/7.50–7.40 (5 H, m), 6.51/6.57
(2 H, dd, J 3.2 and 4.1, 6-H and 7-H), 5.00/4.89 (2 H, m, 5-H
and 8-H), 3.95/3.94 (2 H, m, 10-H and 11-H), 3.21/3.30 (2 H,
OH); in CD3OD solution, saturation at d 6.57 led to NOEs at
d 4.89 (4%) and 3.94 (1.5%), saturation at d 4.89 led to NOEs
at d 6.57 (5%) and 3.94 (5%) and saturation at d 3.94 led to
NOEs at d 6.57 (3%) and 4.89 (9%); dC (CD3OD) 156.1, 131.6
3846 | Org. Biomol. Chem., 2006, 4, 3838–3848
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analysis: found C, 58.35; H, 4.63; N, 11.38%; C18H17N3O6 requires
C, 58.20; H, 4.62; N, 11.32%.
d 7.38 (1%) and 6.61 (3%), saturation at d 5.27 led to NOEs at
d 6.61 (5%) and 4.82 (6%) and saturation at d 4.82 led to NOEs
=
at d 7.38 (1%) and 5.27 (11%); dC (CDCl3) 155.5 (C O), 137.8,
131.0, 129.9 (C-11 and C-12), 129.3, 129.1, 128.5, 125.8, 125.4,
106.8 (C-2), 74.7 (C-3a and C-10a) and 52.3 (C-4 and C-10); m/z
375.1218 (12%, M+, C21H17N3O4 requires 375.1218), 269 (88), 240
(83), 227 (94), 121 (51), 119 (89), 105 (24), 91 (34), 80 (100), 78
(81) and 77 (37).
Conversion of 39 to 42
A solution of 39 (12 mg, 0.042 mmol) in pyridine (1.0 ml) and
acetic anhydride (0.5 ml) was stirred at RT overnight. Aqueous
work-up afforded 42 (14 mg, 90%).
Diels–Alder reaction of 6a with PTAD
Diels–Alder reactions with diethyl azodicarboxylate (DEAD)
PTAD (121 mg, 0.689 mmol) and 6a (105 mg, 0.689 mmol)
provided 43 (256 mg, 97%) as colourless crystals.
A solution of DEAD and the diene in benzene was stirred at
RT for 24 h. The solution was concentrated under vacuum, and
the residue was analyzed by H NMR spectroscopy. In all three
1
For
(3aa,4b,10b,10aa)-3a,4,10,10a-tetrahydro-2,2-dimethyl-
7-phenyl-4,10-etheno-6H-1,3-dioxolo[4,5-d][1,2,4]triazolo[1,2-a]-
pyridazine-6,8(7H)-dione 43: mp 248–250 ◦C; mmax/cm−1 1713; dH
(CDCl3) 7.46–7.36 (5 H, m), 6.42 (2 H, dd, J 3.4 and 3.8, 11-H
and 12-H), 5.15 (2 H, m, 4-H and 10-H), 4.66 (2 H, narrow m,
3a-H and 10a-H), 1.35 (6 H, s, 2 × CH3); saturation at d 6.42
led to NOE at d 5.15 (10%), saturation at d 5.15 led to NOEs at
d 6.42 (9%) and 4.66 (6%), saturation at d 4.66 led to NOEs at d
5.15 (14%) and 1.35 (1%) and saturation at d 1.35 led to NOEs at
d 6.42 (3%) and 4.66 (11%); dC (CDCl3) 155.6, 130.7, 129.1, 128.8
(C-11 and C-12), 128.4, 125.5, 112.1, 73.8 (C-3a and C-10a),
52.3 (C-4 and C-10), 25.4 (CH3) and 25.3 (CH3); m/z 327.1210
(2%, M+, C17H17N3O4 requires 327.1217), 312 (11), 269 (23), 240
(41), 227 (100), 121 (29), 119 (59), 95 (73), 91 (18), 80 (67), 78 (42)
and 43 (83).
instances, signals for only one adduct with DEAD were evident,
although a minor amount (12%) of dimer was noted in the reaction
of 8. Adducts were purified by chromatography (30% EtOAc in
hexanes). Yields are for the isolated adducts.
Diels–Alder reaction of 6a with DEAD
DEAD (123 mg, 0.71 mmol) and 6a (108 mg, 0.71 mmol) provided
46 (223 mg, 96%) as a colourless oil.
For diethyl (3aa,4b,7b,7aa)-3a,4,7,7a-tetrahydro-2,2-dimethyl-
4,7-etheno-1,3-dioxolo[4,5-d]pyridazine-5,6-dicarboxylate
46:
mmax/cm−1 1737 and 1725; dH (CDCl3) 6.51 (1 H, br t, J ≈ 6.3),
6.36 (1 H, br t, J ≈ 7.0), 5.15 (1 H, br m), 5.04 (1 H, br m), 4.47
(2 H, br m), 4.40–4.10 (4 H, br m), 1.36–1.23 (6 H, m), 1.32 (3
H, s) and 1.29 (3 H, s); saturation at d 6.40 led to NOEs at d 5.15
(10%) and 5.04 (11%), saturation at d 5.10 led to NOEs at d 6.51
(11%), 6.36 (11%) and 4.47 (8%), saturation at d 4.47 led to NOEs
at d 5.15 (14%), 5.04 (14%) and 1.29 (0.5%), saturation at d 1.32
led to NOEs at d 6.51 (4%) and 6.36 (3%) and saturation at d
1.29 led to NOE at d 4.47 (9%); dC (CDCl3) (Many signals were
broadened, which did not allow detection of the carbonyls.) 133.5,
128.7, 111.0, 73.7, 73.1, 62.9, 62.6, 53.5, 51.3, 25.5, 25.4, 14.4 and
14.3; m/z 326 (1.5%, M+), 311.1253 (7, M+ − CH3, C14H19N2O6
requires 311.1243), 268 (2), 226 (6), 196 (6), 195 (5), 167 (14), 153
(20), 123 (16), 95 (29), 81 (100), 80 (13) and 43 (22).
Diels–Alder reaction of 7 with PTAD
PTAD (110 mg, 0.63 mmol) and 7 (126 mg, 0.63 mmol) provided
44 (130 mg, 55%) as colourless crystals.
For (2a,3ab,4a,10a,10ab)-3a,4,10,10a-tetrahydro-2,7-diphenyl-
4,10-etheno-6H-1,3-dioxolo[4,5-d]-[1,2,4]triazolo[1,2-a]pyrida-
zine-6,8(7H)-dione 44: mp 193–195 ◦C; mmax/cm−1 1719; 1H NMR
dH (CDCl3) 7.47–7.35 (10 H, m), 6.53 (2 H, dd, J 3.2 and 4.0,
11-H and 12-H), 5.80 (1 H, s, 2-H), 5.29 (2 H, m, 4-H and 10-H)
and 4.73 (2 H, narrow m, 3a-H and 10a-H); saturation at d 6.53
led to NOEs at d 7.40 (1%) and 5.29 (11%), saturation at d 5.80
led to NOEs at d 7.40 (3%) and 4.73 (7%), saturation at d 5.29 led
to NOEs at d 6.53 (7%) and 4.73 (7%) and saturation at d 4.73 led
to NOEs at d 5.80 (17%) and 5.29 (15%); dC (CDCl3) 155.5, 134.6,
131.0, 130.1, 129.1 (C-11, C-12 and aromatic signal), 128.4, 127.2,
125.4, 105.6 (C-2), 74.1 (C-3a and C-10a) and 52.1 (C-5 and
C-10); m/z 375.1225 (8%, M+, C21H17N3O4 requires 375.1217),
269 (58), 240 (58), 227 (65), 153 (18), 121 (37), 119 (61), 105 (33),
91 (32), 81 (100), 80 (78), 78 (57) and 77 (36).
Diels–Alder reaction of 7 with DEAD
DEAD (266 mg, 1.52 mmol) and 7 (153 mg, 0.76 mmol) provided
47 (142 mg, 50%) as a pale yellow oil.
For diethyl (2a,3ab,4a,7a,7ab)-3a,4,7,7a-tetrahydro-2-phenyl-
4,7-etheno-1,3-dioxolo[4,5-d]pyridazine-5,6-dicarboxylate
47:
mmax/cm−1 1737 and 1703; dH (CDCl3) 7.37 (5 H, br m), 6.62 (1 H,
br t, J ≈ 6.1), 6.48 (1 H, br t, J ≈ 7.2), 5.69 (1 H, s), 5.30 (1 H, br
m), 5.20 (1 H, br m), 4.56 (1 H, br m), 4.52 (1 H, br m), 4.34–4.10
(4 H, m) and 1.35–1.23 (6 H, m); saturation at d 6.62 and 6.48 led
to NOEs at d 7.37 (0.6%), 5.30 (4%) and 5.20 (4%), saturation at d
5.69 led to NOEs at d 7.37 (2%) and 4.56 and 4.52 (3%), saturation
at d 5.30 and 5.20 led to NOEs at d 6.62 (6%), 6.48 (6%) and 4.56
and 4.52 (5%), saturation at d 4.54 led to NOEs at d 5.69 (6%),
5.30 (4%) and 5.20 (5%) and saturation at d 4.22 led to NOE at d
1.35–1.23 (1%); dC (CDCl3) (Many signals were broadened, which
did not allow detection of the carbonyls.) 135.1, 133.8, 129.8,
129.0, 128.3, 127.2, 104.7, 73.9, 73.4 (br), 63.0, 62.7, 53.3 (br),
51.0 (br), 14.4 and 14.3; m/z 374.1472 (0.5%, M+, C19H22N2O6
requires 374.1478), 302 (3), 268 (3), 239 (5), 196 (10), 195 (8), 167
Diels–Alder reaction of 8 with PTAD
PTAD (146 mg, 0.83 mmol) and 8 (167 mg, 0.63 mmol) provided
45 (196 mg, 62%) as colourless crystals.
For (2a,3aa,4b,10b,10aa)-3a,4,10,10a-tetrahydro-2,7-diphenyl-
4,10-etheno-6H-1,3-dioxolo[4,5-d]-[1,2,4]triazolo[1,2-a]pyridazine-
6,8(7H)-dione 45: mp 238–239 ◦C; mmax/cm−1 1718; dH (CDCl3)
7.48–7.36 (10 H, m), 6.61 (2 H, dd, J 3.4 and 3.8, 11-H, 12-H),
6.10 (1 H, s, 2-H), 5.27 (2 H, m, 4-H and 10-H) and 4.82 (2 H,
narrow m, 3a-H and 10a-H); saturation at d 6.61 led to NOEs at
d 6.10 (7%) and 5.27 (8%), saturation at d 6.10 led to NOEs at
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(19), 153 (22), 123 (18), 105 (12), 95 (11), 91 (8), 81 (100), 80 (12),
78 (10) and 77 (12).
11 J. R. Gillard and D. J. Burnell, Can. J. Chem., 1992, 70, 1296. (Earlier
communication:; J. R. Gillard and D. J. Burnell, J. Chem. Soc., Chem.
Commun., 1989, 1439).
12 D. R. Boyd, M. R. J. Dorrity, M. V. Hand, J. F. Malone, N. D. Sharma,
H. Dalton, D. J. Gray and G. N. Sheldrake, J. Am. Chem. Soc., 1991,
113, 666; S. M. Resnick, D. S. Torok and D. T. Gibson, J. Org. Chem.,
1995, 60, 3546; D. R. Boyd, N. D. Sharma, B. Byrne, M. V. Hand,
J. F. Malone, G. N. Sheldrake, J. Blacker and H. Dalton, J. Chem. Soc.,
Perkin Trans. 1, 1998, 1935.
13 D. W. Jones, J. Chem. Soc., Chem. Commun., 1980, 739; J. B. Macaulay
and A. G. Fallis, J. Am. Chem. Soc., 1990, 112, 1136; M. A. McClinton
and V. Sik, J. Chem. Soc., Perkin Trans. 1, 1992, 1891; D. F. Harvey and
E. M. Grezner, J. Org. Chem., 1996, 61, 159.
Diels–Alder reaction of 8 with DEAD
DEAD (483 mg, 2.77 mmol) and 8 (222 mg, 1.10 mmol) provided
48 (224 mg, 54%) as a pale pink oil.
For diethyl (2a,3aa,4b,7b,7aa)-3a,4,7,7a-tetrahydro-2-phenyl-
4,7-etheno-1,3-dioxolo[4,5-d]pyridazine-5,6-dicarboxylate
48:
mmax/cm−1 1720; dH (CDCl3) 7.35 (5 H, narrow m), 6.69 (1 H, br t,
J ≈ 6.1), 6.56 (1 H, br t, J ≈ 6.6), 6.02 (1 H, s, 2-H), 5.27 (1 H, br
m), 5.17 (1 H, br m), 4.69 (1 H, br m), 4.56 (1 H, br m), 4.31–4.10
(4 H, m, OCH2CH3) and 1.27 (6 H, br t, J 7.0, OCH2CH3);
saturation at d 6.69 and 6.56 led to NOEs at d 6.02 (8%), 5.27
(10%) and 5.17 (10%), saturation at d 6.02 led to NOEs at d 7.35
(1%), 6.69 (1%) and 6.56 (1%), saturation at d 5.27 and 5.17 led to
NOEs at d 6.69 (11%), 6.56 (11%), 4.69 (9%) and 4.56 (9%) and
saturation at d 4.69 and 4.56 led to NOEs at d 5.27 (12%) and
5.17 (12%); dC (CDCl3) (Many signals were broadened, which did
not allow detection of the carbonyls.) 138.1, 134.3, 130.1, 129.1,
128.3, 125.8, 106.0, 74.7, 73.7 (br), 62.9, 62.6, 53.3, 51.3 (br), 14.3
and 14.2; m/z 374.1466 (0.7, M+, C19H22N2O6 requires 374.1476),
302 (3), 268 (2), 239 (4), 196 (9), 195 (7), 167 (16), 153 (21), 123
(16), 105 (18), 95 (11), 91 (9), 81 (100), 80 (11), 78 (11) and 77
(15).
14 M. A. Wellman, L. C. Burry, J. E. Letourneau, J. N. Bridson, D. O.
Miller and D. J. Burnell, J. Org. Chem., 1997, 62, 939, and references
therein.
15 J. D. Xidos, R. A. Poirier, C. C. Pye and D. J. Burnell, J. Org. Chem.,
1998, 63, 105.
16 V. M. Kobal, D. T. Gibson, R. E. Davis and A. Garza, J. Am. Chem.
Soc., 1973, 95, 4420.
17 C. A. Pittol, R. J. Pryce, S. M. Roberts, G. Ryback, V. Sik and J. O.
Williams, J. Chem. Soc., Perkin Trans. 1, 1989, 1160.
18 P. J. Geary, R. J. Pryce, S. M. Roberts, G. Ryback and J. A. Winders,
J. Chem. Soc., Chem. Commun., 1990, 204.
19 W. Downing, R. Latouche, C. A. Pittol, R. J. Pryce, S. M. Roberts, G.
Ryback and J. O. Williams, J. Chem. Soc., Perkin Trans. 1, 1990, 2613.
20 M. F. Mahon, K. Molloy, C. A. Pittol, R. J. Pryce, S. M. Roberts, G.
Ryback, V. Sik, J. O. Williams and J. A. Winders, J. Chem. Soc., Perkin
Trans. 1, 1991, 1255.
21 J. E. Letourneau, M. A. Wellman and D. J. Burnell, J. Org. Chem.,
1997, 62, 7272.
22 M. G. Banwell and J. R. Dupuche, Chem. Commun., 1996, 869.
23 J. Zezula, T. Hudlicky and I. Ghiviriga, I., Collect. Czech. Chem.
Commun., 2001, 66, 1269.
Acknowledgements
24 T. Hudlicky, H. F. Olivo and B. McKibben, J. Am. Chem. Soc., 1994,
116, 5108.
25 M. G. Banwell, D. C. R. Hockless, J. W. Holman, R. W. Longmore,
K. J. McRae and H. T. T. Pham, Synlett, 1999, 1491.
26 I. C. Cotterill, S. M. Roberts and J. O. Williams, J. Chem. Soc., Chem.
Commun., 1988, 1628.
Financial support from the Natural Sciences and Engineering
Research Council of Canada is gratefully acknowledged. We thank
Ms. N. Brunet for the NMR spectra and Ms. M. Baggs and Dr.
B. Gregory for the MS data.
27 K. Schu¨rrle, B. Beier and W. Piepersberg, J. Chem. Soc., Perkin Trans. 1,
1991, 2407; T. Hudlicky and H. F. Olivo, J. Am. Chem. Soc., 1992, 114,
9694; S. Elango, Y.-C. Wang, C.-L. Cheng and T.-H. Yan, Tetrahedron
Lett., 2002, 43, 3757.
28 A. C. Spivey, C. G. Man˜as and I. Mann, Chem. Commun., 2005, 4426.
29 J. R. Gillard, M. J. Newlands, J. N. Bridson and D. J. Burnell,
Can. J. Chem., 1991, 69, 1337.
30 A. P. Henderson, E. Mutlu, A. Leclercq, C. Bleasdale, W. Clegg, R. A.
Henderson and B. T. Golding, Chem. Commun., 2002, 1956.
31 C. C. Pye, J. D. Xidos, R. A. Poirier and D. J. Burnell, J. Phys. Chem.
A, 1997, 101, 3371.
32 M. Ishida, H. Kobayashi, S. Tomohiro and S. Inagaki, J. Chem. Soc.,
Perkin Trans. 2, 2000, 1625.
33 L. A. Paquette, J. C. Weber, T. Kobayashi and Y. Miyahara, J. Am.
Chem. Soc., 1988, 110, 8591.
34 S. V. Ley, A. J. Redgrave, S. C. Taylor, S. Abmed and D. W. Ribbons,
Synlett, 1991, 741.
35 T. Hudlicky, E. E. Boros, H. F. Olivo and J. S. Merola, J. Org. Chem.,
1992, 57, 1026.
36 T. Hudlicky and C. H. Boros, Tetrahedron Lett., 1993, 34, 2557; M. R.
Stabile, T. Hudlicky and M. L. Meisels, Tetrahedron: Asymmetry, 1995,
6, 537.
References
1 D. T. Gibson, M. Hensley, H. Yoshioka and T. J. Mabry, Biochemistry,
1970, 9, 1626.
2 D. T. Gibson and V. Subramanian, in Microbial Degradation of Organic
Compounds, ed. D. T. Gibson, Marcel Dekker, New York, 1984, ch. 7
and references therein; T. Hudlicky and C. H. Boros, Synthesis, 1992,
174.
3 Reviews: H. A. J. Carless, Tetrahedron: Asymmetry, 1992, 3, 795; T.
Hudlicky and A. J. Thorpe, Chem. Commun., 1996, 1993.
4 M. G. Banwell, A. J. Edwards, G. J. Harfoot and K. A. Jolliffe, J. Chem.
Soc., Perkin Trans. 1, 2002, 2439; M. G. Banwell, A. J. Edwards, M. D.
McLeod and S. G. Stewart, Aust. J. Chem., 2004, 57, 641.
5 D. A. Spiegel, J. T. Njardarson and J. L. Wood, Tetrahedron, 2002, 58,
6545.
6 H. Uno, T. Ishikawa, T. Hoshi and N. Ono, Tetrahedron Lett., 2003,
44, 5163.
7 M. G. Banwell and G. J. Harfoot, Aust. J. Chem., 2004, 57, 895.
8 M. G. Banwell, A. J. Edwards, G. J. Harfoot and K. A. Jolliffe,
Tetrahedron, 2004, 60, 535.
9 M. E. Salvati, A. Balog, W. Shan, D. D. Wei, D. Pickering, R. M. Attar,
J. Geng, C. A. Rizzo, M. M. Gottardis, R. Weinmann, S. R. Krystek,
J. Sack, Y. An and K. Kish, Bioorg. Med. Chem. Lett., 2005, 15, 271.
10 Recent syntheses in which the use of 1a/b was not as a Diels–Alder
diene: J. M. Ready, S. E. Reisman, M. Hirata, M. M. Weiss, K. Tamaki,
T. V. Ovaska and J. L. Wood, Angew. Chem., Int. Ed., 2004, 43, 1270;
37 C. H. Tran, D. H. G. Crout, W. Errington and G. M. Whited,
Tetrahedron: Asymmetry, 1996, 7, 691.
38 J. C. Mcauliffe, G. M. Whited and W. C. Smith, PCT Int. Appl., 2002,
156.
39 N. C. Yang, M.-J. Chen and P. Chen, J. Am. Chem. Soc., 1984, 106,
¨
G. Ozer, N. Saracoglu, A. Menzek and M. Balci, Tetrahedron, 2005, 61,
7310.
1545.
40 A. Baran, H. Sec¸en and M. Balci, Synthesis, 2003, 1500.
3848 | Org. Biomol. Chem., 2006, 4, 3838–3848
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