Generation and Reactions of an Octacyclic Hindered Pyramidalized Alkene

Article abstract of DOI:10.1021/acs.joc.8b00212

Octacyclo[10.6.1.0^1,10.0^3,7.0^4,9.0^8,19.0^11,16.0^13,17]nonadeca-5,8,14-triene (27), a hindered pyramidalized alkene, has been generated from a diiodide precursor. Contrary to the usual behavior of known pyramidalized alkenes, no Diels-Alder adducts were obtained from the present alkene when it was generated by different standard procedures in the presence of different dienes. However, products derived from the reduction, t-BuLi addition, condensation with the solvent, or dimerization were isolated from these reactions, depending on the conditions used to generate it. No [2 + 2] cross product among this pyramidalized alkene and tricyclo[3.3.1.0^3,7]non-3(7)-ene was formed when a mixture of the corresponding precursor diiodides was reacted with sodium amalgam. The analysis of selected geometrical and orbital parameters determined from quantum mechanical calculations indicates that the degree of pyramidalization of this alkene and its higher steric hindrance compared with other polycyclic pyramidalized alkenes may explain its peculiar reactivity.

Full text of DOI:10.1021/acs.joc.8b00212

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Generation and reactions of an octacyclic hindered pyramidalized alkene.
Pelayo Camps, David Lozano, Carla Barbaraci, merce font-bardia, F. Javier Luque, and Carolina Estarellas
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 13 Apr 2018
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Generation and reactions of an octacyclic hindered pyramidalized alkene.
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Pelayo Camps,*† David Lozano,† Carla Barbaraci,† Merce FontꢀBardia,§ǁ F. Javier
Luque,‡ Carolina Estarellas‡
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† Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia
i Ciències de l’Alimentació, and Institut de Biomedicina (IBUB), Universitat de
Barcelona, Av. Joan XXIII 27−31, 08028 Barcelona (Spain).
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§ Departament de Cristal·lografia, Mineralogia i Dipòsits Minerals, Universitat de
Barcelona, Martí Franquès s/n, 08028 Barcelona (Spain).
ǁ Unitat de Difracció de RX, Centres Científics i Tecnològics de la Universitat de
Barcelona (CCiTUB), Solé i Sabarís 1−3, 08028 Barcelona (Spain)
‡ Departament de Nutrició, Ciències de l’Alimentació i Gastronomia, Universitat de
Barcelona, Av. Prat de la Riba 171, 08921 Santa Coloma de Gramenet (Spain) and
Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27−31,
08028 Barcelona (Spain).
I
I
I
I
H
H
H
H
K
18.crown-6
THF/DMF,
0.48% Na/Hg,
1,4-dioxane
H
H
I
I
H
H
27
Several dienes
No Diels-Alder adducts
Abstract. Octacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadecaꢀ5,8,14ꢀtriene (27) a
hindered pyramidalized alkene, has been generated from a diiodide precursor. Contrary
to the usual behavior of known pyramidalized alkenes, no DielsꢀAlder adducts were
obtained from the present alkene when it was generated by different standard
procedures in the presence of different dienes. However, products derived from the
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reduction, tꢀBuLi addition, condensation with the solvent, or dimerization, were isolated
from these reactions, depending on the conditions used to generate it. No [2+2] cross
product among this pyramidalized alkene and tricyclo[3.3.1.03,7]nonꢀ3(7)ꢀene was
formed when a mixture of the corresponding precursor diiodides was reacted with
sodium amalgam. The analysis of selected geometrical and orbital parameters
determined from quantum mechanical calculations indicates that the degree of
pyramidalization of this alkene and its higher steric hindrance compared with other
polycyclic pyramidalized alkenes may explain its peculiar reactivity.
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Introduction
The chemistry of highly pyramidalized alkenes has been the subject of several reviews1ꢀ
7 and new highly reactive intermediates of this kind have been recently described.8ꢀ12 In
a pyramidalized alkene, the olefinic carbon atoms are rehybridized by admixture of
additional p character into the original sp2
σꢀorbitals. This makes the geometry around
the olefinic carbon atoms nonꢀplanar. The
π bond is now formed from two pꢀorbitals
with some sꢀcharacter. These orbitals are well aligned (torsion angle = 0), but they are
not parallel. Consequently, the distance between them increases and the neat overlap
decreases, affecting the intrinsic reactivity properties of the pyramidalized double bond.
From a structural point of view, the degree of pyramidalization of synꢀpyramidalized
alkenes belonging to the C2v point group of symmetry (left structure of Figure 1) can be
described by the pyramidalization angle (Φ), which corresponds to the angle between
the plane containing one of the olefinic carbon atoms and the two substituents attached
to it and the elongation of the C=C bond. Its value can be obtained according to the
formula given in Figure 1 from the RCC (α) and RCR (β) angles. For alkenes belonging
to the Cs point group of symmetry (right structure of Figure 1), the flap or hinge angle
(
Ψ
), corresponding to the dihedral angle among the R2CCR2 and R1CCR1 planes, or its
supplementary angle ( ), are usually used. While pyramidalized alkenes are generally
ζ
related to the geometrical strain of the olefinic carbon atoms, it is worth noting that
alkene pyramidalization may also occur due to electronic effects.13
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Figure 1. Pyramidalization angle (
Φ), flap angle (Ψ), and supplementary flap angle (ζ =
180º − ) in synꢀpyramidalized alkenes
Ψ
With regard to the synthetic accessibility, the more pyramidalized alkenes are usually
generated by reaction of a vicinal double bridgehead diiodide or dibromide with an
organolithium reagent in THF, sodium/potassium alloy or sodium amalgam in an ether
solvent or molten sodium in boiling 1,4ꢀdioxane. Scheme 1 collects several of the most
representative reactions of pyramidalized alkenes.
Borden et al.14 generated pyramidalized alkene 2 (tricyclo[3.3.1.03,7]nonꢀ3(7)ꢀene) on
reaction of diiodide 1 with nꢀbutyllithium in THF at low temperature and isolated the
cyclobutane dimer 3 in good yield. Also, reaction of diiodide 1 with liquid sodium
amalgam in the presence of ethyleneꢀbis(triphenylphosphine)Pt(0), gives the Pt complex
4 derived from pyramidalized alkene 2.15,16
Paquette, Borden et al.17 also generated the pyramidalized alkene 6 (a bisethano
derivative of bicyclo[3.3.0.03,7]octꢀ1(5)ꢀene) on reaction of diiodide 5 with tꢀBuLi in
THF, isolating the reduction product 7 and product 8 derived from the addition of tꢀ
BuLi to alkene 6. The ratio 7/8 was temperature dependent, formation of 8 highly
increasing with temperature. Our group generated the pyramidalized alkene 10 from
diiodide 9 on reaction with molten sodium in boiling 1,4ꢀdioxane, isolating diene 12 in
good yield.18 This product might be derived from pyramidalized alkene 10 by
dimerization to the highly strained cyclobutane derivative 11 followed by a thermal
[2+2] retrocycloaddition process. In fact, irradiation of diene 12 gave cyclobutane dimer
11, which slowly reverted in CDCl3 solution at room temperature to diene 12.
Lukin and Eaton19 generated 1,2ꢀdehydrocubane (cubene, 15), one of the most highly
pyramidalized alkenes ever prepared, by reaction of 1ꢀiodoꢀ2ꢀ(trimethylsilyl)cubane
with fluoride anions. This alkene was trapped as a DielsꢀAlder adduct (16) with diene
14. In the absence of diene 14, cubene dimerized to a cyclobutane dimer that
experiences different kinds of intramolecular [2+2] retrocycloaddition processes (not
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shown in Scheme 1). Our group carried out cross coupling reactions among different
pyramidalized alkenes with ether or acetal functionalized diiodide precursors. For
instance, reaction of a mixture of diiodides 9 and 17 with molten sodium in boiling 1,4ꢀ
dioxane gave a mixture of the cyclobutane and diene cross products, 22 and 23,
respectively, derived from the corresponding pyramidalized alkenes, 18 and 10. The
diene dimer 12 and other side products, such as 19, a product of addition of alkene 10 to
the solvent, or 20, a dihydrodimer of 10, were also isolated.5
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Scheme 1. Described procedures to generate pyramidalized alkenes and reaction products.
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n-BuLi, THF,
-78 ºC
ref. 14
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8
3
I
I
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1
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[(C6H5)3P]2Pt(CH2=CH2)
Na/Hg, THF
ref. 15, 16
ref. 17
Pt
(C6H5)3P
P(C6H5)3
4
+
t-BuLi
I
H
7
C(CH3)3
8
I
H
H
6
5
THF, 78 ºC, ratio 7/8 = 2:1
ether/pentane, 0 ºC, ratio 7/8 = 1:20
Na,
1,4-dioxane,
reflux
h
ref. 18
I
I
10
11
12
9
14
(n-Bu)4N
ref. 19
SiMe3
F
THF, 0 5 ºC
I
15
13
16
Molten Na,
1,4-dioxane, reflux
O
O
O
O
O
O
O
O
9
+
10
+
I
I
17
18
O
O
O
O
12 +
H
H
O
H
+
+
H
H
O
21
ref. 5
19
20
O
O
O
O
O
O
O
O
+
+
22
23
Molten Na,
1,4-dioxane, reflux
ref. 20
I
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I
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26
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When diiodide 24 was reacted with molten sodium in boiling 1,4ꢀdioxane, product 26, a
dimer from a formal [2+2+2+2]ꢀcycloaddition of pyramidalized alkene 25 was isolated
in 24% yield.20 This is the only example of such a kind of dimerization of a
pyramidalized alkene.
Pyramidalized alkenes show a certain biradical character,19 and their contribution might
be important in reactions, such as the [2+2] and the [2+2+2+2] cyclizations, which are
likely to be stepwise biradical processes.
Following our previous efforts,5,18,20 in this study we report the generation of
octacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadecaꢀ5,8,14ꢀtriene (27), a hindered
pyramidalized alkene, by using standard procedures from a diiodide precursor.
Furthermore, we provide an exhaustive characterization of its chemical reactivity, which
strikingly was unable to form DielsꢀAlder adducts in contrast with the usual behavior of
pyramidalized alkenes.
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Results and Discussion
Recently, we have described21 the preparation of octacycle 28 as a possible precursor of
pyramidalized alkene 27 (Scheme 2) by reaction with fluoride anions, following the
procedure described by Lukin and Eaton19 to generate cubene 15. However, all attempts
to generate 27 on reaction with CsF alone or in combination with AgF in the presence
of dienes, such as 1,3ꢀdiphenylisobenzofuran, tetraphenylcyclopentadienone, furan or
anthracene at different temperatures, left the starting compound unchanged. When
compound 28 was reacted with dimethyl acetylenedicarboxylate 29, CsF and AgF in the
presence of tris(dibenzylideneacetone)dipalladium(0)·CHCl3 [Pd(dba)2·CHCl3] as
catalyst, product 30 was obtained as a result of cocyclotrimerization of 29 and 28, at the
C=C bond further from the iodine and trimethylsilyl groups. In all the reactions, the
obtained products always contained the trimethylsilyl group. The lack of reactivity of
the trimethylsilyl group towards fluoride anions is likely due to the steric hindrance
experienced by this group.
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Scheme 2. Attempted generation of 27 from 28.
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To solve this problem, we have prepared diiodide 38 according to Scheme 3. 5,5ꢀ
Bisacetoxymethylꢀ1,3ꢀcyclopentadiene22 31 was reacted with ethyneꢀ1,2ꢀ
diylbis(phenyl)iodonium ditriflate 32, prepared as described,23 and the crude product
was directly reacted with an equimolar mixture of NaI and CuI to give the diiodide 34
in 35% yield.
Scheme 3. Preparation of octacycle 38 from cyclopentadiene 31.
Reaction of 31 with the less electrophilic, but much more readily available dienophile,
2ꢀiodoethynyl(phenyl)iodonium triflate,24 in acetonitrile at reflux for 64 h, followed by
treatment with NaI / CuI did not give the expected diiodide 34. Reaction of 34 with
methanol catalyzed by K2CO3 gave in good yield the corresponding diol 35, which was
transformed into the corresponding bismesylate 36 on reaction with MsCl in the
presence of Et3N. Reaction of 36 with NaI in acetone at reflux gave the tetraiodide 37 in
good yield. Reaction of 37 with potassium cyclopentadienide in a mixture THF/DMF in
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the presence of a catalytic amount (5 mol %) of 18ꢀcrownꢀ6 gave in high yield the
desired octacyclic diiodide 38. As in the preparation of 28, this transformation implies a
double domino nucleophilic substitution of neopentylꢀtype iodides by the
cyclopentadienide anion followed by a double intramolecular DielsꢀAlder reaction, with
formation of six new CꢀC bonds and four new cycles apart from those of the
cyclopentadienide. Thus, the octacyclic product 38 is formed from the bicyclic
precursor 37 in only one step. Although the structure of the symmetric compound 38 (Cs
point group) was clearly deduced from the 1Hꢀ and 13CꢀNMR data, it was confirmed by
Xꢀray diffraction analysis. See ORTEP structure of diiodide 38 in the SI.25
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When a cold solution of diiodide 38 and 1,3ꢀdiphenylisobenzofuran 42 in THF was
treated with a pentane solution of tꢀBuLi, the expected DielsꢀAlder adduct from the
reaction of the pyramidalized alkene 27 and diene 42 was not observed in the crude
1
product by HꢀNMR. After column chromatography, the only isolated product was 39
(26% yield), which must derive from the reaction of 27 with tꢀBuLi followed by
protonation during the quenching of the reaction mixture.17 Similar results were
obtained when diene 42 was replaced by anthracene or diene 14 in the above reaction.
1
In both cases, the HꢀNMR spectrum of the crude product did not show the expected
signals for the corresponding DielsꢀAlder adducts and, after column chromatography,
the only isolated product was always 39 (Scheme 4).
To solve this problem, a solution of diiodide 38 and diene 14 in 1,4ꢀdioxane was added
1
to an excess of 0.48% sodium amalgam. The HꢀNMR spectrum of the crude product
from this reaction did not show the presence of the expected DielsꢀAlder adduct from
pyramidalized alkene 27 and diene 14. By column chromatography, two hydrocarbon
products were isolated, the reduction product 40 (5%) and the [2+2+2+2] dimer 43
(16%). Worthy of note, when a solution of diiodide 38 in 1,4ꢀdioxane was reacted with
0.48% sodium amalgam in the absence of diene 14, the formation of dimer 43 was not
observed. Compound 40 was the only isolated product (61% yield). The structure of 40
was easily deduced from its NMR data, which show the high symmetry of this
compound (C2v point group of symmetry) and later confirmed by Xꢀray diffraction
analysis. See ORTEP structure of compound 40 in the SI.26
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Scheme 4. Transformations of octacycle 38.
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5
Ha
Ha Hb
Hb
40 (55%)
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7
8
9
1
2
18
3
+
17
15
4
11
10
9
5
16
H
H
H
H
14
13
19
12
H
8H7
C(CH3)3
6
40
(61% yield)
H
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H
H
39
(26%)
H
H
O
C6H5
O
0.48% Na/Hg,
1,4-dioxane,
r.t. 24 h
O
41
(25%)
Molten Na
1,4-dioxane,
reflux, 4 h
C6H5
42
t-BuLi (1.3 M, pentane),
anh. THF, −67 ºC, 30 min
then, r.t., 30 min
38
14
1
0.48% Na/Hg,
1,4-dioxane
r.t. 24 h
0.47% Na/Hg,
1,4-dioxane,
r.t. 24 h
38
7
6
5
24
8
23
26
16
17
14
10
22
21
27 + 2
9
15
25
19
12
4
11
13
40
(5%)
+
27
3
20
28
18
1
2
37
3
40
(36%)
(20%) +
30
29
34
36
31
35
43 (16%)
32
33
In the case of dimer 43, the structure was first obtained by Xꢀray diffraction analysis,
and the data showed that the unit cell of 43 contains one molecule of each enantiomer
(Figure 2).27
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Figure 2. (Top) ORTEP representation of diiodide 43: ellipsoid contour at 50% probability level.
(Bottom) unit cell of dimer 43.
Keeping in mind the C2 symmetry point group of 43 and the fact that all signals of the
13
different protons and C atoms of 43 appear clearly separated, except for both pairs of
1
13
methylenic protons, we could fully assign its Hꢀ and CꢀNMR spectra with the aid of
1
1
the H/1H homocorrelation spectra (COSY and NOESY) and H/13C heterocorrelation
spectra (sequence gHSQC for one bond correlations and gHMBC for long range
correlations). Specially significant to carry out this assignment was the observation of
correlations among pairs of protons belonging to different half of the molecule, such as
13(30)ꢀH (
= 2.24−2.29 ppm) and 14(29)ꢀH/18(25)ꢀH (
spectrum (Figure 3).
δ
= 1.70 ppm)/18(25)ꢀH (
δ
= 1.98 ppm)/, 14(29)ꢀH (
δ
= 1.63 ppm)/17(26)ꢀH
1
(δ
δ
= 1.98 ppm) in its H/1H NOESY
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1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
2.5
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2 .6
2 .5
2 .4
2 .3
2.2
2.1
2.0
1.9
1.8
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1.6
1.5
1.4
1.3
f2 (p pm )
Figure 3. Significant 1H/1H correlations among protons of different half of 43 in its NOESY spectrum.
When diiodide 38 was added to molten sodium in boiling 1,4ꢀdioxane, the standard
conditions used by our group to obtain dimers from pyramidalized alkenes,5,18,20 once
again no dimer was observed in the crude reaction product (1HꢀNMR) and, after column
chromatography, compounds 40 (55% yield) and 41 (25% yield) were the only isolated
products. The last one is a formal addition product of pyramidalized alkene 27 to the
solvent.
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Pyramidalized alkene 27 contains the tricyclo[3.3.1.03,7]nonane substructure of 2. Since
pyramidalized alkene 2 dimerizes to a cyclobutane dimer 3,14 a cross coupling reaction
among the pyramidalized alkenes 27 and 2 might give a cross cyclobutane product.
When a solution of diiodides 38 and 1 (ratio 38/1 = 1/3) in 1,4ꢀdioxane was reacted with
liquid (0.47%) sodium amalgam, the only isolated products were the cyclobutane dimer
3 (20% yield) and the reduction product 40 (36% yield).
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Attempted formation of a bis(triphenylphosphine)Pt(0) complex derived from 27 was
carried out by reacting a THF solution of 38 and ethyleneꢀbis(triphenylphosphine)Pt(0)
with liquid (0.47%) sodium amalgam, following the procedure described by Borden et
al.15,16 to prepare complex 4 from pyramidalized alkene 2 (Scheme 1). However, a
complex mixture of products was obtained, from which the expected complex could not
be isolated.
The preceding results might be explained by assuming the formation of pyramidalized
alkene 27 on reaction of diiodide 38 with tꢀBuLi, sodium amalgam or molten sodium in
boiling 1,4ꢀdioxane. Thus, although it does not react with the different studied dienes, it
does not experience cross coupling with tricyclo[3.3.1.03,7]nonꢀ3(7)ꢀene 2, and it does
not form a complex with bis(triphenylphosphine)Pt(0), it reacts however with tꢀBuLi to
give the addition product 39, with 1,4ꢀdioxane to give the reduction product 40 or the
addition product 41, and in only one occasion, dimer 43, a kind of reactions also
observed for other pyramidalized alkenes. On the contrary, pyramidalized alkene 6
(Scheme 1), generated by reaction of diiodide 5 with liquid sodium amalgam, gave in
good yields DielsꢀAlder adducts with many dienes, such as 14 (Scheme 1), 1,3ꢀ
diphenylisobenzofuran 42, furan or 2,5ꢀdimethylfuran,28 as well as a cross coupling
product with pyramidalized alkene 10 (see structure on Scheme 1).29 Moreover, the
related pyramidalized alkene 18 from diiodide 17, also gave cross coupling reaction
with pyramidalized alkene 10 (Scheme 1) and a DielsꢀAlder adduct with 1,3ꢀ
diphenylisobenzofuran 42.5
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Figure 4. Calculated structures for pyramidalized alkenes 27, 25 and 6: Pyradimalization angles (ϕ), flap
angles (ψ), supplementary flap angles (ζ), dihedral angles formed by the shown planes (º) and biradical
character (number of unpaired electrons). Numbering of the different carbon atoms correspond to their
IUPAC names as bridged polycyclic compounds.
The results herein described can be partly explained on the basis of the lower
pyramidalization and greater steric hindrance of alkene 27 compared with the related
alkenes 6, 18 or 25. Using the optimized geometries of pyramidalized alkenes 27, 6 and
25 obtained from M06ꢀ2X/6ꢀ311+G(d)30,31 calculations (Figure 4), the pyramidalization
angle (ϕ) of alkenes 6 and 25, which contain the substructure of tricyclo[3.3.0.03,7]octꢀ
1(5)ꢀene, were calculated to be both equal to 68.3º. Since for symmetry reasons, the
pyramidalization angle of alkene 27 is not applicable, comparison will be performed on
the basis of their flap (ψ) or complementary flap angles (ζ). The complementary flap
angles of alkenes 6 and 25 were calculated to be 70.1º and 70.2º, respectively, quite
close to their pyramidalization angles. However, in alkene 27, a value of 52.0º
calculated for the complementary flap angle is indicative of a much lower degree of
pyramidalization, in concordance with the fact that this alkene contains the substructure
of tricyclo[3.3.1.03,7]nonꢀ3(7)ꢀene (2), for which a pyramidalization angle (ϕ) of 53.7º
had been calculated with the B3LYP/6ꢀ31G(d) basis set.5
The differences in the degree of pyramidalization of alkenes 27, 6, and 25 are also
reflected in the orbitalic features of the double bond (Figure 5), as revealed from the
analysis of the natural bond orbitals (NBO)32 derived at the CISD/6ꢀ31G(d)33 level. For
standard double bonds (i.e., without geometrical strain), the sp2 hybridization implies a
spatial orientation of the π orbital of 90º. In pyramidalized alkenes, however,
geometrical distortion introduces a deviation in the angle formed by the atomic hybrid
orbital. The results indicate that the deviation angle for alkenes 25 and 6 amounts to
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124º and 123º, respectively, while the deviation angle for alkene 27 is 114o. This
confirms that the structural stress in alkene 27, which contains the
tricyclo[3.3.1.03,7]nonꢀ3(7)ꢀene subunit, is lower than in the more reactive alkenes 6 or
25, which contains the tricyclo[3.3.0.03,7]octꢀ1(5)ꢀene moiety.
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Figure 5. Representation of molecular orbitals obtained via CISD/6ꢀ31G(d) for alkenes 27, 25 and 6.
Furthermore, the biradical character of compounds 27, 25 and 6 was examined
following the method of Takatsuka et al.,34 which relies on the number of unpaired
electrons (Ne; Eq. 1) determined from the occupancy of the natural orbitals obtained
from brokenꢀsymmetry calculations at the UHF/6ꢀ31G(d) level.
(1)
N = n 2− n
∑
(
)
e
i
i
i
where
denotes the occupation number.
ni
The results point out that Ne increases from 27 (1.37) to 6 (1.51) and to 25 (1.85). This
can be interpreted from the larger degree of pyramidalization of the double bond in the
two latter compounds (see above). Nevertheless, keeping in mind the similar
geometrical features of 25 and 6 (see Figure 4), the larger value of Ne determined for
alkene 25 compared to compound 6 reveals the contribution played by the double bonds
located at the two ends of the molecule (between atoms 5 and 6 as well as 11 and 12;
Figure 4). A similar effect can be expected for compound 27 due to the presence of the
double bond (between atoms 5 and 6; Figure 4). Indeed, calculations performed for the
compound obtained upon saturation of this double bond leads to an estimated Ne value
of 1.18. Accordingly, it can be concluded that the geometrical differences introduced by
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the distinct bridges in the skeleton of these alkenes increase effectively the biradical
character of the most strained compounds.
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Finally, to evaluate the relative steric hindrance of alkenes 6, 25 and 27, the external
angles among the planes defined by the atoms C8, C9, C11 and C12, on one hand, and
C8, C9, C5 and C6, on the other hand, were calculated (see Figure 6). For alkenes 6 and
25, which contain the same carbocyclic skeleton, angles of 192.3º and 193.0º were
calculated. However, for alkene 27, the corresponding value was 170.7º. These values
show that the external face of the pyramidalized C=C bond in compounds 6 and 25 is
much more accessible than in alkene 27.
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Overall, the combination of lower degree of pyramidalization and higher steric
hindrance can explain the reactivity observed for the hypothetical pyramidalized alkene
27. From the obtained results, it may be assumed that alkene 27 might be generated
from diiodide 38 under the different reaction conditions studied: a) reaction with tꢀBuLi
in THF, since product 39, derived from the addition of the tꢀbutyl group to 27 was
obtained; b) reaction with sodium amalgam, since the reduction product 40 and dimer
43 were isolated; c) reaction with molten sodium in boiling 1,4ꢀdioxane, since the
reduction product 40 and the product of addition of 27 and the solvent were isolated.
The lack of reactivity of 27 towards different dienes, ethyleneꢀ
bis(triphenylphosphine)Pt(0) or tricyclo[3.3.1.03,7]nonꢀ3(7)ꢀene
2
(generated
simultaneously in situ) can be explained on the basis of the steric hindrance and the
possibility of alternative transformations. For instance, in the attempted cross coupling
among pyramidalized alkenes 2 and 27, compound 3, the cyclobutane dimer of 2, and
the reduction product 40 were the only isolated products. Reasonably, the formation of
these products must be faster than the cross coupling of 2 and 27, mainly due to the
steric hindrance of 27. However, alternative mechanisms to explain these results can not
be ruled out.
CONCLUSION
Octacyclic diiodide 38 was prepared from cyclopentadiene 31, following a synthetic
sequence parallel to that previously used to prepare the octacyclic iodo trimethylsilyl
derivative 28. Pyramidalized alkene 27 may be assumed to be generated from diiodide
38 under the usual conditions utilized to generate most of the pyramidalized alkenes
described to date, i.e.: reaction with tꢀBuLi/THF/low temperature, liquid sodium
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amalgam/1,4ꢀdioxane at room temperature, or molten sodium in boiling 1,4ꢀdioxane.
However, 27 could not be trapped with dienes 14 (see Scheme 1), 1,3ꢀ
diphenylisobenzofuran 42, or anthracene, no matter the conditions used to generate it.
Different products derived from 27 have been isolated from these reactions, among
them 39, on reaction with tꢀBuLi, 40 and 41 on reaction with the solvent 1,4ꢀdioxane,
and dimer 43. At present, however, alternative pathways for the formation of these
products not implying the intermediate formation of pyramidalized alkene 27 can not be
excluded. From the calculated structures, a lower pyramidalization and a greater steric
hindrance of 27 compared with alkenes 6 and 25 was deduced. The combination of
these two factors might explain the obtained results. From a synthetic point of view, it is
worth noting that the bicyclic tetraiodide 37 is transformed in only two steps into
nonadecacycle 43, via the octacyclic diiodide 38.
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EXPERIMENTAL
General Experimental Methods. Melting points were determined in open capillary
tubes with a MFB 595010M Gallenkamp melting point apparatus. All new compounds
were fully characterized by their analytical (melting point, elemental analysis and/or
accurate mass measurement, spectroscopic data (IR, 1H NMR and 13C NMR) and in the
cases of compounds 38, 40 and 43, also by XꢀRay diffraction analysis. Assignments
1
given for the NMR spectra are based on DEPT, H/1H homocorrelations (COSY and
1
1
NOESY), H/13C single quantum correlation (gHSQC sequence) and H/13C multiple
1
13
bond correlation (gHMBC sequence) spectra. Hꢀ and CꢀNMR spectra were recorded
1
on a Varian Mercury 400 (400 MHz for H and 100.6 MHz for 13C) spectrometer.
Unless otherwise stated, the NMR spectra have been performed in CDCl3. Chemical
1
shifts (
δ
) are reported in parts per million related to internal TMS or CDCl3 for H and
13C NMR, respectively. Multiplicities are reported using the following abbreviations: s,
singlet; d, doublet; t, triplet; m, multiplet; br, broad; or their combinations. IR spectra
were registered on a FTIR Perkin−Elmer Spectrum RX1 spectrometer using the
attenuated total reflectance (ATR) technique or a Nicolet Avantar 320 FTꢀIR
spectrometer. Absorption values are given as wavenumbers (cm−1), only significant
absorptions are given. The intensity of the absorptions is given as strong (s), medium
(m) or weak (w). High resolution mass spectra (HRMS) were carried out at the Mass
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Spectrometry Unity of the Centres Científics i Tecnològics of the Universitat de
Barcelona (CCiTUB) and are reported as m/z. LC/MSDꢀTOF spectrometer with
electrospray ionization (ESIꢀTOFꢀMS) from Agilent Technologies was used. Low polar
compounds (37−40 and 43) did not ionized under the usual electrospray ionization
conditions used. The elemental analyses were carried out at the IQAC (CSIC) of
Barcelona, Spain, in elemental microanalyzers (A5) model Flash 1112 series from
Thermofinnigan for (C, H, N) determinations, and in a titroprocessor Methrom model
808 for the halogen determination. Automatized chromatography was carried out on a
Combiflash RF 150 psi from Teledyne Isco. For the flash column chromatography,
silica gel 60 AC (35−70 ꢁm, SDS, ref. 2000027) was used. The eluents employed are
reported as volume/volume percentages. Thinꢀlayer chromatography (TLC) was
performed on aluminumꢀbacked sheets with silica gel 60 F254 (Merck, ref. 1.05554)
and spots were visualized with UV light or a 1% aqueous solution of KMnO4. XꢀRay
diffraction analysis of compounds 38, 40 and 43 were performed in a D8 Venture
diffractometer at the CCiTUB of the University of Barcelona. The compounds and
reagents were purchased to the following companies: DMAD, iodosobenzene diacetate,
trimethylsilyl trifluoromethanesulfonate, dicyclopentadiene, KOBuꢀt, silica gel, 30%
KH in mineral oil, and CuI were obtained from SigmaꢀAldrich, trimethylsilyl cyanide,
trimethylsilylacetylene, 1,4ꢀdichloroꢀ2ꢀbutene, tꢀBuLi, 1,2ꢀbis(tributylstannyl)ethyne,
ethyleneꢀbis(triphenylphosphine)platinum(0), MsCl, 18ꢀcrownꢀ6 and NaI from ACROS
Organics, CF3SO3H from Fluorochem, 1,3ꢀdiphenylisobenzofuran from Fluka,
anthracene from Merck and iodine from Scharlau chemicals. All of them were used
without further purification.
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[(1R,4S)-2,3-Diiodobicyclo[2.2.1]hepta-2,5-diene-7,7-diyl]bis(methylene) diacetate
34. A solution of ethyneꢀ1,2ꢀdiylbis(phenyliodonium) ditriflate23 32 (2.37 g, 3.25 mmol)
in anhydrous acetonitrile (20 mL) was prepared in a 50 mL roundꢀbottomed flask
provided with Ar atmosphere and magnetic stirring. The solution was cooled to − 35 °C
and a solution of cyclopentadiene 31 (569 mg, 2.71 mmol) in anhydrous CH3CN (7 mL)
was added dropwise and the mixture was stirred at rt for 17 h. The solution was cooled
to −35 °C, powdered NaI (828 mg, 5.52 mmol) and CuI (1.05 g, 5.51 mmol) were added
and the mixture was stirred at rt for 20 h. The solvent was distilled under reduced
pressure, and to eliminate the formed iodobenzene, toluene (10 mL) was added and the
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solvent and volatiles were distilled off under reduced pressure, repeating this process
three more times. The black solid residue (4.03 g) was subjected to automatic column
chromatography [35−70 ꢁm silica gel (40 g), hexane / EtOAc mixtures]. On elution
with hexane / EtOAc from 85:15 to 80:20 (4 min), diacetate 34 (466 mg, 35% yield)
9
1
was obtained as light yellow oil. Rf: 0.19 (silica gel, 10 cm, hexane / EtOAc 8:2); H
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NMR (400 MHz, CDCl3): δ = 2.02 (s, 3H, synꢀCH3COO), 2.06 (s, 3H, antiꢀCH3COO),
3.51−3.52 [m, 2H, 1(4)ꢀH], 4.20 (s, 2H, antiꢀCH2OAc), 4.27 (s, 2H, synꢀCH2OAc),
6.81−6.84 ppm [m 2H, 5(6)ꢀH]; 13C NMR (100.6 MHz, CDCl3): δ = 20.8 (antiꢀ
CH3COO and synꢀCH3COO), 64.2 (CH2, antiꢀCH2OAc), 64.3 (CH2, synꢀCH2OAc), 65.6
[CH, C1(4)], 85.6 (C, C7), 113.5 [C, C2(3)], 139.4 [CH, C5(6)], 170.55 (C) and 170.56
ppm (C) (synꢀCH3COO and antiꢀCH3COO); IR (NaCl): ῦ = 1740 (s), 1243 (s), 1035
cm−1 (s); HRMS (ESIꢀTOF) m/z: [M + NH4]+ Calcd for C13H18I2NO4 505.9320; Found
505.9323.
[(1R,4S)-2,3-Diiodobicyclo[2.2.1]hepta-2,5-diene-7,7-diyl]dimethanol 35. A solution
of diacetate 34 (151 mg, 0.31 mmol) in anhydrous MeOH (7.4 mL) was placed in a
roundꢀbottomed flask provided with Ar atmosphere, magnetic stirring and reflux
condenser. Anhydrous K2CO3 (11 mg, 80 ꢁmol) was added and the mixture was heated
at reflux for 2 h. The solvent was eliminated under reduced pressure to give a brown
solid residue (145 mg) that was subjected to automatic column chromatography (35−70
ꢁm silica gel, 12 g, hexane / EtOAc mixtures) to give diol 35 (93 mg, 74% yield) as a
yellowish solid, on elution with hexane / EtOAc from 15:85 to 30:70. The analytical
sample of 35 (74 mg) was obtained as white solid by crystallization of the above
product from a 1:3 mixture CH2Cl2 / pentane (1 mL). Rf = 0.18 (silica gel, 10 cm,
hexane / EtOAc 1:1), m.p. 89−90 °C (CH2Cl2 / pentane); 1H NMR (400 MHz, CDCl3): δ
= 2.13−2.18 (broad s, 1H, synꢀCH2OH) and 2.26−2.31 (broad s, 1H, antiꢀCH2OH), 3.55
3
[pseudo t, J(H,H) = 4J(H,H) = 2.0 Hz, 2H, 1(4)ꢀH], 3.85−3.87 (broad s, 2H, antiꢀCH2OH),
3.96−3.98 (broad s, 2H, synꢀCH2OH), 6.82 ppm [pseudo t, 3J(H,H) = 4J(H,H) = 2.0 Hz, 2H,
5(6)ꢀH]; 13C NMR (100.6 MHz, CDCl3): δ = 65.2 [CH, C1(4)], 65.7 (CH2, antiꢀ
CH2OH), 66.1 (CH2, synꢀCH2OH), 90.3 (C, C7), 114.0 [C, C2(3)], 139.5 ppm [CH,
C5(6)]; IR (NaCl): ῦ = 3100−3600 [broad band, max. at 3342 (s)], 1019 cm−1 (s);
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C9H11I2O2 404.8843; Found: 404.8839;
elemental analysis calcd (%) for C9H10I2O2: C 26.75, H 2.50, I 62.83; found: C 26.94, H
2.43, I 62.66.
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[(1
R
,4
S)-2,3-Diiodobicyclo[2.2.1]hepta-2,5-diene-7,7-diyl]bis(methylene)
6
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bismethanesulfonate 36. A solution of diol 35 (199 mg, 0.49 mmol) in anhydrous
CH2Cl2 (4.5 mL) was prepared in a roundꢀbottomed flask provided with Ar atmosphere
and magnetic stirring. Anhydrous Et3N (0.27 mL, 1.97 mmol) was added dropwise, the
solution was cooled to 0 °C (iceꢀwater bath), MsCl (90 ꢁL, 1.18 mmol) was added
dropwise and the reaction mixture was stirred at 0 °C for 2 h. Saturated aqueous
solution of NaHCO3 (0.5 mL) was added. The aqueous phase was separated and the
organic one was washed with more saturated aqueous solution of NaHCO3 (3 × 5 mL).
The combined aqueous phases were extracted with CH2Cl2 (3 × 5 mL), the combined
organic phase and extracts were washed with water (7 mL), dried (anhyd Na2SO4) and
concd in vacuo to give crude dimesylate 36 (298 mg), which was subjected to automatic
column chromatography (35−70 ꢁm silica gel, 12 g, hexane / EtOAc mixtures) to give
dimesylate 36 (271 mg, 98% yield) as a yellow oil, on elution with hexane / EtOAc
from 65:35 to 10:90. The analytical sample of 36 (203 mg) was obtained as yellow solid
by crystallization of the above product from a 1:3 mixture CH2Cl2 / pentane (2 mL). Rf
= 0.30 (silica gel, 10 cm, hexane / EtOAc 1:1); m.p. 154−155 °C (CH2Cl2 / pentane); 1H
NMR (400 MHz, CDCl3) δ: 3.01 (s, 3H) and 3.05 (s, 3H) [synꢀ and antiꢀ
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3
4
CH2OS(O2)CH3], 3.62 [pseudo t, J(H,H) = J(H,H) = 2.0 Hz, 2H, 1(4)ꢀH], 4.41 (s, 2H,
antiꢀCH2OMs), 4.45 (s, 2H, synꢀCH2OMs), 6.89 [pseudo t, 3J(H,H) = 4J(H,H) = 2.0 Hz, 2H,
13
5(6)ꢀH]; C NMR (100.6 MHz, CDCl3) δ: 37.3 (2 CH3, CH3SO3), 64.9 [CH, C1(4)],
68.7 (CH2, antiꢀCH2OMs), 69.3 (CH2, synꢀCH2OMs), 84.7 (C, C7), 113.2 [C, C2(3)],
139.5 [CH, C5(6)]; IR (NaCl): ῦ = 1355 (s), 1174 (s) cm−1 (s); HRMS (ESIꢀTOF) m/z:
[M + NH4]+ Calcd for C11H18I2NO6S2 577.8659; Found: 577.8682; elemental analysis
calcd (%) for C11H14I2O6S2: C 23.59, H 2.52, I 45.31, S 11.45; found: C 23.83, H 2.51, I
45.34, S 11.32.
(1R,4S)-2,3-Diiodo-7,7-bis(iodomethyl)bicyclo[2.2.1]hepta-2,5-diene 37. A solution
of dimesylate 36 (200 mg, 0.36 mmol) in anhydrous acetone (3.1 mL) was placed in a
roundꢀbottomed flask provided with Ar atm, magnetic stirring and reflux condenser.
Powdered NaI (550 mg, 3,65 mmol) was added and the reaction mixture was heated to
reflux for 17 h. The solvent was evaporated under reduced pressure to give a yellow
residue (770 mg) that was subjected to column chromatography (35−70 ꢀm silica gel, 3
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g, hexane) to give tetraiodide 37 (190 mg, 85% yield) as a yellow viscous oil. Rf = 0.67
4
5
6
7
8
9
1
(silica gel, 10 cm, hexane / EtOAc 8:2); H NMR (400 MHz, CDCl3): δ = 3.59 [pseudo
3
4
t, J(H,H) = J(H,H) = 2.0 Hz, 2H, 1(4)ꢀH], 3.65−3.67 (m, 2H, antiꢀCH2I), 3.70−3.72 (m,
2H, synꢀCH2I), 6.66 ppm [pseudo t, J(H,H) = J(H,H) = 2.0 Hz, 2H, 5(6)ꢀH]; 13C NMR
(100.6 MHz, CDCl3): δ = 12.0 (CH2, synꢀCH2I), 12.8 (CH2, antiꢀCH2I), 69.1 [CH,
C1(4)], 87.5 (C, C7), 113.6 [C, C2(3)], 139.7 ppm [CH, C5(6)]; IR (NaCl): ῦ = 1417 (s),
1217 (s), 1197 (s), 734 (s), 639 cm−1 (s); elemental analysis calcd (%) for
C9H8I4·0.1hexane: C 18.23, H 1.50, I 80.27; found: C 18.03, H 1.34, I 80.59.
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(1s,3s,4R,7S,8R,9S,10S,11R,12S,13R,16S,17s,19R)-8,9-
Diiodooctacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadeca-5,14-diene 38.
a) Preparation of a potassium cyclopentadienide THF 0.2 M solution. In a 10 mL flask,
KH (30% in mineral oil, 134 mg, 1.00 mmol) was washed with anhydrous THF (5 × 5
mL) under an Ar atm. To the washed KH, anhyd THF (5 mL) was added and the
suspension was cooled to 0 °C (iceꢀwater bath). Freshly distilled cyclopentadiene (120
ꢁL, 99 mg, 1.5 mmol) was added and the mixture was stirred at this temperature for 10
min. 18ꢀcrownꢀ6 (13 mg, 49 ꢁmol, about 5% with respect to KH) was added and the
mixture was stirred at 0 °C for 10 min and at rt for 15 min to give a pink suspension.
b) Substitution reaction: In a 25 mL flask provided with magnetic stirring, reflux
condenser and Ar atmosphere, a solution of tetraiodide 37 (187 mg, 0.30 mmol) in
anhydrous DMF (2.2 mL) was prepared. The solution was cooled to 0 °C (iceꢀwater
bath) and then part of the above solution of potassium cyclopentadienide (3.3 mL, 0.66
mmol) was added dropwise. The mixture was stirred at 0 °C for 5 min, at rt for 10 min
and then it was heated at 90 °C for 17 h. The mixture was allowed to cool to rt, MeOH
(0.1 mL) was added and the mixture was stirred for 10 min. Then, EtOAc (5 mL) and
water (5 mL) were added and the organic phase was separated. The aqueous phase was
extracted with EtOAc (3 × 8 mL) and the combined organic phases were washed with
saturated aqueous solution of NaHCO3 (3 × 8 mL), water (2 × 8 mL) and brine (8 mL),
dried (anhydrous Na2SO4) and concd in vacuo to give a brown oily residue (213 mg),
which was subjected to column chromatography [35−70 ꢁm silica gel (4 g)
pentane/EtOAc mixtures] to give on elution with pentane, octacycle 38 (128 mg, 85%
yield) as white solid. An analytical sample of 38 (97 mg) was obtained as white solid,
by crystallization of the above product from CH2Cl2/MeOH 1:3 (2 mL). Rf = 0.62 (silica
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gel, 10 cm, hexane / EtOAc 9:1); m.p. 236.8−237.5 °C (CH2Cl2/MeOH); 1H NMR (400
MHz, CDCl3): δ = 1.39 (d, 3J(H,H) = 2.8 Hz, 2H, 18ꢀH2), 1.68 (d, 3J(H,H) = 2.8 Hz, 2H, 2ꢀ
H2), 1.71−1.74 (m, 1H, 17ꢀH), 1.87 [s, 2H, 10(19)ꢀH], 2.00−2.03 (m, 1H, 3ꢀH), 2.12 [s,
3
3
4
2H, 11(12)ꢀH], 2.41 [pseudo q, J(H,H) = J(H,H) = J(H,H) = 1.7 Hz, 2H, 13(16)ꢀH], 3.09
[pseudo q, 3J(H,H) = 3J(H,H) = 4J(H,H) = 1.9 Hz, 1H, 4(7)ꢀH], 6.12 [pseudo t, 3J(H,H) = 4J(H,H
)
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= 1.8 Hz, 2H, 14(15)ꢀH], 6.25 ppm [pseudo t, 3J(H,H) = 4J(H,H) = 1.8 Hz, 2H, 5(6)ꢀH]; 13C
NMR (100.6 MHz, CDCl3): δ = 34.1 (CH2, C2), 34.9 (CH2, C18), 43.9 (C, C1), 47.8
[CH, C11(12)], 49.3 [CH, C13(16)], 52.1 (CH, C17), 52.7 (CH, C3), 58.7 [CH,
C10(19)], 59.8 [CH, C4(7)], 70.7 [C, C8(9)], 137.2 [CH, C14(15)], 141.5 ppm [CH,
C5(6)]; IR (NaCl): ῦ = 3067 (w), 2954 (m), 2915 cm−1 (m); elemental analysis calcd
(%) for C19H18I2: C 45.63, H 3.63, I 50.75; found: C 45.40, H 3.64, I 50.62.
Reaction of diiodide 37 with
(1R*,3S*,4S*,7R*,8R*,9S*,10S*,11S*,12R*,13S*,16R*,17R*,19S*)-8-
butyloctacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadeca-5,14-diene
t-BuLi in the presence of diene 42: Isolation of
t-
39.
A
solution of octacycle 38 (90 mg, 0.18 mmol) and diene 42 (58 mg, 0.22 mmol) in
anhydrous THF (2.9 mL) was prepared in a twoꢀnecked roundꢀbottomed flask provided
with Ar atmosphere, magnetic stirring and low temperature thermometer. The solution
was cooled to −67 °C and a solution of tꢀBuLi in pentane (1.7 M, 110 ꢁL, 0.19 mmol)
was added dropwise, the color of the solution changed from yellow to dark brown. The
mixture was stirred at this temperature for 30 min and it was allowed to heat to rt for 30
min. MeOH (0.15 mL), water (2 mL) and Et2O (3 mL) were successively added, the
organic phase was separated and the aqueous one was extracted with Et2O (3 × 4 mL).
The combined organic phase and extracts were dried (anhydrous Na2SO4) and
concentrated in vacuo to give a yellow oil (108 mg) that was subjected to column
chromatography (35−70 ꢀm silica gel, 3.5 g, pentane / EtOAc mixtures). On elution
with pentane, compound 39 (14 mg, 26% yield) was obtained as a grey solid. The
analytical sample of 39 (11 mg) was obtained by sublimation in a cold finger (60 °C /
about 0.01 Torr for 6 h) as a white solid. Rf = 0.73 (silica gel, 10 cm, hexane / EtOAc
1
9:1); m.p. 144–145 °C; H NMR (400 MHz, CDCl3): δ = 0.96 [s, 9H, C(CH3)3], 1.37
(overlapped dd, 2J(H,H) = 14,8 Hz, 3J(H,H) = 2.8 Hz, 1H) and 1.39 (overlapped dd, 2J(H,H)
=
14.8 Hz, 3J(H,H) = 2.8 Hz, 1H) (18ꢀHa and 18ꢀHb), 1.41 (overlapped dd, 2J(H,H) = 14.0 Hz,
3J(H,H) = 2.8 Hz, 1H) and 1.43 (overlapped dd, 2J(H,H) = 14.0 Hz, 3J(H,H) = 2.8 Hz, 1H) (2ꢀ
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Ha and 2ꢀHb), 1.50 (s, 1H, 10ꢀH), 1.57 (d, 3J(H,H) = 6.0 Hz, 1H, 11ꢀH), 1.63 (d, 4J(H,H)
=
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1.6 Hz, 1H, 19ꢀH), 1.68 (s, 1H, 9ꢀH), 1.77−1.81 (complex signal, 2H, 3ꢀH and 17ꢀH),
2.22−2.24 (broad s, 1H, 4ꢀH), 2.27 (d, 3J(H,H) = 6.0 Hz, 1H, 12ꢀH), 2.30 (broad s, 1H, 13ꢀ
H), 2.38 (broad s, 1H, 16ꢀH), 2.41−2.43 (broad s, 1H, 7ꢀH), 5.95 (dd, 3J(H,H) = 5.6 Hz,
4J(H,H) = 3.2 Hz, 1H, 5ꢀH), 6.03 (overlapped dd, 3J(H,H) = 5.6 Hz, 4J(H,H) = 3.2 Hz, 1H, 15ꢀ
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H), 6.05 (overlapped dd, 3J(H,H) = 5.6 Hz, J(H,H) = 3.2 Hz, 1H, 14ꢀH), 6.24 ppm (dd,
3J(H,H) = 5.6 Hz, 4J(H,H) = 3.2 Hz, 1H, 6ꢀH); C NMR (100.6 MHz, CDCl3): δ = 33.4
13
[CH3, C(CH3)3], 35.9 (CH2, C18), 36.09 (CH2, C2), 36.12 [C, C(CH3)3], 41.8 (C, C1),
44.3 (CH, C12), 45.1 (CH, C11), 47.9 (CH, C9), 49.2 (CH, C13), 49.7 (CH, C16), 52.0
(CH, C4), 52.8 (CH, C17), 53.4 (CH, C7), 54.2 (CH, C10), 57.2 (CH, C19), 58.3 (CH,
C3), 61.1 (C, C8), 133.1 (CH, C5), 137.2 (CH, C15), 137.4 (CH, C14), 143.9 ppm (CH,
C6). IR (NaCl): ῦ = 3055 (w), 2934 (s), 2917 (s), 2898 (s), 719 (s), 707 (s), 660 cm−1
(s); elemental analysis calcd (%) for C23H28·1/4H2O: C 89.41, H 9.30; found: C 89.11,
H 9.24.
Reaction of diiodide 38 with Na/Hg in the presence of 11,12-dimethylene-9,10-
dihydro-9,10-ethanoanthracene
(3 ,4 ,7 ,8 ,9S,10 ,11 ,12 ,13
octacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadeca-5,14-diene,
14:
Isolation
of
s
R
S
R
s
R
S
R,16
S,17
s
,19
s)-
40
and
(1R*,2S*,3R*,4R*,5S*,6R*,8R*,9R*,12S*,13R*,14S*,15R*,16R*,17R*,18S*,19S*,20
R*,21S*,22S*,23R*,24S*,25S*,26R*,27R*,28R*,29S*,30R*,31S*,34R*,35R*)nonade
cacyclo
[17.17.1.16,24.01,28.02,30.03,18.03,27.04,16.04,25.05,13.06,15.08,12.09,14.016,23.017,21.020,27.022,26.029,3
4.031,35] octatriaconta-10,32-diene 43. Sodium amalgam [0.48% from Hg (11.4 g) and
Na (54 mg)] was prepared in a twoꢀnecked roundꢀbottomed flask provided with Ar
atmosphere and magnetic stirring. A solution of diiodide 38 (90 mg, 0.18 mmol) and
diene 14 (50 mg, 0.22 mmol) in anhydrous 1,4ꢀdioxane (1.2 mL) was added at rt and the
mixture was stirred at this temperature for 24 h. The solution was decanted from the
amalgam and was filtered through a short pad of Celite, washing the filter with Et2O (5
× 10 mL). The combined filtrate and washings were concd in vacuo to give a viscous
yellow oil (122 mg) which was subjected to column chromatography (35−70 ꢀm silica
gel, 4 g, pentane / EtOAc mixtures). On elution with pentane, a mixture of 40 and dimer
43 in a molar ratio 40/43 = 1:0.6 (12 mg) and a mixture of unknown products plus
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anthracene (9 mg) were obtained as grey solids. The mixture of 40 and 43 (12 mg) was
sublimed in a cold finger (50 ºC / about 0.01 Torr for 6 h) to give sublimed 40 (2 mg,
5% yield) and a residue that was washed with pentane to give dimer 43 (7 mg, 16%
yield) as a white solid. No dimer was present in the pentane washing.
9
Analytical and spectroscopic data of 40: Rf = 0.64 (silica gel, 10 cm, hexane / EtOAc
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1
9:1); m.p. 133–134 °C (CH2Cl2 / MeOH); m.p. 131–132 ºC (sublimed); H NMR (400
MHz, CDCl3): δ = 1.38−1.45 [m, 10H, 8(9,11,12)ꢀH, 10(19)ꢀH and 2(18)ꢀH2],
3
3
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1.78−1.83 [m, 2H, 3(17)ꢀH], 2.36 [pseudo q, J(H,H) = J(H,H) = J(H,H) = 2.0 Hz, 4H,
4(7,13,16)ꢀH], 6.04 ppm [pseudo t, J(H,H) = J(H,H) = 2.0 Hz, 4H, 5(6,14,15)ꢀH]; 13C
NMR (100.6 MHz, CDCl3): δ = 34.5 [CH2, C2(18)], 41.7 (C, C1), 46.5 [CH,
C8(9,11,12)], 49.5 [CH, C4(7,13,16)], 50.8 [CH, C10(19)], 53.1 [CH, C3(17)], 137.0
ppm [CH, C5(6,14,15)]; IR (NaCl): ῦ = 3044 (w), 2944 (s), 2834 (m), 705 cm−1 (m);
elemental analysis calcd (%) for C19H20: C 91.88, H 8.12; found: C 91.77, H 8.34.
Analytical and spectroscopic data of 43: Rf = 0.64 (silica gel, 10 cm, hexane / EtOAc
3
4
1
9:1); m.p. >300 °C (pentane); H NMR (400 MHz, CDCl3): δ = 1.39 [s, 2H, 15(28)ꢀH],
3
3
1.42 [d, J(H,H) = 2.8 Hz, 4H, 7(36)ꢀH2], 1.44 [d, J(H,H) = 2.8 Hz, 4H, 37(38)ꢀH2], 1.53
3
3
[s, 2H, 2(5)ꢀH], 1.63 [d, J(H,H) = 6.0 Hz, 2H, 14(29)ꢀH], 1.70 [d, J(H,H) = 6.4 Hz, 2H,
3
13(30)ꢀH], 1.73−1.76 [m, 2H, 8(35)ꢀH], 1.89 [broad d, J(H,H) = 2.4 Hz, 2H, 20(23)ꢀH],
1.98 [broad d, 3J(H,H) = 4.0 Hz, 2H, 18(25)ꢀH], 2.24−2.29 [dd, 3J(H,H) = 10.0 Hz, 3J(H,H)
=
4.4 Hz, 2H, 17(26ꢀH)], 2.32 [broad s, 2H, 9(34)ꢀH], 2.38 [broad s, 2H, 12(31)ꢀH],
3
2.43−2.48 [m, 2H, 21(22)ꢀH], 2.55−2.58 [m, 2H, 19(24)ꢀH], 6.04 [dd, J(H,H) = 5.6 Hz,
4J(H,H) = 2.8 Hz, 2H, 10(33)ꢀH], 6.08 ppm [dd, J(H,H) = 5.4 Hz, J(H,H) = 3.0 Hz, 2H,
11(32)ꢀH]; 13C NMR (100.6 MHz, CDCl3): δ = 34.0 [CH2, C37(38)], 34.6 [CH2,
C7(35)], 42.2 [CH, C13(30)], 42.5 [CH, C14(29)], 49.2 [C, C1(6)], 49.68 [CH, C9(34)],
49.74 [CH, C12(31)], 50.5 [CH, C17(26)], 52.3 [CH, C21(22)], 53.1 [CH, C8(35)], 53.3
[CH, C19(24)], 54.02 [CH, C2(5)], 54.05 [CH, C15(28)], 57.9 [CH, C20(23)], 59.8
[CH, C18(25)], 65.8 [C, C3(4)], 69.2 [C, C16(27)], 137.0 [CH, C10(33)], 137.1 ppm
[CH, C11(32)]; IR (NaCl): ῦ = 3058 (w), 2938 (s), 2924 cm−1 (s); elemental analysis
calcd (%) for C38H36·1/3H2O: C 86.03, H 7.64; found: C 85.81, H 7.32.
3
4
Reaction of diiodide 38 with molten sodium in 1,4-dioxane at reflux: Isolation of 39
and the stereoisomeric mixture of 4-[1,4-dioxan-2(R*)-yl]- and 4-[1,4-dioxan-2(S*)-
yl]-(1S*,3R*,4R*,7S*,8S*,9R*,10R*,11R*,12S*,13R*,16S*,17S*,19R*)-
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octacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadeca-5,14-diene 41. In a twoꢀ
necked roundꢀbottomed flask provided with Ar atmosphere and reflux condenser,
sodium (60 mg, 2.6 mmol) and anhydrous 1,4ꢀdioxane (2.5 mL) were placed. The
mixture was heated at reflux till the sodium was molten and then diiodide 38 (121 mg,
0.24 mmol) was added at once and the reaction mixture was heated at reflux for 4 h.
The formation of a yellow solid was observed. The mixture was allowed to cool to rt,
MeOH (0.5 mL) was added and the mixture was stirred for 30 min. The mixture was
filtered through a short pad of Celite washing the filter with Et2O (3 × 10 mL) and
pentane (1 × 10 mL). The combined filtrate and washings were concd in vacuo to give a
beige solid (125 mg) that was subjected to column chromatography (35–70 ꢀm silica
gel, 4 g, pentane / EtOAc mixtures). On elution with pentane, compound 40 (33 mg,
55% yield) was obtained as white solid. On elution with a mixture of pentane / EtOAc
(90:10), the stereoisomeric mixture 41 (20 mg, 25% yield) was isolated as brown solid.
The analytical sample of 40 (24 mg) was obtained as white solid by crystallization of
the above product (33 mg) from a mixture CH2Cl2 / MeOH (1:3, 1.5 mL). The
analytical sample of 41 (12 mg) was obtained as white solid by crystallization of the
above product (20 mg) from a mixture CH2Cl2 / MeOH (1:3, 1.5 mL).
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Analytic and spectroscopic data of the stereoisomeric mixture 41: Rf = 0.57 (silica gel,
1
10 cm, hexane / EtOAc 9:1); H NMR (400 MHz, CDCl3): δ = 1.40−1.60 (complex
signal, 8H), 1.76−2.01 (complex signal, 3H), 2.27−2.42 (complex signal, 4H),
3.35−3.75 (complex signal, 7H), 5.98−6.20 ppm (complex signal, 4H); 13C NMR (100.6
MHz, CDCl3): δ = 34.90 (CH2), 34.97 (CH2), 35.25 (CH2), 35.32 (CH2), 42.2 (CH),
42.4 (CH), 42.55 (C), 45.0 (CH), 45.4 (CH), 48.8 (CH), 49.1 (CH), 49.3 (CH), 49.6
(CH), 49.8 (CH), 50.8 (CH), 50.85 (CH), 51.77 (CH), 51.84 (CH), 52.2 (2 CH), 52.6
(CH), 52.8 (CH), 53.0 (CH), 53.1 (CH), 54.8 (C), 55.2 (CH), 55.6 (CH), 56.1 (C), 66.6
(CH2), 66.7 (CH2), 67.6 (2 CH2), 69.64 (CH2), 78.6 (CH), 80.7 (CH), 134.7 (CH), 137.0
(CH), 137.1 (2 CH), 137.3 (CH), 137.4 (CH), 137.9 (CH), 138.5 ppm (CH). IR (NaCl):
ῦ = 3059 (w), 2943 (s), 2924 cm−1 (s); HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C23H27O2 335.2006; Found: 335.2006.
Attempted formation of dimer 43 by reaction of diodide 38 with sodium amalgam
in the absence of diene 14: isolation of 40. Sodium amalgam [0.47% from Hg (9.55 g)
and Na (45 mg, 1.96 mmol)] was prepared in a twoꢀnecked roundꢀbottomed flask
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provided with Ar atm and magnetic stirring. A solution of diiodide 38 (80 mg, 0.16
mmol) in anhydrous 1,4ꢀdioxane (1.1 mL) was added at rt and the mixture was stirred at
this temperature for 24 h. The solution was decanted from the amalgam and was filtered
through a short pad of Celite, washing the filter with Et2O (5 × 3 mL). The combined
filtrate and washings were concentrated in vacuo to give a viscous yellow oil (139 mg)
which was subjected to column chromatography (35−70 ꢀm silica gel, 3 g, pentane /
EtOAc mixtures). On elution with pentane, 40 (12 mg) as white solid and impure 40 (19
mg) as grey solid were obtained. The second fraction (19 mg) was sublimed (60 °C,
about 0.01 Torr) to give pure 40 (12 mg, 61% overall yield).
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Attempted cross coupling among pyramidalized alkenes 2 and 27: Isolation of 40
and dimer 3. Sodium amalgam [0.47% from Hg (11.1 g) and Na (50 mg, 2.18 mmol)]
was prepared in a twoꢀnecked roundꢀbottomed flask provided with Ar atm and magnetic
stirring. A solution of diiodide 38 (84 mg, 0.17 mmol) and diiodide 1 (188 mg, 0.50
mmol) in anhydrous 1,4ꢀdioxane (2 mL) was added at once at rt and the mixture was
stirred at this temperature for 24 h. The solution was decanted from the amalgam and
was filtered through a short pad of Celite, washing the filter with Et2O (5 × 4 mL). The
combined filtrate and washings were concd in vacuo to give a viscous yellow oil (115
mg) which was subjected to column chromatography (35−70 ꢀm silica gel, 3.5 g,
pentane / EtOAc mixtures). On elution with pentane, a mixture of 40 and dimer 3 in a
1
ratio 40 / 3 about 1:2.5 by HꢀNMR (31 mg) as white solid and impure mixture of the
above products (14 mg) as grey solid were obtained. The second fraction (14 mg) was
sublimed (60 °C, about 0.01 Torr) to give a mixture of 40 and dimer 3 in a ratio 40 / 3
about 1:0.3 by 1H NMR (8 mg) (36% overall yield of 40 and 20% of 3). The residue of
the above sublimation contained mainly dimer 3 (MS, EI).
X-ray crystal-structure determination of compound 38. A colorless prismꢀ
like specimen of C19H18I2, approximate dimensions 0.214 mm × 0.226 mm × 0.365 mm,
was used for the Xꢀray crystallographic analysis. The Xꢀray intensity data were
measured on a D8 Venture system equipped with a Multilayer monochromator and a
Mo microfocus (λ = 0.71073 Å). The frames were integrated with the Bruker SAINT
software package35 using a narrowꢀframe algorithm. The integration of the data using
an orthorhombic unit cell yielded a total of 10601 reflections to a maximum θ angle
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of 30.53° (0.70 Å resolution), of which 4596 were independent (average
4
5
redundancy 2.307,
completeness
= 98.0%,
Rint = 3.26%,
Rsig = 6.07%)
and 4000 (87.03%) were greater than 2σ(F2). The final cell constants
of a = 11.9655(3) Å, b = 15.3718(4) Å, c = 16.7007(4) Å, volume = 3071.78(13) Å3, are
based upon the refinement of the XYZꢀcentroids of reflections above 20 σ(I). Data were
corrected for absorption effects using the multiꢀscan method (SADABS).35 The
calculated minimum and maximum transmission coefficients (based on crystal size)
are 0.6280 and 0.7461. The structure was solved and refined using the Bruker
SHELXTL Software Package,36 using the space group P b c a, with Z = 8 for the
formula unit, C19H18I2. The final anisotropic fullꢀmatrix leastꢀsquares refinement on
F2 with 190 variables converged at R1 = 2.53%, for the observed data and wR2 = 7.11%
for all data. The goodnessꢀofꢀfit was 1.040. The largest peak in the final difference
electron density synthesis was 0.700 e Å−3 and the largest hole was −1.040 e Å−3 with
an RMS deviation of 0.167 e Å−3. On the basis of the final model, the calculated density
was 2.163 g cm−3 and F(000), 1904 e. For more details, see Table 1 in the Supporting
Information.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
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X-ray crystal-structure determination of compound 40. A colorless prismꢀ
like specimen of C19H20, approximate dimensions 0.058 mm × 0.103 mm × 0.440 mm,
was used for the Xꢀray crystallographic analysis. The Xꢀray intensity data were
measured on a D8 Venture system equipped with a multilayer monochromator and a Mo
microfocus (λ = 0.71073 Å). The frames were integrated with the Bruker SAINT
software package,35 using a narrowꢀframe algorithm. The integration of the data using
a triclinic unit cell yielded a total of 71539 reflections to a maximum θ angle of 30.57°
(0.70 Å resolution), of which 7702 were independent (average redundancy 9.288,
completeness = 99.2%, Rint = 4.49%, Rsig = 2.43%) and 6307 (81.89%) were greater
than 2σ(F2). The final cell constants of a = 5.9104(4) Å, b = 11.1856(8) Å,
c = 19.9679(14) Å, α = 105.046(2)°, β = 96.566(2)°, γ = 90.113(2)°, volume
= 1265.80(15) Å3, are based upon the refinement of the XYZꢀcentroids of reflections
above 20 σ(I). Data were corrected for absorption effects using the multiꢀscan method
(SADABS).35 The calculated minimum and maximum transmission coefficients (based
on crystal size) are 0.6714 and 0.7461. The structure was solved and refined using the
Bruker SHELXTL Software Package,36 using the space group P −1, with Z = 4 for the
formula unit, C19H20. The final anisotropic fullꢀmatrix leastꢀsquares refinement on
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F2 with 343 variables converged at R1 = 5.45%, for the observed data and wR2
= 17.00% for all data. The goodnessꢀofꢀfit was 1.044. The largest peak in the final
difference electron density synthesis was 0.505 e Å−3 and the largest hole was −0.338 e
Å−3 with an RMS deviation of 0.064 e Å−3. On the basis of the final model, the
calculated density was 1.303 g cm−3 and F(000), 536 e. For more details, see Table 1 in
the Supporting Information.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
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X-ray crystal-structure determination of compound 43. A colorless plateꢀ
like specimen of C38H36, approximate dimensions 0.062 mm × 0.204 mm × 0.307 mm,
was used for the Xꢀray crystallographic analysis. The Xꢀray intensity data were
measured on a D8 Venture system equipped with a multilayer monochromator and a Mo
microfocus (λ = 0.71073 Å). The frames were integrated with the Bruker SAINT
software package,35 using a narrowꢀframe algorithm. The integration of the data using
a triclinic unit cell yielded a total of 64261 reflections to a maximum θ angle of 30.66°
(0.70 Å resolution), of which 7215 were independent (average redundancy 8.907,
completeness = 99.4%, Rint = 4.19%, Rsig = 2.51%) and 5824 (80.72%) were greater
than 2σ(F2). The final cell constants of a = 7.3827(3) Å, b = 11.4509(5) Å,
c = 14.5547(6) Å,
α
= 77.556(2)°,
β
= 86.847(2)°,
γ
= 77.599(2)°, volume
= 1173.44(9) Å3, are based upon the refinement of the XYZꢀcentroids of reflections
above 20 σ(I). Data were corrected for absorption effects using the multiꢀscan method
(SADABS).35 The calculated minimum and maximum transmission coefficients (based
on crystal size) are 0.7149 and 0.7461. The structure was solved and refined using the
Bruker SHELXTL Software Package,36 using the space group P −1, with Z = 2 for the
formula unit, C38H36. The final anisotropic fullꢀmatrix leastꢀsquares refinement on
F2 with 343 variables converged at R1 = 4.45%, for the observed data and wR2
= 12.41% for all data. The goodnessꢀofꢀfit was 1.018. The largest peak in the final
difference electron density synthesis was 0.414 e Å−3 and the largest hole was −0.240 e
Å−3 with an RMS deviation of 0.058 e Å−3. On the basis of the final model, the
calculated density was 1.394 g cm−3 and F(000), 528 e. For more details, see Table 1 in
the Supporting Information.
Computational Methods. Full geometry optimizations were performed with the M06ꢀ
2X density functional method30 by using the 6ꢀ311+G(d)31 basis set. The nature of the
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stationary points was verified by inspection of the vibrational frequencies within the
harmonic oscillatorꢀrigid rotor approximation. Molecular Electrostatic Potential analysis
was performed from the optimized geometries. The Natural Bond Orbital analysis
(NBO)32 was carried out at CISD/6ꢀ31G(d) level of theory,33 in order to evaluate the
orbitals of the pyramidalized double bounds. All DFT computations were carried out
using the keyword Integral(Grid=Ultrafine) as implemented in Gaussian09,37 which was
used to carry out these calculations. The biradical character of pyramidalized alkenes
was examined following the method of Takatsuka et al.,34 which relies on the number of
unpaired electrons determined from the occupancy of the natural orbitals obtained from
brokenꢀsymmetry calculations at the UHF/6ꢀ31G(d) level.
10
11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
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Nomenclature. The complex name of these polycyclic compounds have been obtained
by using the POLCYC program.38
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
at DOI: xxxx, It contains copies of the 1H NMR, 13C NMR, DEPT, 1H/1H
1
homocorrelation (NOESY and COSY), H/13C heterocorrelation (gHSQC and gHMBC
sequences) spectra of all of the new compounds (34−41 and 43), ORTEP
representations of compounds 38, 40 and 43, experimental data of the Xꢀray crystalꢀ
structure determination of compounds 38, 40 and 43 (Table 1), DFT calculations data of
pyramidalized alkenes 6, 25 and 27 and CIF data of compounds 38, 40 and 43.
AUTHOR INFORMATION
Corresponding author:
E.mail: camps@ub.edu
ORCID:
Pelayo Camps 0000ꢀ0002ꢀ9633ꢀ3525
David Lozano: 0000ꢀ0003ꢀ3348ꢀ9781
Carla Barbaraci: 0000ꢀ0002ꢀ6155ꢀ6702
Merce FontꢀBardia: 0000ꢀ0002ꢀ7892ꢀ8744
F. Javier Luque: 0000ꢀ0002ꢀ8049ꢀ3567
Carolina Estarellas: 0000ꢀ0002ꢀ0944ꢀ9053
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Notes
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The authors declare no competing financial interest.
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Acknowledgements
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We thank the Ministerio de Economía y Competitividad (MINECO: SAF2014ꢀ57094ꢀ
R) and the Generalitat de Catalunya (2014SGR1189) for financial support, CCiTUB for
NMR and MS facilities, the Institut de Química Avançada de Catalunya (IQAC, CSIC,
Barcelona) for elemental analyses and the Consorci de Serveis Universitaris de
Catalunya (CSUC) for their computational facilities. FJL acknowledges the support
from ICREA Academia. We thank Dr. Santiago Vázquez for his help in naming the
polycyclic compounds with the POLCYC program and Prof. J. M. Bofill for valuable
suggestions.
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