Intramolecular hetero Diels-Alder reactions of vinyl allenes and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2003.09.091

Compounds containing a vinyl allene moiety linked to an aldehyde by a tether have been synthesised and shown to undergo the intramolecular hetero Diels-Alder reaction. Only one compound with stereochemistry consistent with an exo approach of the dienophile to the dienic portion of the vinyl allene was obtained in each case. Depending on the length of the tether and on the substitution pattern on the allene the reactions were spontaneous at room temperature or required heating or the presence of a Lewis acid to proceed.

Full text of DOI:10.1016/j.tetlet.2003.09.091

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8471–8474
Intramolecular hetero Diels–Alder reactions of vinyl allenes and
aldehydesꢀ
David Rega´s, Juan M. Ruiz, Mar´ıa M. Afonso, Antonio Galindo and J. Antonio Palenzuela*
Instituto Universitario de Bio-Orga´nica ‘Antonio Gonza´lez’, Departamento de Qu´ımica Orga´nica, Universidad de La Laguna,
38206 La Laguna, Tenerife, Spain
Received 16 July 2003; revised 3 September 2003; accepted 12 September 2003
Abstract—Compounds containing a vinyl allene moiety linked to an aldehyde by a tether have been synthesised and shown to
undergo the intramolecular hetero Diels–Alder reaction. Only one compound with stereochemistry consistent with an exo
approach of the dienophile to the dienic portion of the vinyl allene was obtained in each case. Depending on the length of the
tether and on the substitution pattern on the allene the reactions were spontaneous at room temperature or required heating or
the presence of a Lewis acid to proceed.
© 2003 Published by Elsevier Ltd.
Vinyl allenes have been successfully used as dienes in
the intramolecular Diels–Alder reaction leading to
polycyclic compounds, which can be used to synthesise
complex natural products.1–4 A classification scheme
has been suggested for these reactions based on the
location of the tether on the vinyl allene.5 Of all the
possible types included in that classification, only two,
confer a high degree of rigidity to the system, making
the intramolecular Diels–Alder reaction of this type of
compounds a highly selective process. The length of the
tether also plays a role in the reactivity of the system.5
In Type I systems, it was observed that when the
bicyclic compound formed was of the hydrindane type,
the reaction proceeded at room temperature or below
depending on the substituents on the allene. When
decalin-type systems were prepared, higher tempera-
tures were required to effect the cyclization.
Types I1–3 and VE (Fig. 1), have been experimentally
4
carried out, an important difference being observed
between these two types in the stereochemical outcome
of the reaction.
We have recently shown that semicyclic vinyl allenes
can act as dienes in the hetero Diels–Alder reaction
with aldehydes as heterodienophiles in the presence of
Lewis acids, and that the reactivity observed was simi-
lar to that of dienes substituted with alkoxy or silyloxy
groups.6
In Type VE the system is more flexible and gives
mixtures of compounds resulting from the endo or exo
approach of the dienophile to the vinyl allene. In Type
I systems, the structural features of the allene moiety
Following our interest in the pericyclic reactivity of
vinyl allenes, we decided to test the feasibility of carry-
ing out the intramolecular variant of this reaction.
Although only a few examples of intramolecular hetero
Diels–Alder reactions in which the heterodienophile is a
carbonyl compound exist,7 we were intrigued by the
effect of the allene on the reactivity. For this task, we
needed to devise a procedure to prepare compounds
containing the vinyl allene system with different sub-
stituents and an aldehyde group, linked by a tether of
variable length. Based on the above considerations for
the intramolecular Diels–Alder reaction of vinyl allenes,
we decided to place the tether on the terminus of the
Figure 1.
Keywords: vinyl allene; intramolecular hetero Diels–Alder; cycloaddi-
tion.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.091
* Corresponding author. Tel.: +34-922-318443; fax: +34-922-318442;
e-mail: jpalenz@ull.es
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.091

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D. Rega´s et al. / Tetrahedron Letters 44 (2003) 8471–8474
This aldehyde 7 was then placed under the conditions
developed for the intermolecular reaction of vinyl
allenes and aldehydes,6 that is, diethyl ether as solvent,
BF3·Et2O as Lewis acid and room temperature. After 8
h of reaction followed by purification by flash column
chromatography, tricyclic compound 8 was obtained in
18% yield.12
The structure of 8 was established by a combination of
spectroscopic techniques,13 and the relative stereochem-
istry shown in Scheme 3 was deducted from goesy
experiments.14 This structure is consistent with an
intramolecular hetero Diels–Alder reaction in which the
aldehyde has effected an exo approach to the dienic
portion of the vinyl allene, which is the most feasible
due to the constraints imposed by the allene and the
length of the tether.
Scheme 1.
Although the yield obtained was disappointingly low,
we had anticipated that compound 3 should be less
reactive than 5 or 6, since these two possess an alkyl
substituent on the allene and in a position in which it
can act as an activating group for the diene. In fact,
when alcohol 5 was subjected to Swern oxidation under
the same conditions used for 3, no aldehyde was
obtained after purification. Instead, the tricyclic system
9, resulting from the intramolecular hetero Diels–Alder
reaction, was isolated in a 67% yield (Scheme 4).
Scheme 2. Reagents and conditions: (Bz=COPh) (a) n-BuLi,
−78°C, OHC(CH2)3OTBDMS, THF, 90%; (b) Ph3P, DEAD,
o-NO2C6H4SO2NHNH2, THF, −15°C, 68%; (c) TBAF, THF,
97%; (d) n-BuLi, PhCOCl, −78°C, THF, 93%; (e) EtMgBr,
CuBr·Me2S, −60°C, THF, 44%; (f) t-BuLi, CuCN, −78°C,
Et2O, 46%.
When the oxidation reaction was repeated keeping the
temperature below rt during the workup, the corre-
sponding aldehyde was observed as the major compo-
nent in the crude reaction mixture by 1H NMR
spectroscopy. This aldehyde was converted into 9 upon
standing in solution or when its purification was
attempted by column chromatography.
allene (Type I), and devise a synthetic strategy that
allowed us to introduce either a hydrogen or an alkyl
group on the allene. Since different alkyl groups exert a
similar electronic influence on cycloadditions and the
differences in their roles are mainly steric,8 we chose a
simple alkyl group (methyl, ethyl) and a bulky one
(t-butyl) for these studies. Thus, the required systems
for our study were of the type shown in Scheme 1.
We started by studying the compounds with n=1,
which by similarity with the all-carbon version of the
reaction, should be more reactive5 and should yield an
octahydro-cyclopenta[b]chromene system. The syn-
thetic process for the preparation of those compounds
is outlined in Scheme 2.
Scheme 3. Reagents and conditions: (a) DMSO, (COCl)2
−50°C, then Et3N −50°C to rt (83%); (b) BF3·Et2O, Et2O, rt
(18%).
The propargyl alcohol 2 prepared by the addition of the
lithium salt of 1-ethynylcyclohexene
1 to 4-tert-
butyldimethylsilyloxybutanal9 was treated with o-
nitrobenzenesulfonylhydrazide (o-NBSH), DEAD and
PPh3 following Myers protocol10 to give the vinyl
allenol 3 after deprotection of the silyl group. Com-
pound 2 was also transformed into the corresponding
benzoate 4, which was treated with different cuprates11
to give, after a SN2% reaction and deprotection, vinyl
allenols 5 and 6.
Compound 3 was converted in good yield into the
aldehyde 7 required for the intramolecular hetero
Diels–Alder reaction by a Swern oxidation (Scheme 3).
Scheme 4. Reagents and conditions: (a) DMSO, (COCl)2
−50°C, then Et3N −50°C to rt (R=Et, 67%; R=t-Bu, 86%).

D. Rega´s et al. / Tetrahedron Letters 44 (2003) 8471–8474
8473
This result implies a very easy intramolecular hetero
Diels–Alder reaction with an aldehyde as the hetero-
dienophile, since it occurs at rt without the need of a
Lewis acid.
follow the pattern found before, which implies an exo
approach of the aldehyde to the diene.
The behaviour of vinyl allenes in the intramolecular
hetero Diels–Alder reaction is thus parallel to that of
the all-carbon version of the reaction. The substituents
on the allene act as activating groups facilitating the
reaction, whereas the length of the tether plays an
important role in the reactivity.16
A similar result was obtained when 6 was subjected to
the same oxidising conditions, tricyclic compound 10
was isolated in an 86% yield. Again the corresponding
aldehyde was observed in the crude reaction mixture
prior to purification.
The fact that several of the vinyl allenals used react
under thermal conditions, at room temperature or
higher, depending on the structure, without the need of
a Lewis acid seems to point to a truly pericyclic mecha-
nism as opposed to a cationic stepwise one. Although
no experiments have been carried out to ascertain the
mechanism involved, preliminary ab initio calculations
on model systems17 (Scheme 6) indicate, in the absence
of Lewis acid, a concerted reaction with some degree of
asynchronicity, which is greater in the alkyl substituted
systems. Table 1 shows the calculated activation energy
and the variation of bond index at the transition state
(dBi)18 for the four models considered.
We then turned our attention to the homologous vinyl
allenals containing one more carbon atom in the tether
(compounds 11–13, n=2, Scheme 1), which would yield
octahydroxanthene-type products. The three com-
pounds chosen were selected using the same criteria
employed before, i.e. different and differently-sized sub-
stituents on the allene.
The preparation of vinyl allenols 11–13 was carried out
following the same procedure shown in Scheme 2 using
5-tert-butyldimethylsilyloxypentanal15 in the first step.
The yields obtained were similar to those described for
3, 5 and 6.
It can be observed that a good correlation exists
between the calculated values for the activation energy
on the models and the observed reactivity for the
experimental counterparts. Model B (R=Me, n=1) is
predicted to react more easily than A (R=H, n=1) and
D (R=Me, n=2), and model C (R=H, n=2) is pre-
dicted to be the least reactive. Experimentally, com-
pounds 5 and 6 (R=alkyl, n=1) react spontaneously at
room temperature, 7 (R=H, n=1), 12 and 13 (R=
alkyl, n=2) need Lewis acid activation and 11 (R=H,
n=2) does not react under the conditions assayed.
No cyclization products were observed after purifica-
tion of the oxidation reactions, which was expected
based on the literature reports on the lower reactivity of
the higher homologues in intramolecular Diels–Alder
reactions. The aldehydes were unstable and thus had to
be used immediately to avoid decomposition.
Under Lewis acid catalysis, only 12 and 13 yielded the
expected cyclization products 15 and 16, respectively, in
moderate yields, whereas with 11 there was no reaction,
only decomposition when longer reactions times were
used (Scheme 5).
The variation of bond indices indicates that, as
expected for a hetero Diels–Alder reaction, in all cases
The easy transformation of 5 and 6 at room tempera-
ture led us to wonder whether their homologues 11–13
would react under strictly thermal conditions, and thus
11 and 12 were dissolved in toluene and heated to
reflux. Under these conditions, 11 decomposed without
any sign of transformation, whereas after 12 h, 12
afforded the tricyclic compound 15 in a 48% yield.
The structure and relative stereochemistry of these new
tricyclic systems, deducted from goesy experiments,14
Scheme 6. Model compounds used in ab initio calculations.
Arbitrary numbering.
Table 1. Activation energy, relative activation energy and
variation of bond indices at the transition state for model
systems calculated by ab initio methodsa
Model
Ea (kcal/mol)
DEa (kcal/mol)
dB1–6 dB4–5
A
B
C
D
20.60
19.45
22.15
20.95
1.15
0.0
2.70
1.50
0.27
0.25
0.27
0.25
0.44
0.46
0.42
0.43
Scheme 5. Reagents and conditions: (a) Refluxing toluene, 12
h (R=Me, 48%); (b) BF3·Et2O, CH2Cl2, rt (R=H, 0%;
R=Me, 45%; R=t-Bu, 48%).
a B3LYP/6-31G(d)//B3LYP/6-31G(d) calculations. ZPVE scaled by
0.98 are included. For the arbitrary numbering, see Scheme 6.

8474
D. Rega´s et al. / Tetrahedron Letters 44 (2003) 8471–8474
there is some asynchronicity, with the carbonꢀcarbon
bond formed to a larger extent in the transition state
(42–44%) than the carbonꢀoxygen bond (25–27%). The
introduction of the methyl groups on the allene
enhances this asynchronicity.
mmol) in diethyl ether (2 mL). The reaction was stirred
overnight and then Et3N (1 mL) was added followed by
water. The reaction was extracted with diethyl ether
(3×15 mL), dried and concentrated. After flash column
chromatography (3% EtOAc in hexanes), 8 was obtained
1
as a clear oil (18 mg, 18%). H NMR (400 MHz, C6D6)
In conclusion, we have found that the intramolecular
hetero Diels–Alder reaction of vinyl allenes with alde-
hydes can occur to give polycyclic compounds, pro-
vided that the right substitution pattern and length of
tether are used. The reaction proceeds thermally, with-
out Lewis acid, in several of the examples studied.
l 6.11 (s, 1H), 5.44 (s, 1H), 4.71 (t, J=7.0 Hz, 1H), 4.23
(dd, J=4.5, 11.9 Hz, 1H), 2.27–2.32 (m, 3H), 2.14–2.16
(m, 1H), 1.99–1.79 (m, 4H), 1.58–1.64 (m, 2H), 1.08–1.22
(m, 2H); 13C NMR (100 MHz, C6D6) l 144.5, 139.5,
121.0, 113.9, 77.0, 76.1, 34.5, 33.6, 31.2, 30.0, 28.3, 25.1;
HRMS (EI) m/z calcd for C12H16O 176.1201, found
176.1205.
13. All new compounds reported exhibit spectroscopic data
(1H and 13C NMR, COSY, HSQC and HMBC) consis-
tent with the proposed structures.
Acknowledgements
14. Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am.
This research was made possible by grant BQU2001-
3184 from the Spanish Ministry of Science and Tech-
nology. D.R. thanks the M.E.C. for a FPU fellowship.
Chem. Soc. 1994, 116, 6037.
15. Marshall, J. A.; Shearer, B. G.; Crooks, S. L. J. Org.
Chem. 1987, 52, 1236.
16. Other vinyl allenals 17 and 18 with a one carbon atom
shorter and longer tether, respectively, than those studied
in this work were also prepared following the same
strategy and subjected to the same reaction conditions.
As expected from the literature data neither one reacted
to give cyclization products.5
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