Synthesis of substituted [3dendralenes and their unique cycloaddition reactions

Article abstract of DOI:10.1039/c1cc14211a

Dimethylsulfonium methylide mediated olefination of 2-phenylethenylidene phosphonoacetate followed by the Horner-Wadsworth-Emmons reaction with aromatic aldehydes provided access to reactive 1,5-diaryl-2-ethoxycarbonyl [3dendralenes which in situ underwen

Full text of DOI:10.1039/c1cc14211a

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COMMUNICATION
Synthesis of substituted [3]dendralenes and their unique cycloaddition
reactionsw
Rekha Singh and Sunil K. Ghosh*
Received 13th July 2011, Accepted 15th August 2011
DOI: 10.1039/c1cc14211a
Dimethylsulfonium methylide mediated olefination of 2-pheny-
lethenylidene phosphonoacetate followed by the Horner–
Wadsworth–Emmons reaction with aromatic aldehydes provided
access to reactive 1,5-diaryl-2-ethoxycarbonyl [3]dendralenes
which in situ underwent Diels–Alder cyclodimerisation leading
to highly functionalised cyclohexenes with very high regio- and
stereoselectivity.
Fig. 2 Carbene anion.
been made to make a substituted version of these cross-conjugated
molecules. Only a handful of methods can introduce substituents
like alkyl groups at specific positions such as at the termini of the
central double bond 2 and 2-substituted 3 or 1,4-disubstituted
[3]dendralenes19 4 (Fig. 1). Highly functionalised compounds such
as 1,2,5-trialkyl substituted cross-conjugated trienes 5 have also
been reported by metal-catalysed dimerisation of allenes.20
As a continuation of our work on versatile olefin synthesis
using dimethylsulfonium methylide 6,21 we have reported22 an
interesting observation that 6 in excess or in the presence of a
base undergoes a tandem ylide addition–eliminative olefination
on various activated olefins thus acts as an equivalent of the
carbene anionz (Fig. 2). This strategy has been used for the
preparation of 1-substituted vinyl silanes, styrenes and products
derived from them.23 The methodology has been applied for
sequential tandem double olefination of vinyl phosphonates
and aldehydes to provide di and tri-substituted 1,3-dienes with
very high regio and stereoselectivity.24 This strategy has also been
used25 for the olefination of extended conjugated systems like
1,3-diendioates or 1,3,5-trienedioates leading to 1,3-butadien-
2-yl- or 1,3,5-hexatriene-2-yl-malonates. We report herein a
sequential double olefination process for the synthesis of 1,5-
diaryl-2-alkoxycarbonyl [3]dendralenes. The unique reactivity
of these specially substituted cross-conjugated trienes for a
highly regio- and stereoselective Diels–Alder cyclodimerisation
leading to complex cyclohexenes has also been presented.
Knoevenagel condensation of ethyl bis-(2,2,2-trifluroethyl)-
phosphonoacetate with cinnamaldehyde in the presence of
piperidinium benzoate provided the desired 2-phenylethenylidene
phosphonoacetate 7 in 84% yield (Scheme 1). When this
phosphonoacetate 7 was added to ylide 6, generated25 using
Me3SI and n-BuLi in THF and the intermediate was quenched
with p-bromobenzaldehyde, the desired [3]dendralene 8a was
formed. The triene 8a must have formed via the dienic ylide 9
Acyclic cross-conjugated polyolefins, also known as [n]den-
dralenes 1 (Fig. 1), have received renewed attention. Besides
their attracted interest in polymer chemistry1 and theoretical
chemistry,2 they have high synthetic potential3 especially in
sequential cycloaddition reactions for easy access to polycyclic
systems.4–6 Various approaches such as metal-catalysed
coupling reactions,6–8 Peterson type elimination,9 thermal
decomposition of vinyl sulfolene,10 pyrolysis,11 Mitsunobu
dehydration12 and Hofmann elimination13 have provided access
to types of [n]dendralenes. Recent success of the Sherburn
group for practical syntheses8,14 of several unsubstituted
dendralenes [n = 3–8] and efforts from Hopf and Yildizhan,15
Fallis5,12 and others16,17 also brought significant advancement
in this area of research. These synthetic methodologies helped
in the study of the reactivity of unsubstituted [n]dendralenes
including their conversion to a new class of hydrocarbons, the
ivyanes.18 Unlike unsubstituted dendralenes, very little effort has
Fig. 1 Various dendralenes.
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay,
Mumbai, India. E-mail: ghsunil@barc.gov.in; Fax: +91-22-25505151;
Tel: +91-22-25595012
w Electronic supplementary information (ESI) available: Typical
experimental procedure, full characterisation data, copies of 1H and
13C NMR. CCDC 833098. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c1cc14211a
followed by
a
Horner–Wadsworth–Emmons reaction
(Scheme 2) with the added aldehyde. The formation of the
triene 8a could be monitored by TLC, but could not be isolated
because of its high reactivity. Under the reaction conditions, it
underwent an in situ Diels–Alder (D–A) cyclodimerisation to
c
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Scheme 1 Synthesis of 2-phenylethylidene phosphonoacetate.
Scheme 3 Crossover experiment.y
the similar regioselectivity in D–A cyclodimerisation of
unsubstituted [3]dendralene which has been explained by the
biradical mechanism proposed by Dewar et al.26
Scheme 2 Synthesis of cyclohexene 10a.y
To interrupt this D–A homodimerisation of the triene 8a,
we added dienophiles such as N-phenylmalemide or dimethyl
acetylene dicarboxylate after 15 min of the addition of
p-bromobenzaldehyde. We did not find any D–A adduct from
these dienophiles, only the cyclohexene 10a was obtained.
Interruption of the homodimerisation also failed with the
addition of an external diene such as isoprene. We have also
carried out crossover experiments to confirm the intermediacy
of [3]dendralene in this reaction. For this, phosphonoacetate 7
was added to ylide 6 and quenched with an equimolar mixture
of p-bromobenzaldehyde and pyridine-3-carboxaldehyde.
After usual workup, we obtained all four possible D–A
adducts (Scheme 3) (35% combined yield). The cyclohexenes
10a and 10b were formed by D–A homodimerisation of trienes
8a and 8b, respectively. The cyclohexenes 11a and 11b were
formed by the cross D–A reaction of the trienes 8a and 8b
wherein triene 8a acted as diene and triene 8b acted as
dienophile or vice versa. No other regio- and stereoisomers
were obtained. The observed yield was poor. But, considering
the number of elementary steps and complexity of the process,
the yield at this stage was acceptable.
give the cyclohexene 10a as a racemic compound wherein one
molecule of the triene 8a behaved as a diene and another as a
dienophile. The overall process proceeded with moderate
(ca. 33%) yield but with excellent regio- and stereoselectivity.
A racemic but single diastereoisomer 10a was obtained
from the reaction whose structure was confirmed by X-ray
crystallographyw (Fig. 3). The D–A reaction was very unique
in the sense that the 3-methylene group of the triene 8a
exclusively participated as the dienophile component. Looking
through the structure of 8a, it was not so apparent that this
double bond is the most electronically deactivated. More
interestingly, this 3-methylene group and the 4-position double
bond of the triene together acted as the diene component. The
orientation of the diene component and the dienophile
component was such that bonding took place between the
unsubstituted carbons of the 3-methylene groups (from diene
and dienophile, both) and two substituted carbons, at
3-position (dienophile) and 5-position (diene) leading to one
regio-isomer only with the generation of a quaternary
stereogenic centre. Although, Sherburn et al.14 have shown
Fig. 3 ORTEP plot of racemic 10a.z
Scheme 4 Improved synthesis of cyclohexene 10a.y
c
10810 Chem. Commun., 2011, 47, 10809–10811
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Chemistry: Syntheses, Concepts, Perspectives, Wiley-VCH,
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Scheme 5 Synthesis of cyclohexenes 10a–h.y
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A significant improvement of the overall yield for 10a
starting from phosphonoacetate 7 was observed when the
reaction was performed in two stages instead of one-pot. Thus
the phosphonoacetate 7 was added to ylide 6 and then
quenched with water to give the 1,3-butadien-2-ylphosphono-
acetate 12 in 88% yield. This phosphonate was then mixed
with 1 equiv. of p-bromobenzaldehyde and reacted with NaH
in THF which resulted in the formation of the D–A
homodimerisation product 10a (Scheme 4) in 72% yield
(63%) overall from dienic phosphonoacetate 7.
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To show the generality of the process, dienyl phosphonate
12 was reacted with sodium hydride and various aromatic
aldehydes as described for 10a. The reaction of substituted
benzaldehydes (Scheme 5) proceeded well with varying
substituents and patterns. Heteroaromatic aldehyde such as
3-pyridine carboxaldehyde also reacted well to give the D–A
dimer. In each case, the isolated product was found to be the
cyclohexene, resulted from the D–A homodimerisation of the
corresponding [3]dendralene. The cyclohexenes 10a–h were
formed with very high regio- and stereoselectivity and only
one diastereoisomer was obtained in each case.
´
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In conclusion, a novel route to functionalised [3]dendralenes
has been developed. Interestingly, the substituents on these
dendralenes made them reactive enough to undergo a facile
intermolecular D–A cyclodimerisation at room temperature
giving highly substituted cyclohexenes with very high
regio- and stereoselectivity. Efforts are ongoing to interrupt
this self-dimerisation and also to induce asymmetry for
enhancement of the utility of the present method.
Notes and references
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z For the use of this terminology; see: T. Cohen and L. C. Yu, J. Org.
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y The products 10a–h or 11a,b are obtained as racemic compounds
only.
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z X-Ray crystallographic data were collected at the X-ray diffraction
facility, Department of Chemistry, IIT, Mumbai.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10809–10811 10811