A comparison of the benzylic and the allylic group as a donor in the formal [4+2] cycloaddition to tetrahydropyrans using donor-acceptor cyclobutanes

Article abstract of DOI:10.1016/j.tetlet.2017.06.046

The allyl group was shown to be preferred over the benzyl group as a donor in the formal [4+2]-cycloaddition reaction between a donor-acceptor cyclobutane and various aldehydes to give tetrahydropyrans.

Full text of DOI:10.1016/j.tetlet.2017.06.046

Accepted Manuscript
A Comparison of the Benzylic and the Allylic Group as a Donor in the Formal
[4+2] Cycloaddition to Tetrahydropyrans using Donor-Acceptor Cyclobutanes
Awais Ahmed, Steven D.R. Christie, Gareth J. Pritchard
PII:
S0040-4039(17)30777-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.046
TETL 49038
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 April 2017
6 June 2017
14 June 2017
Please cite this article as: Ahmed, A., Christie, S.D.R., Pritchard, G.J., A Comparison of the Benzylic and the Allylic
Group as a Donor in the Formal [4+2] Cycloaddition to Tetrahydropyrans using Donor-Acceptor Cyclobutanes,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.046
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A Comparison of the Benzylic and the Allylic
group as a Donor in the Formal [4+2]
Cycloaddition to Tetrahydropyrans using
Donor-Acceptor Cyclobutanes.
Awais Ahmed, Steven D. R. Christie* and Gareth J. Pritchard*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A Comparison of the Benzylic and the Allylic Group as a Donor in the Formal [4+2]
Cycloaddition to Tetrahydropyrans using Donor-Acceptor Cyclobutanes
Awais Ahmed, Steven D. R. Christie* and Gareth J. Pritchard*
Department of Chemistry, University of Loughborough, Loughborough, Leicestershire, LE11 3TU, UK.
ARTICLE INFO
ABSTRACT
Article history:
Received
The allyl group was shown to be preferred over the benzyl group as a donor in the formal
[4+2]-cycloaddition reaction between a donor-acceptor cyclobutane and various aldehydes to
give tetrahydropyrans.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Cyclobutanes
Tetrahydropyrans
Cycloaddition
Lewis Acids
1. Introduction
closely related to ours;8 the use of an oxygen atom as the donor
has been established by Pagenkopf and others;9 the use of
cyclobutanones as shown by Matsuo;10 and the construction of
heteroaromatic systems using cyclobutanes as reported by Rao.11
Heterocyclic motifs play a key role in organic chemistry,
embracing pharmaceutical drugs, natural products and material
chemistry. The development of new routes towards heterocyclic
compounds is a key challenge for synthetic chemists. We have
added to this field a number of methodologies, including
stoichiometric organometallic;1,2 palladium mediated reactions;3
biomimetic methods;4 condensation of reactive electrophilic
systems;5 and Lewis acid mediated reactions.6 As part of our
studies, we have previously reported the formal
Herein, we report a recent study where we have added extra
to
complexity
the
donor-acceptor
cyclobutane
[4+2]-cycloaddition reaction. Johnson and co-workers have
previously shown that both an aromatic or allylic group can act
as the donor in the cyclobutane starting material,8 but there was
no discussion as to which was preferred. We have therefore
devised an experiment to compare the reactivity of these donor
groups. If there are two donor groups on the cyclobutane, one
phenyl and one allyl group, it would be interesting to observe
which bond will cleave to allow the formal [4+2]-cycloaddition
to occur under Lewis acid conditions (Scheme 2). This would
provide more insight into the mechanism of the
[4+2]-cycloaddition reaction, as well as the introduction of extra
substitution to the tetrahydropyran product, resulting in new
compounds difficult to access by other means.
[4+2]-cycloaddition
reaction
between
donor-acceptor
cyclobutanes and aldehydes to give tetrahydropyrans, under
Lewis acid conditions (Scheme 1).2
Scheme 1. Formal [4+2]-cycloaddition reaction between
donor-acceptor cyclobutane and aldehydes.
The use of donor-acceptor cyclobutanes in synthesis has
expanded since its initial report.7 Of note amongst those reports
are: Johnson and co-workers simultaneous report of chemistry
Scheme 2. Alternate donors on the cyclobutane ring.
__________
2. Results and Discussion
* Corresponding authors.
We based our route to compound 1 on the elegant chemistry
developed by Boeckman and co-workers, who used an anionic
ring closure reaction to prepare enantiomerically pure
E-mail addresses: G.J.Pritchard@lboro.ac.uk (G. J. Pritchard),
S.D.Christie@lboro.ac.uk (S. D. R. Christie).

2
Tetrahedron
vinylcyclobutane derivatives.12 Staring with the Michael
addition reaction between dimethyl malonate and
We were able to determine the regiochemistry of the dimer
product but not its stereochemistry. Both the cyclohexene 6 and
dimer 7 are also the result of the bond cleavage that leads to the
allyl cation, in accordance to the formation of tetrahydropyran 5.
cinnamaldehyde under the reaction conditions developed by Ma
and co-workers,13 the Michael product 2 was formed in 45%
yield. We did not attempt to optimize the reaction or control the
enantioselectivity of the reaction at this stage. Subsequent Wittig
reaction with acetylmethylene triphenylphosphorane gave ketone
3 in 70% yield. Following the steps developed by Boeckman and
co-workers, Luche reduction of the ketone and conversion into
the phenyl carbonate gave an inseparable mixture of
diastereoisomers (1:1). Cyclisation to the required cyclobutane 4
was carried out using sodium hydride in toluene at 50 ºC. An
inseparable 3:1 mixture of diastereoisomers was isolated in 88%
yield. Replacing the leaving group with methyl carbonate did not
change the ratio of the diastereoisomers but also lowered the
yield. The change in the diastereomeric ratio suggests that one
isomer is more readily able to cyclise.
We next tried to optimize the reaction conditions in order to
improve the ratio of the target tetrahydropyran product to
side-products by experimenting with different solvents and
catalysts (Table 2). Despite our best efforts, the initial reaction
conditions appeared to be best suited to this formal
[4+2]-cycloaddition reaction. Changing the solvent had
a
detrimental effect on the reaction outcome and other Lewis acids
did not provide any advantage over Sc(OTf)3, similar to the
findings of Johnson and co-workers.8
Table 2. Variations of solvent and Lewis acid catalyst used in
cycloaddition reaction between cyclobutane 4 and PhCHO.
Solvent
Catalyst
(10 mol%)
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
ZnBr2
Yield 5
Yield 6
Yield 7
(%)
0
(%)
17
0
(%)
10
0
Toluene
DMSO
DMF
THF
0
0
0
0
0
0
0
DCE
DCM
DCM
0
17
2
0
2
25
0
FeCl3
10
0
Reagents and conditions: PhCHO (5.0 equiv.), 40 °C, 8 h.
Scheme 3. Synthetic route to donor-acceptor cyclobutane 4.
With the encouraging result of successful tetrahydropyran
formation, we repeated the [4+2]-cycloaddition reaction with a
limited range of aromatic and unsaturated aldehydes using the
optimized conditions (Scheme 5, Table 3).
With a suitably substituted cyclobutane 4 in hand, we were
able to carry out the key formal [4+2]-cycloaddition. Using
previously developed reaction conditions, cyclobutane 4 was
treated with varying equivalents of benzaldehyde in the presence
of Sc(OTf)3 (10 mol%) in DCM. Gratifyingly the desired formal
[4+2]-cycloaddition tetrahydropyran product was obtained along
with various by-products, which were all isolated and identified
(Scheme 4, Table 1). It was immediately apparent that
cyclobutane 4 was less reactive than analogous literature
compounds, since larger equivalents of the aldehyde was required
to achieve workable yields. This could possibly be explained by
the increased steric demand of the cyclobutane starting material
which is known to hinder cycloaddition reactions.
Scheme 5. Cycloaddition reactions using different aldehydes.
Table 3. Yields for the cycloaddition reactions using different
aldehydes.
8 (%)
Traces
0
9 (%)
10 (%) 11 (%)
RCHO (equiv.)
4-MeOC6H4CHO (1.0)
4-NO2C6H4CHO (1.2)
Ph-CH=CH-CHO (1.2)
CH2=CH-CHO (3.0)
Scheme 4. Initial attempt of formal [4+2]-cycloaddition
reaction using cyclobutane 4.
0
0
9
8
0
0
0
3
2
33
10
15
27
12
Table 1. Comparison of different amounts of benzaldehyde.
PhCHO (equiv.)
Yield 5 (%)
Yield 6 (%) Yield 7 (%)
1.2
2.2
5.0
18
18
47
20
25
17
0
2
0
Introducing either electron-donating or electron-withdrawing
groups to the aromatic ring had detrimental effects on the
reaction, shutting down formation of the desired tetrahydropyran
product; the major product being the rearrangement to give
cyclohexene 10 (Table 3). More investigation is needed to
account for this unusual observation. However, the unsaturated
aldehydes acrolein and cinnamaldehyde did produce the desired
tetrahydropyran products 8 and 9. Unlike benzaldehyde, these
tetrahydropyran products lack a high diastereomeric excess and
structural analysis showed them to be epimeric at the 4-position.
This may suggest a change in the reaction mechanism; the
stereochemical outcome of the reaction may be related to the
stereochemistry of the starting cyclobutane, further studies are
underway regarding the reaction mechanism. Significant amounts
of rearranged cyclohexene by-product 10 and trace amounts of
The target pyran product 5 was purified and spectroscopic
analysis, including nOe experiments, showed it to be the single
diastereoisomer 5, arising from breaking of the cyclobutane bond
that would give rise to an allyl cation. The best yield (47%) was
obtained when a large excess of aldehyde (5 equiv.) was used.
We did not observe, or isolate, any tetrahydropyran products that
would arise from ring opening to give the benzyl cation. The
major by-product of the reaction was the rearranged cyclohexene
product 6, the stereochemistry of this product was also
established by nOe experiments. A small amount of dimer 7 was
also isolated from the complex reaction mixture on one occasion.

3
dimer 11 were also present, but no adducts were observed from
the bond cleavage leading to the benzylic cation.
3. Conclusion
We have successfully carried out a unique investigation
comparing an aromatic ring and an allyl group as donors in the
donor-acceptor cyclobutane [4+2]-cycloaddition reaction. The
crucial fact that cyclobutane ring cleavage exclusively led to the
allylic cation with no sign of the alternate bond cleavage
demonstrated, at least for this system, allylic stablisation is
superior to benzylic stablisation for this [4+2]-cycloaddition. We
have shown that when the donor-acceptor cyclobutane has a
choice of cleavage between a benzylic bond and an allylic bond,
only the allylic bond is broken under Lewis acid conditions. We
are currently looking at making use of this knowledge in
expanding the reaction and the synthesis of highly substituted
tetrahydropyrans.
References
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4
Tetrahedron
A Comparison of the Benzylic and the
Allylic Group as a Donor in the Formal
[4+2] Cycloaddition to Tetrahydropyrans
using Donor-Acceptor Cyclobutanes
Highlights:-
A formal [4+2]-cycloaddition reaction of donor-
acceptor cyclobutanes gives tetrahydropyrans.
The allyl group was shown to be a better donor than
benzyl.
A number of highly substituted tetrahydropyrans
were prepared.

5
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template box below.
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A Comparison of the Benzylic and the Allylic
group as a Donor in the Formal [4+2]
Cycloaddition to Tetrahydropyrans using
Donor-Acceptor Cyclobutanes.
Awais Ahmed, Steven D. R. Christie* and Gareth J. Pritchard*
Fonts or abstract dimensions should not be changed or altered.