Indirect support for a stepwise carbonium ion pathway operating in (4+3)-cycloaddition reactions between furanoxonium ions and 1,3-dienes

Article abstract of DOI:10.1055/s-0033-1339893

Treatment of solutions of the furfuryl alcohol 6 in dichloromethane- methanol with buta-1,3-diene or cyclohexa-1,3-diene or with cyclopentadiene in the presence of trifluoroacetic acid leads to the corresponding substituted furyl tetrahydrofurans, 8, 12 and 15 respectively, rather than to the products 10, 13 and 16 anticipated from intermolecular (4+3)-type cycloaddition reactions. These outcomes provide indirect experimental support for a stepwise carbonium ion pathway operating in (4+3)-cycloaddition reactions between furanoxonium ions and 1,3-dienes. Alongside other results, the outcomes also highlight a limitation to (4+3) cycloadditions in cycloheptene ring synthesis when the precursors contain hydroxyl groups capable of intercepting any carbonium ion intermediates leading to O-heterocyclic by-products. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339893

2720▌
LETTER
lIenttedr irect Support for a Stepwise Carbonium Ion Pathway Operating in
(4+3)-Cycloaddition Reactions between Furanoxonium Ions and 1,3-Dienes
Carbonium Ion Pathway Operating in (4+3) Cycloaddition
Matthew J. Palframan, Gerald Pattenden*
School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax +44(115)9513530; E-mail: gp@nottingham.ac.uk
Received: 23.08.2013; Accepted: 05.09.2013
incorporate additional juxtaposed hydroxyl substituents.
Abstract: Treatment of solutions of the furfuryl alcohol 6 in dichlo-
We anticipated that these hydroxyl groups would inter-
romethane–methanol with buta-1,3-diene or cyclohexa-1,3-diene or
cept any carbonium ion intermediates produced during
any addition reactions between the starting materials, and
with cyclopentadiene in the presence of trifluoroacetic acid leads to
the corresponding substituted furyl tetrahydrofurans, 8, 12 and 15
respectively, rather than to the products 10, 13 and 16 anticipated thus inhibit the formation of products resulting from
from intermolecular (4+3)-type cycloaddition reactions. These out-
comes provide indirect experimental support for a stepwise carbo-
nium ion pathway operating in (4+3)-cycloaddition reactions
(4+3)-type cycloaddition reactions. The outcome of this
premise is presented here.
between furanoxonium ions and 1,3-dienes. Alongside other re-
R
sults, the outcomes also highlight a limitation to (4+3) cycloaddi-
tions in cycloheptene ring synthesis when the precursors contain
hydroxyl groups capable of intercepting any carbonium ion inter-
mediates leading to O-heterocyclic by-products.
R
O–
OH
+
O
O
2
1
Key words: furfuryl alcohols, (4+3)-type cycloadditions, furanox-
onium ions
R
+
O
+
O
3
Furfuryl alcohols 1 are readily available compounds and
they have been used widely as starting materials in a myr-
iad of synthetic transformations. For example, they show
a high propensity to react with oxidants and also with ac-
ids leading to synthetically useful pyrylium and furanox-
onium ion intermediates 2 and 3, respectively.1 These
intermediates then undergo novel [(5+2), (4+3) and
(4+2)] cycloaddition reactions with appropriate alkenes
and 1,3-dienes leading to polycyclic ring systems, as
found in some important biologically active natural prod-
ucts.2,3 In earlier research we evaluated the scope for
(4+3) and then (4+2) intramolecular cycloaddition reac-
tions from appropriately substituted furanoxonium ion in-
termediates in approaches to the cycloheptene and
cyclohexene ring-containing natural products, ra-
meswaralide (4) and plumarellide (5), respectively (Fig-
ure 1).4,5 Although we initially represented these separate
furanoxonium ion cycloaddition reactions as (4+3) or
(4+2) processes, subsequent synthetic work accompanied
by density functional theory (DFT) calculations, first by
Winne et al.6 and then by ourselves, have given credence
to the notion that the cycloadditions are more likely to be
stepwise processes involving discrete carbonium ion in-
termediates.7 We have now taken the opportunity to ex-
amine the likelihood of carbonium ion intermediates in
the aforementioned (4+3) cycloaddition reactions leading
to cycloheptenes, and studied the acid-catalysed addition
reactions between 1,3-dienes and furfuryl alcohols which
HO
O
CO2Me
HO
H
H
H
CH2OH
OH
OH
H
H
H
O
O
H
H
O
H
O
O
Rameswaralide (4)
Plumarellide (5)
Figure 1
We first examined the reactivity of the vicinal diol-based
furfuryl alcohol 68 with buta-1,3-diene in the presence of
trifluoroacetic acid (TFA) in dichloromethane–methanol.9
Whatever the mechanism, that is, a concerted reaction or
a stepwise carbonium ion process, with no intervention by
the additional tertiary hydroxyl group in 6, the anticipated
product from this reaction would be the furan ring-fused
cycloheptene 10 resulting from an intermolecular (4+3)-
type cyclisation (Scheme 1). However, the product we ob-
tained was the substituted furyl tetrahydrofuran 8 in a very
good 75% yield. The structure and stereochemistry of the
major diastereoisomer produced in the reaction (i.e., 8),
followed from analysis of its relevant spectroscopic data.
The new compound exhibited the expected molecular ion
at m/z 287.1261 [M + Na]+ in its high resolution mass
spectrum, corresponding to the molecular formula
C15H20O4. The 13C NMR spectrum showed signals for 15
carbon atoms, and the DEPT spectra revealed the pres-
ence of four methyl, two methylene, five methine and four
quaternary carbons.
SYNLETT 2013, 24, 2720–2722
Advanced online publication: 14.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339893; Art ID: ST-2013-D0816-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carbonium Ion Pathway Operating in (4+3) Cycloaddition
2721
MeO2C
MeO2C
MeO2C
HO
OH
HO
HO
TFA
CH2Cl2
O+
O
+
O
7
6
(4+3)-type
concerted
MeO2C
MeO2C
MeO2C
+
O
O
O
O
OH
OH
8
9
10
MeO2C
MeO2C
MeO2C
O
+
TFA, CH2Cl2
6/7
O
O
O
OH
11
12
OH
13
MeO2C
MeO2C
MeO2C
O
+
TFA, CH2Cl2
6/7
O
O
O
OH
14
15
OH
16
Scheme 1
The presence of the carbon signal at δ 106.9 showing an failure to observe formation of the compounds 10, 13 and
HSQC correlation to the 1H NMR resonance at δ 6.33 was 16 in these reactions probably reflects the differing rates
indicative of a furan CH. Also of note were the carbon sig- of oxygen-to-carbon over carbon-to-carbon bond forma-
nals at δ 139.2 and δ 116.1 associated with proton reso- tion from the common intermediates 9, 11 and 14, respec-
nances at δ 5.89 (δ 139.2), δ 5.27 and δ 5.12 (δ 116.1), tively. These outcomes therefore indirectly provide some
with the proton signals showing coupling to each other, useful experimental support for a stepwise carbonium ion
thus establishing the presence of the vinyl group in the pathway operating in intermolecular (4+3)-cycloaddition
new structure. The full structure was assigned following reactions between furanoxonium ions and 1,3-dienes.
examination of COSY, HSQC and HMBC NMR spectra.
In a similar manner, treatment of the same furfuryl alcohol
6 separately with cyclohexa-1,3-diene and cyclopentadi-
ene under the same reaction conditions to those used with
In other studies, we examined the outcomes of the acid-
catalysed reactions involving the furfuryl alcohols 6 and
22,10 and a selection of furans 17, and the diene 20. Thus,
reaction between 6 and the furans 17 in dichloromethane–
buta-1,3-diene led to the corresponding furyl tetrahydro-
methanol in the presence of trifluoroacetic acid gave only
furans 12 (70%) and 15 (65%), respectively. We were not
the bis-furanmethyl substituted tertiary alcohols 18, with
no evidence of the co-formation of the products (e.g. 19),
anticipated from a (4+3)-type cycloaddition reaction
able to obtain any evidence for the co-formation of the
products, 13 and 16 respectively, resulting from compet-
ing (4+3)-type cycloaddition reactions involving 6 and
(Scheme 2). The corresponding reactions between 6 and
cyclohexa-1,3-diene or cyclopentadiene.
the diene 20, and between the furfuryl alcohol 22 and
The production of the substituted tetrahydrofurans 8, 12 buta-1,3-diene led, perhaps not unexpectedly, to the sub-
and 15 from the aforementioned reactions with the furfu- stituted dioxolane 21 and to the substituted tetrahydro-
ryl alcohol 6 result from initial formation of the corre- furan 23, respectively.
sponding allylic carbonium ion intermediates, 9, 11 and
14, respectively, produced from electrophilic substitution
In conclusion, our study has provided some support for a
stepwise carbonium ion pathway operating in (4+3)-type
of the 1,3-dienes by the furfurylcarbonium/furanoxonium
intermolecular cycloaddition reactions between furanoxo-
ion intermediate 7. These allylic carbonium ion interme-
nium ions and 1,3-dienes leading to cycloheptene-ring
diates, 9, 11 and 14 are then trapped by their proximate
tertiary hydroxyl groups, leading to the observed substi-
tuted furyl tetrahydrofuran products (8, 12 and 15). The
synthesis, and has also highlighted a limitation to the same
reactions.11 Thus, when there are hydroxyl groups in the
precursors in close proximity to any allylic (or other) car-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2720–2722

2722
M. J. Palframan, G. Pattenden
LETTER
MeO2C
R2
MeO2C
O
O
R2
R1
TFA, CH2Cl2
6
+
O
O
R1
O
17a, R1 = R2 = H
OH
18
OH
17b, R1 = Me, R2 = H
19
17c, R1 = Me, R2 = CO2Me
MeO2C
MeO2C
MeO2C
OMe
OH
O
O
O
O
O
OTBS
O
OTMS
O
OH
HO
20
22
23
21
Scheme 2
Hoye, T. R. Org Lett. 2012, 14, 828. (c) Zapf, C. W.;
Harrison, B. A.; Drahl, C.; Sorensen, E. J. Angew. Chem. Int.
Ed. 2005, 44, 6533. (d) Couladouros, E. A.; Bouzasa, E. A.;
Magos, A. D. Tetrahedron 2006, 62, 5272.
bonium ion intermediates, these centres will inhibit the
formation of any anticipated (4+3) cycloaddition prod-
ucts, at the expense of formation of O-heterocyclic by-
products.
(4) (a) Pattenden, G.; Winne, J. M. Tetrahedron Lett. 2010, 51,
5044. (b) Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28,
1269.
(5) Palframan, M. J.; Pattenden, G. Tetrahedron Lett. 2013, 52,
324.
Acknowledgment
We thank The University of Nottingham and other sponsors for fi-
nancial support.
(6) Winne, J. M.; Catak, S.; Waroquier, M.; Speybroeck, V. V.
Angew. Chem. Int. Ed. 2011, 50, 11990.
(7) Our own DFT calculations were made by Professor Barry
Lygo of this School of Chemistry, and will be published
separately at a later date.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(8) The synthesis of furfuryl alcohol 6 was achieved in three
steps from methyl 2-methyl-3-furoate via: (i) an initial
Vilsmeier reaction to afford the corresponding aldehyde, (ii)
a Wittig reaction with isobutyl(triphenyl)phosphonium
iodide, and (iii) a Sharpless dihydroxylation. For full details,
see the Supporting Information.
(9) For a general experimental procedure for treatment of the
vicinal diol based furfuryl alcohol 6 with TFA and a range of
dienes, see the Supporting Information.
References
(1) For illustrations of the scope for the products of oxidative
cleavage of the furan ring in furfuryl alcohols, i.e., the
Achmatowicz reaction, in synthesis, see: Burke, M. D.;
Berger, E. M.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126,
14095; and references therein.
(2) (a) For recent examples of the scope for [5+2]-cycloaddition
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(11) For recent synthetic applications of (4+3)-type
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Synlett 2013, 24, 2720–2722
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