Photosensitized intramolecular cyclization of furan and non-activated alkene: pathway switching by the substituent on the furan ring

Article abstract of DOI:10.1016/j.tetlet.2009.12.123

A photosensitized reaction of furan with a non-activated simple alkene was investigated. Intramolecular Diels-Alder-type cycloaddition reactions between furan and a trisubstituted alkene were found to proceed in high yield in the presence of 9,10-dicyanoanthracene under UV irradiation to afford oxabicyclo[2.2.1]heptane derivatives in high stereoselectivity when the furan was alkyl substituted. On the other hand, the aryl-substituted furan cyclized via a completely different pathway to give spirocyclic and tricyclic products.

Full text of DOI:10.1016/j.tetlet.2009.12.123

Tetrahedron Letters 51 (2010) 1273–1275
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photosensitized intramolecular cyclization of furan and non-activated
alkene: pathway switching by the substituent on the furan ring
*
*
Noriyoshi Arai , Koichiro Tanaka, Takeshi Ohkuma
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A photosensitized reaction of furan with a non-activated simple alkene was investigated. Intramolecular
Diels–Alder-type cycloaddition reactions between furan and a trisubstituted alkene were found to
proceed in high yield in the presence of 9,10-dicyanoanthracene under UV irradiation to afford oxabicy-
clo[2.2.1]heptane derivatives in high stereoselectivity when the furan was alkyl substituted. On the other
hand, the aryl-substituted furan cyclized via a completely different pathway to give spirocyclic and tri-
cyclic products.
Received 18 November 2009
Revised 17 December 2009
Accepted 22 December 2009
Available online 4 January 2010
Keywords:
Photochemistry
Furan
Ó 2009 Elsevier Ltd. All rights reserved.
Alkene
Cycloaddition
Diels–Alder reaction
Diels–Alder reaction of furans is known as a powerful synthetic
tool to construct a six-membered ring system equipped with oxy-
gen functionality.1 The intramolecular Diels–Alder reaction of fur-
ans is a particularly attractive method, since two or more ring
systems can be constructed in a single step with high regio- and
stereoselectivity.2 In these reactions, based on the well-known
frontier orbital theory, the dienophiles coupled with furans should
have an electron-withdrawing group in order for the reaction to
proceed smoothly.3 A wide range of cyclo-adducts can be obtained
in reactions with such combinations of furans and electron-defi-
cient dienophiles; however, a readily proceeding reverse reaction
sometimes lowers the yields of the products.4,5 Development of
Diels–Alder reactions between furans and electron-rich dieno-
philes under mild conditions would enhance the synthetic versatil-
ity of the reaction. In general, Diels–Alder reactions between
electron-rich dienes and dienophiles are known to proceed with
difficulty and to require harsh reaction conditions.6 Even when
the reaction was performed in an intramolecular manner, only
40% conversion was reported in the reaction of allyl(2-furylmeth-
yl)malonate.7 Sternbach et al. reported that intramolecular Diels–
Alder reaction of furan and simple alkenes gave adducts in high
yields when the substrates had appropriate substituents on the
linker moiety.8,9 Quite recently, Hsung and Lohse reported intra-
molecular [4+2] cycloaddition of furans through tandem propargyl
amide isomerization-cyclization.10
The use of cycloaddition reactions through radical ions or
excited states can be an effective method for making the Diels–Al-
der reaction between electron-rich dienes and alkenes proceed
more easily. Bauld and co-workers reported that Diels–Alder-type
dimerization of 1,3-cyclohexadiene and other electron-rich dienes
proceeded well via single electron transfer with triarylamminium
salts.11–13 A radical cation chain process was proposed for these
reactions.12
Several research groups described that the [4+2] cycloaddition
reactions of 1,3-cyclohexadiene and related compounds with elec-
tron-rich dienophiles were catalyzed by cyanoarenes under UV
irradiation.14,15 Schuster and co-workers proposed that these reac-
tions proceed through intermediate excited-state ternary com-
plexes.15 To our knowledge, however, this reaction strategy has
never been applied to furan and its derivatives.16 We therefore
investigated the intramolecular Diels–Alder reaction of furans un-
der photosensitized conditions and found that the reactions with
appropriately designed furyl alkenes proceeded in high yield with
excellent stereoselectivity.17 In the course of this study, we also
found that the substituent on the furan ring had a dramatic effect
on the reaction pathway.
We chose diethyl malonate derivative 1a as a substrate, and
examined the photocycloaddition reaction in various solvents in
the presence of 9,10-dicyanoanthracene (DCA). The results are
summarized in Table 1.
* Corresponding authors. Tel.: +81 11 706 6600; fax: +81 11 706 6598 (N.A.); tel.:
+81 11 706 6599; fax: +81 11 706 6598 (T.O.).
E-mail addresses: n-arai@eng.hokudai.ac.jp (N. Arai), ohkuma@eng.hokudai.ac.jp
(T. Ohkuma).
All reactions were carried out in a PyrexÒ tube under irradiation
by a high-pressure mercury lamp.18 Irradiation of 8 h gave the cor-
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.123

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N. Arai et al. / Tetrahedron Letters 51 (2010) 1273–1275
Table 1
DCA resulted in quantitative recovery of 1a and (2) Treatment of
Solvent effect on the photocycloaddition of 1aa
1a with (4-BrC6H4)3N+Å(SbCl6À) in CH2Cl2 resulted in the recovery
of 1a without the production of 2a.
With regard to the choice of photosensitizer, 1,4-dicyanoben-
zene (DCB) and 1,4-dicyanonaphtharene (DCN) gave much poorer
results (<10% yield of 2a).
In the above investigation, benzene seemed to be the solvent of
choice, since the yield of 2a was relatively high and the sensitizer
was less decomposed in that solvent (entry 2). We next tried the
reaction in benzene for a prolonged period of time and found that
the yield of 2a increased to a synthetically useful level (89%, entry
9). We also carried out the reaction under the condition of high
DCA loading, with the hope of increasing the reaction rate, and
found that the cyclized product 2a was obtained with a yield as
high as that in entry 9, though the expected acceleration was not
observed (entry 10).
We next examined the effect of substituents around the alkene
and the tether moiety. The results are summarized in Table 2. The
structure around the olefinic moiety had a pronounced effect on
the yield of the cyclized products. In contrast to 1a (entry 1), nei-
ther the simple allyl substrate 1b, methallyl type 1c, or trisubsti-
tuted substrate 1d underwent the cyclization under the standard
reaction conditions, resulting in the recovery of the starting mate-
rials (entries 2–4). Only tetrasubstituted alkene 1e afforded the
sterically congested product in 2e 35% yield after 64 h irradiation
(entry 5). It is quite interesting that only the most bulky substrate
could afford the product, and although the reason for this finding is
unclear at this stage, both electronic and steric factors might be
involved.
On the other hand, the tether moiety was found to be less crit-
ical for the cyclization. That is, alkenyl furan tethered by amine
linkage (1f) cyclized under the standard reaction conditions de-
scribed above to afford the product 2f in moderate yield with com-
plete stereoselectivity (entries 6 and 7). In regard to 1f, dioxane
gave a better yield than benzene.
The diester moiety can be replaced with other functionalities.
For instance, diether 1g also gave the corresponding cyclized prod-
uct 2g in good yield (entry 8).
Substitution on the furan ring did not have an inhibitory effect
on the reaction. Thus, when the 5-methyl derivative 1h was em-
ployed as a substrate, the corresponding cyclized product 2h was
obtained in high yield and exclusive stereoselectivity (entry 9). It
should be noted that the trimethyl-substituted oxabicy-
clo[2.2.1]heptane moiety with high steric hindrance was con-
structed by a simple operation, as well as 2e.
Entry
Solvent
Irr. time (h)
Yield of 2ab (%)
Recov. of 1ab (%)
1
2
3
4
5
6
7
8
Toluene
Benzene
THF
DME
1,4-Dioxane
AcOEt
CH3CN
CH3OH
Benzene
Benzene
8
8
8
8
8
8
9
9
84
85
21
36
25
31
31
40
2
0
78
61
71
63
65
58
87
94
2
9
89 (79)c
85
10d
10
a
The reaction was conducted under the following conditions: initial concentra-
tion of 1a, 0.04 M; DCA, 5 mol %; temperature, 20 °C; carried out in a PyrexÒ tube
under irradiation by high-pressure mercury lamp.
Estimated by 1H NMR integration by using pyrazine as an internal standard.
b
c
Isolated yield.
1a, 0.016 M; DCA, 25 mol %.
d
responding product 2a in moderate yields in non-polar solvents
(entries 1 and 2), as well as medium polar ones (entries 3–6). We
confirmed that 2a was stable under the conditions employed
because irradiation of 2a resulted in quantitative recovery of 2a
without isomerization. The cyclized product 2a was obtained in
diastereomerically pure form, judging from the 1H NMR spectrum.
The relative configuration was determined by a NOE experiment
(Fig. 1). When Ha was irradiated, clear NOE enhancements were
observed for the signals of Hb, Hc, and Hd. This observation indi-
cates that compound 2a has the relative configuration depicted
in the figure (exo-adduct). In the endo-adduct, Ha and Hd are
located too far apart to show the NOE correlation. The relative con-
figurations of the following compounds were determined in the
same way.
It should be noted that cyclization between a trisubstituted alkene
and a furan affording the multi-substituted oxabicyclo[2.2.1]heptane
moiety in high selectivity has never been reported. The cyclizations of
furan with only a terminal non-substituted alkene (vinyl type) have
been investigated,8,9 with the exception that the cyclization with
methylenecyclopropane derivatives gave the corresponding adducts
under high-pressure conditions.19
In the course of the study of substituents on the furan ring, we
also observed a unique behavior of phenyl-substituted furan 3.
Irradiation of 3 under the conditions described above did not gave
[4+2]-type products, but two new compounds. Detailed investiga-
tion of the NMR spectra revealed that these products have the
structures of spirocyclic 4 and tricyclic 5 depicted in Scheme 1.
The yields estimated by 1H NMR integration are shown because
the quantity of these compounds was somewhat decreased after
purification, probably due to decomposition. They were diastereo-
merically pure, though the relative configurations have not been
determined yet. In contrast to the reaction of 1, this cyclization
proceeded in polar solvents such as methanol and acetonitrile as
well as benzene and ethyl acetate. The ratio of produced 4–5 de-
pended on the solvents to some extent. To our knowledge, this type
of cyclization of furan is unprecedented. Though the details of the
reaction mechanism are not clear at this stage, it is conceivable
that the process may involve radical ions instead of short-lived
biradicals, especially in a polar solvent.
In contrast to the results in entries 1–6, the reactions in highly
polar solvents hardly proceeded and resulted in almost complete
recovery of 1a (entries 7 and 8). This result strongly suggests that
the cycloaddition of 1 proceeds not through the electron transfer
producing 1a+Å and DCAÀÅ, but through the formation of an exciplex
between 1a and DCA, as proposed by Schuster and co-workers.15
We also observed the following results which support the above
consideration: (1) Irradiation of 1a in benzene for 15 h without
In conclusion, we investigated the photosensitized Diels–Alder
reaction between furan and non-activated alkenes and found that
appropriately substituted substrates (1a, 1e, 1f, 1g, and 1h) gave
Figure 1. NOE enhancements for 2a. Ethoxycarbonyl groups are omitted in the
stereographic for clarity.

N. Arai et al. / Tetrahedron Letters 51 (2010) 1273–1275
1275
Table 2
Substituent effect on the photocycloaddition
Entry
Compound
R1
R2
R3
R4
Z
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1f
1g
1h
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
Me
H
H
Me
Me
Me
Me
Me
Me
Me
H
H
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
NBoc
NBoc
C(CH2OMe)2
C(CO2Et)2
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Dioxane
Benzene
Benzene
84
72
72
84
64
93
93
72
68
2a, 79
0
0
Trace
2e, 35b
2f, 38b
2f, 55b
2g, 82
2h, 82
H
Me
Me
Me
Me
Me
Me
a
Isolated yield.
b
Contains small amounts (approx. 2–3%) of inseparable DCA.
Scheme 1. Photosensitized cyclization of 3.
5. Halogen effect on reactivity and reversibility: Pieniazek, S. N.; Houk, K. N.
Angew. Chem., Int. Ed. 2006, 45, 1442–1445.
the cyclized products in good to moderate yields with excellent
stereoselectivity. When a phenyl group was introduced to the
furan ring, the reaction proceeded along a completely different
pathway to afford the spirocompound 4 and tricyclic compound 5.
6. Prajapati, D.; Laskar, D. D.; Sandhu, J. S. Tetrahedron Lett. 2000, 41, 8639–8643.
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Acknowledgment
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This work was supported by a Grant-in-Aid from the Japan Soci-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.123.
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