Investigating the arenyl-diene double [3 + 2] photocycloaddition reaction

Article abstract of DOI:10.1021/jo101927a

The double [3 + 2] photocycloaddition reaction involving arenyl-dienes has been used to assemble seven separate [5.5.5.5] fenestrane structures that include ether and aza variants. The primary photolysis step was a meta photocycloaddition reaction, while

Full text of DOI:10.1021/jo101927a

pubs.acs.org/joc
Investigating the Arenyl-Diene Double [3 þ 2]
Photocycloaddition Reaction
Clive S. Penkett,*,† Jason A. Woolford, Timothy W. Read, and Rachel J. Kahan
Department of Chemistry, University of Sussex, Brighton, BN1 9QJ, U.K. †Previous address. Please use
email for correspondence.
Clive.Penkett@googlemail.com
Received October 28, 2010
The double [3 þ 2] photocycloaddition reaction involving arenyl-dienes has been used to assemble
seven separate [5.5.5.5] fenestrane structures that include ether and aza variants. The primary
photolysis step was a meta photocycloaddition reaction, while a secondary photocycloaddition step
formed the fenestrane structure. Investigations involving the insertion of an additional methylene
group into the basic arenyl-diene skeleton failed to afford the desired [5.5.5.6] fenestrane structure.
The presence of an oxime moiety in the aromatic photosubstrate allowed the primary photolysis step
to take place; however, an attempted secondary photocycloaddition reaction involving the oxime did
not provide the intended polyheterocyclic fenestrane. An alternative strategy to form various “criss-
€
cross” double meta photocycloadducts was investigated and led to the discovery of a Paterno-Buchi
cycloaddition reaction between acetone and an angular meta photocycloadduct. Other novel
thermally and photochemically mediated skeletal rearrangement reactions were also recorded.
Introduction
dioxafenestrane Penifulvin A,3 which shows efficacy as an
insecticide toward the fall armyworm, provides an indication
that the potentially useful properties of compounds containing
fenestrane scaffolds may have been overlooked.
Consequently, a route toward fenestranes that is simple to
perform and permits the attachment of different functional
groups could provide libraries of novel compounds for the
management of disease and infection. Our initial communic-
ation1 revealing the double [3 þ 2] photocycloaddition reaction
focused on the conversion of the acetal substrate 1 into the
fenestrane4 product 2 via the linear meta photocycloadduct 3.
This article will display the reaction’s wider application particu-
larly with respect to the formation of ether and amino analogues.
The generation of structurally complex molecules in a
concise step-efficient manner is one of the primary challenges
facing organic synthesis. Our previously reported double
[3 þ 2] photocycloaddition reaction1 is a remarkable chemi-
cal process that addresses this issue by converting simple
arenyl-diene substrates into products with architecturally
complex three-dimensional structures in two photochemical
steps (Scheme 1). During the course of such a process four
new carbon-carbon bonds, five new rings, and up to nine
new stereocenters are created.
As previously highlighted by Wender, Dore, and deLong,2
fenestranes compare favorably to the steroid class of com-
pounds in that they are “conformationally rigid and chemically
robust”. A lack of wider interest in the usage of fenestranes as
materials and in medicinal research has been largely due to
their unavailability. However, the recent total synthesis of the
Results and Discussion
Acetal Fenestranes. The conversion of arenyl-diene acetal
1 into fenestrane 2 was found to be a two-stage process. The
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Soc. 2010, 132, 4.
(2) Wender, P. A.; Dore, T. M.; deLong, M. A. Tetrahedron Lett. 1996,
37, 7687.
(3) Gaich, T.; Mulzer, J. J. Am. Chem. Soc. 2009, 131, 452.
(4) (a) Mani, J.; Keese, R. Tetrahedron 1985, 41, 5697. (b) Mani, J.;
€
€
Schuttel, S.; Zhang, C.; Bigler, P.; Muller, C.; Keese, R. Helv. Chim. Acta
1989, 72, 487. (c) Thommen, M.; Keese, R. Synlett 1997, 231. (d) Denmark,
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DOI: 10.1021/jo101927a
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Published on Web 02/04/2011
J. Org. Chem. 2011, 76, 1295–1304 1295
2011 American Chemical Society

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SCHEME 1. The Double [3 þ 2] Photocycloaddition Reaction
SCHEME 3. Proposed Mechanism to Account for the Conver-
sion of Linear meta Photoadduct 3 into Fenestrane 2
SCHEME 2. Intramolecular meta Photocycloaddition of
Arenyl-Diene 1 Involving Exciplex 1*
SCHEME 4. Proposed Mechanism to Account for the Conver-
sion of Angular meta Photoadduct 4 into Compound 7
relative proportions of 3 and 4 being observed. This meant
that either the linear or the angular meta photocycloadducts
(3 or 4) would undergo conversion to fenestrane 2 during a
second irradiation step. The efficiency of fenestrane forma-
tion from either meta photocycloadduct was dramatically
improved by the addition of a triplet sensitizer. It was also
found that the amount of observed decomposition was
reduced, if the second stage photolysis reaction was per-
formed in acetonitrile instead of cyclohexane. Under these
circumstances fenestrane 2 was prepared from the linear
photoadduct 3 in 50% yield after irradiation for 3.75 h in
the presence of acetophenone using a 6 W low pressure
mercury vapor lamp in a quartz immersion-well photoreac-
tor. It was discovered that fenestrane formation was inhib-
ited if either of the linear or angular forms were irradiated in
the presence of a triplet quencher, which indicated that
fenestrane formation was occurring through the triplet
manifold. We accounted for the formation of fenestrane 2
by proposing the reaction mechanism presented in Scheme
3.1 Diradical 6 was generated by the homolytic fission of the
external cyclopropane bond of the linear meta photocycload-
duct 3, which then cyclized onto the tethered vinyl group to
form fenestrane 2.
FIGURE 1. The ortho-derived photocycloadducts 5a and 5b gen-
erated from the arenyl diene photosubstrate 1.
first step involved the familiar intramolecular meta photo-
cycloaddition reaction.5 The generally accepted mechanism5
for this transformation begins with the absorption of a
photon of 254 nm UV light by the aromatic ring of 1 and
formation of its first singlet excited state. Interaction with
one of the alkenes would afford exciplex 1* and subsequent
cyclopropane ring-closure would then lead to the form-
ation of the linear and angular meta photoadducts 3 and 4
(Scheme 2).1
In addition to the meta adducts, this methoxy-substituted
arenyl-diene 1 also generated ortho-derived photocycload-
ducts6 5a and 5b (Figure 1).
The linear form 3 was found to be the major isomer,
although interconversion between it and the angular form
4 occurred during irradiations and resulted in variable
(5) (a) Wilzbach, K. E.; Kaplan, L. J. Am. Chem. Soc. 1966, 88, 2066.
(b) Bryce-Smith, D.; Gilbert, A.; Orger, B. H. J. Chem. Soc., Chem. Commun.
1966, 512. (c) Cornelisse, J. Chem. Rev. 1993, 93, 615. (d) Wender, P. A.;
Siggel, L.; Nuss, J. M. In Organic Photochemistry; Padwa, A., Ed.; Marcel-
Dekker: New York, 1989; Vol 10, Chapter 4, p 357. (e) Wender, P. A.; Siggel,
L.; Nuss, J. M. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 5, p 645. (f) Wender, P. A.;
Ternansky, R.; deLong, M.; Singh, S.; Olivero, A.; Rice, K. Pure Appl. Chem.
1990, 62, 1597. (g) Hoffmann, N. Synthesis 2004, 481. (h) Chappell, D.;
Russell, A. T. Org. Biomol. Chem. 2006, 4, 4409. (i) Mattay, J. Angew. Chem.,
Int. Ed. 2007, 46, 663. (j) Streit, U.; Bochet, C. G. Chimia 2008, 62, 962.
As well as forming fenestrane 2 during the irradiation of
the linear or angular meta adducts (3 or 4), a novel photo-
induced 1,2-methoxy migration reaction was discovered that
resulted in the formation of angular tricycle 7. This type of
triquinane is a common structural motif found in a range of
natural products; a noteworthy example being the crinipellin
series of antibiotics.7
€
(6) (a) Ayer, D. E.; Buchi, G. U.S. Patent 2,805,252, 1957. (b) Atkinson,
J. E.; Ayer, D. E.; Buchi, G.; Robb, E. W. J. Am. Chem. Soc. 1963, 85, 2257.
(c) Al-Qaradawi, S. Y.; Cosstick, K. B.; Gilbert, A. J. Chem. Soc., Perkin
Trans. 1 1992, 1145. (d) Hoffmann, N.; Pete, J.-P. J. Org. Chem. 1997, 62,
6952. (e) Avent, A. G.; Byrne, P. W.; Penkett, C. S. Org. Lett. 1999, 1, 2073.
The extent of compound 7 formation appeared to be
dependent on the age and condition of the lamp used, while
the presence of a triplet sensitizer in the reaction mixture
€
ꢀ ꢀ
(f) Vızvardi, K.; Toppet, S.; Hoornaert, G. J.; De Keukeleire, D.; Bako, P.;
´
van der Eycken, E. J. Photochem. Photobiol. A: Chem. 2000, 133, 135.
(g) Hoffmann, N.; Pete, J.-P.; Inoue, Y.; Mori, T. J. Org. Chem. 2002, 67,
2315. (h) Wagner, P. J.; Lee, J.-I. Tetrahedron Lett. 2002, 43, 3569.
(7) (a) Kupka, J.; Anke, T.; Oberwinkler, F.; Schramm, G.; Steglich, W.
J. Antibiot. 1979, 32, 130. (b) Wender, P. A.; Dore, T. M. Tetrahedron Lett.
1998, 39, 8589.
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SCHEME 5. Thermolytic Conversion of Linear meta Photoad-
duct 3 into Tricyclic Acetal 11
SCHEME 6. Summary of Photochemical and Thermochemical
Transformations Involving the Arenyl-Diene 1
during this secondary photolysis step prevented its formation.
This indicated that the 1,2-methoxy migration reaction to
form 7 was occurring through the singlet manifold. We
accounted for the formation 7 by proposing the reaction
mechanism presented in Scheme 4.1 Diradical 8 was gener-
ated by the homolytic fission of the external cyclopropane
bond of the angular meta photocycloadduct 4, which then
underwent single electron transfer (SET) from the methoxy
lone pair to create the radical cation moiety of species 9.
Radical-radical recombination resulted in the formation of
the zwitterion 10, which ring-opened to afford 7.
SCHEME 7. Photoconversion of o-Tolualdehyde-Derived meta
Photoadduct 142 into Fenestrane 16a
Although not reported in the original communication,
the thermolysis properties of the meta adduct 3 were also
investigated. The linear form 3 was found to undergo a
fragmentive elimination-addition reaction to afford the
tricyclic acetal 11 when heated for 2 h at 200 °C in deuterated
toluene (Scheme 5). The formation of 11 can be explained by
invoking zwitterion 12 as an intermediate, which would form
following the fragmentation of the strained three-membered
ring with the assistance of the methoxy group’s oxygen lone
pair of electrons. The alkoxy anion moiety of 12 would then
ring-close onto the oxonium ion to afford 11. Related events
have been observed by us on previous occasions.8 It should
be pointed out that the structural characteristics of the
angular form 4 do not lend themselves to undergoing a
similar transformation and unsurprisingly 4 was found, to
be thermally stable at 230 °C for many hours.
The photochemical and thermochemical transformations
involving the arenyl-diene 1 are summarized in Scheme 6.
Wender et al.2 showed that irradiation of the o-tolualde-
hyde-derived acetal 132 resulted in the formation of linear
and angular meta adducts 14 and 15, the former of which was
converted into a [5.5.5.5] fenestrane using a radical-based
method.2 By comparison; our own photochemical method
furnished the alternative fenestrane 16 from 14. Our initial
attempt of directly irradiating 14 for a week using a 6 W low
pressure mercury vapor lamp and cyclohexane as the solvent
gave less than 10% yield of 16.1 Repetition of this transfor-
mation using acetophenone as a triplet sensitizer and acet-
onitrile as the solvent afforded the fenestrane 16 free of other
impurities in 31% yield after 4.5 h (Scheme 7).
aConditions: (a) hv, 254 nm, cyclohexane;2 (b) hv, 254 nm, MeCN,
acetophenone, 4.5 h, 31%.
Ether Fenestrane Formation. To investigate the generality
of this fenestrane-forming process the two ether photosub-
strates 17 and 18 were prepared with either a methoxy or a
methyl substituent on the aromatic ring. A simple yet flexible
route to preparing the photosubstrates was chosen that
involved attaching the alkenyl chain to the aromatic core
using the Weinreb amide 19.9 The ketones 22 and 23 were
reduced with sodium borohydride and the resulting second-
ary alcohols 2410 and 25 were allylated under phase transfer
conditions to afford the methoxy and methyl substituted
ether photosubstrates 17 and 18, respectively (Scheme 8).
During the initial photolysis stage the methoxy arenyl-
diene 17 was directly irradiated with 254 nm light until it had
been completely consumed. As was expected for ether 17
compared with acetal 1, a more complex mixture of isomeric
products was created. This was due to one alkene of 17 being
tethered through an all-carbon chain, while the other was
tethered through an ether chain. We were able to isolate four
of the photoadducts free of contamination, however several
different isomeric products coeluted, which hindered their
structural determination. In addition to the creation of
various meta photoadducts the methoxy substituent on the
It was noteworthy that no equivalent 1,2-methyl migration
product (c.f. compound 7) was formed following prolonged
direct irradiation and no thermal rearrangement of the linear
meta adduct 14 occurred even when heated above 230 °C for
many hours. This revealed that an alkoxy group on the aromatic
ring of the arenyl-diene photosubstrate had quite a profound
influence on the subsequent chemical pathways available to it.
ꢀ
(9) Fournial, A.; Ranaivondrambola, T.; Mathe-Allainmat, M.; Robins,
(8) (a) Penkett, C. S.; Byrne, P. W.; Teobald, B. J.; Rola, B.; Ozanne, A.;
Hitchcock, P. B. Tetrahedron 2004, 60, 2771. (b) Prantz, K.; Mulzer, J. Chem.
Rev. 2010, 110, 3741.
R. J.; Lebreton, J. Eur. J. Org. Chem. 2010, 152.
(10) Timmermans, J. L.; Wamelink, M. P.; Lodder, G.; Cornelisse, J.
Eur. J. Org. Chem. 1999, 463.
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SCHEME 8. Formation of Arenyl-Diene Photosubstrates 17
SCHEME 10. The Conversion of Linear meta Photoadducts 26
and 18a
and 27 into Fenestranes 30 and 31a
aConditions: (a) n-BuLi then 19, -78 °C, THF, 62%; (b) Li then
19, 0 °C, Et2O, 50%; (c) NaBH4, 0 °C, MeOH, (d) Bu4NHSO4,
NaOH(aq), CH2Cl2, allyl bromide.
SCHEME 9. Collection of Photoadducts Formed during
Primary Photolysis Stage Involving Arenyl-Diene
Photosubstrate 17
aConditions: (a) hv 254 nm, acetophenone 150 mol %, cyclohexane.
SCHEME 11. The Conversion of Arenyl-Diene 18 into Fenes-
tranes 32 and 33a
aromatic ring also caused the formation of ortho-derived
photoadducts. The four isolated isomers were the linear meta
photoadduct with the ether in the core structure 26, the linear
meta photoadduct with the ether outside the core structure
27, the angular meta photoadduct with the ether outside the
core structure 28, and an ortho-derived photoadduct with the
ether outside the core structure 29 (Scheme 9). It was
interesting that the ether-tethered alkene showed no signifi-
cant preference for undergoing photocycloaddition com-
pared to the all-carbon tethered equivalent.
Gratifyingly both linear meta photoadducts 26 and 27
were available from the primary photolysis step involving
arenyl-diene 17. meta Photoadduct 26 had an all-carbon
tethered vinyl group that was available to undergo secondary
photolysis to form fenestrane 30, while meta photoadduct 27
had an ether tethered vinyl group that was available to
undergo secondary photolysis to form fenestrane 31. These
two secondary photolysis reactions were performed in cyclo-
hexane using acetophenone as the triplet sensitizer to afford
fenestranes 30 and 31 in 27% and 31% yields, respectively
(Scheme 10). It should be noted that, when these reactions
were performed, acetonitrile was unavailable due to a world-
wide shortage of the solvent.
aConditions: (a) hv 254 nm, acetophenone 150 mol %, cyclohexane.
in addition to the fenestranes 32 and 33 and the intermediary
linear meta photocycloadducts 34 and 35. A further 8 h of
irradiation of this reaction mixture afforded the fenestranes
32 and 33 in 18% and 8% yields, respectively (Scheme 11).
If acetonitrile was used as the solvent for the primary
photolysis step of the arenyl-diene 18, the linear meta
photocycloadducts 34 and 35 were formed without any
noticeable conversion to their respective fenestranes. Un-
fortunately the complexity of this process meant that it was
not possible to obtain either linear meta photocycloadduct
34 or 35 free of other coeluting contaminants.
Investigations into the Formation of [5.5.5.6] Fenestranes.
The fenestranes reported thus far have incorporated the
same [5.5.5.5] structure. We therefore believed it would be
prudent to attempt to expand the potential application of our
double [3 þ 2] photocycloaddition reaction by investigating
the construction of a different type of fenestrane. For
instance, a [5.5.5.6] fenestrane could be generated via the
incorporation of an extra methylene group into one of the
alkene tethers. We initially attempted the formation of
photosubstrate 36 by alkylating 18 with butenyl bromide,
but found, this to be a very ineffective process (Scheme 12).
Hence the alternative strategy of incorporating the extra
methylene group into the all-carbon chain was adopted with
The photochemical transformation of the methyl analo-
gue 18 deviated from the normally observed two-step beha-
vior in cyclohexane, with fenestrane formation occurring
prior to the complete consumption of the arenyl-diene
photosubstrate. Direct irradiation of 18 for an initial 8 h in
cyclohexane using 254 nm UV light revealed a complex
mixture of products that still included the arenyl-diene 18,
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SCHEME 16. Formation of Photosubstrate 46a
SCHEME 12. Failed Attempt To Convert Alcohol 18 into Arenyl-
Diene 36
aConditions: (a) NH4OAc, NaCNBH3, MeOH, rt, 3 days; (b) NEt3,
ClCO2Me, Et2O, rt, 62% over two steps; (c) NaH, allyl bromide, DMF,
rt, 83%.
SCHEME 13. Formation of Photosubstrate 39a
SCHEME 17. meta Photoadduct 47 formed during Primary
Photolysis Stage Involving Arenyl-Diene 46
aConditions: (a) pentenyl magnesium bromide, o-tolualdehyde, 0 °C,
Et2O, 81%; (b) Bu4NHSO4, NaOH(aq), CH2Cl2, allyl bromide, 74%.
SCHEME 14. meta Photoadducts 40 and 41 formed during
Primary Photolysis Stage Involving Arenyl-Diene 39
linear and angular primary photoadducts could be recovered
from the crude residue, this time with the angular form 41
being the major component in a ratio of 5:1. It is likely that
the longer alkene tether of 40 compared with 34 hindered the
adoption of an appropriate conformation that would have
allowed a secondary cycloaddition process to take place.
[5.5.5.6] Fenestrane formation was too slow when compared
with the interconversion between the linear and angular
forms and the various other decomposition processes.
Aza-Fenestrane Formation. Gilbert and Blakemore11
found, that an amino tethered variant of the intramolecular
meta photocycloaddition reaction could be accomplished
provided the nitrogen was protected with an electron-with-
drawing group. Following this precedent we conceived that
an aza-fenestrane2d could be created from the arenyl-diene
photosubstrate 46, which was synthesized from ketone 22.
Reductive amination of 22 using sodium cyanoborohy-
dride12 afforded the primary amine 44, which was protected
as the methoxy carbamate 45 and subsequently converted to
46 using allyl bromide and sodium hydride (Scheme 16).
Irradiation of 46 using 254 nm UV light provided mainly
the linear meta photocycloadduct 47 along with an impure
sample of the ortho-photocycloadduct 48 (Scheme 17). It is
worth noting that only the nitrogen-tethered alkene under-
went cycloaddition to a significant degree, even though both
alkenes of amino arenyl-diene 46 were attached by three-
atom tethers. This may have been due to the sp2-hybridized
nature of the protected nitrogen, which also added addi-
tional complexity to NMR interpretation due to the exis-
tence of two rotameric forms.
SCHEME 15. Failed Attempt To Convert meta Photoadduct 40
into a [5.5.5.6] Fenestrane
the preparation of 39 (Scheme 13). This was achieved by
adding pentenyl magnesium bromide to o-tolualdehyde and
then alkylating the secondary alcohol 38 with allyl bromide
to afford ether 39.
Cycloaddition of alkenes connected via a 3-atom chain are
known to be kinetically favored over that of a 4-atom chain
due to having fewer degrees of freedom.5h Hence as expected
the shorter ether tethered alkene of 39 preferentially under-
went meta photocycloaddition to afford the linear and
angular meta photoadducts 40 and 41 in a ratio of 10:3
(Scheme 14).
The near coelution of these linear and angular products 40
and 41 hindered their separation and prevented the isolation
of a pure sample of each. When a mixture rich in the linear
meta photoadduct 40 was irradiated under triplet sensitized
conditions using acetophenone, there was no evidence to
indicate the formation of fenestranes 42 or 43 (Scheme 15).
Significant decomposition took place during the course of
this photoreaction. Only 11% of the original mixture of
Irradiation of the linear meta adduct 47 in the absence of a
triplet sensitizer rapidly resulted in its decomposition. How-
ever when 47 was irradiated in acetonitrile in the presence of
acetophenone it underwent conversion to the amino fenes-
trane 49 (Scheme 18).
(11) Gilbert, A.; Blakemore, D. C. Tetrahedron Lett. 1994, 35, 5267.
(12) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006,
128, 3748.
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SCHEME 18. Conversion of Linear meta Photoadduct 47 into
Aza-Fenestrane 49
SCHEME 21. Failed Attempt to Convert meta Photoadduct 53
into Fenestrane 56
SCHEME 19. Formation of Photosubstrate 52a
SCHEME 22. Proposed Strategy to form Criss-Cross Double
meta Photocycloadducts
aConditions: (a) acetone oxime, KOH, DMSO, 80 °C, 94%; (b)
Bu4NHSO4, NaOH(aq), CH2Cl2, allyl bromide, 83%.
SCHEME 20. Collection of Photoadducts Formed during
Primary Photolysis Stage Involving Arenyl-Diene
Photosubstrate 52
Investigations into the “Criss-Cross” Double meta Photo-
cycloaddition Reaction. So far the focus of this research
project was to assemble related fenestrane structures. This
was achieved by attaching a bifurcating dienyl chain onto an
aromatic ring adjacent to an electron-donating group. The
electron-donating group directed the initial meta photocy-
cloaddition onto the aromatic ring, while a second cycload-
dition process led to the formation of a fenestrane by inserting
the remaining tethered alkene into the external cyclopropane
bond of the linear meta photocycloadduct. A variation on
the double cycloaddition process using a different arrange-
ment of tethered alkenes is presented in Scheme 22 that
potentially would lead to the formation of criss-cross photo-
cycloadducts.
The two tethered alkenes (-1 and -2) would be attached
from different points about the aromatic ring, with alkene-1
being attached via a carbon atom to the aromatic ring and
alkene-2 via an oxygen atom to the aromatic ring. The
strongly electron-donating oxygen atom would control the
initial meta photocycloaddition between the aromatic ring
and the carbon-tethered alkene-1. The remaining oxygen-
tethered alkene-2 would then undergo a secondary photo-
cycloaddition process and insert into the internal cyclopropane
bond of either the linear or angular meta photocycloadduct.
The overall effect would be of a double meta photocycloaddi-
tion reaction taking place with the two alkenes sandwiching
the former aromatic ring from above and beneath in a criss-
cross fashion.
Investigations into Oxime Photocycloaddition Reactions.
Booker-Milburn13 recently showed the first example of a
higher order [5 þ 2] photocycloaddition to maleimides using
an oxime or hydrazone in exchange for an alkene as the
ground-state reacting partner. We postulated that an oxime
could be substituted for an alkene during a double [3 þ 2]
photocycloaddition. To test this proposal, photosubstrate 52
was prepared by opening up the epoxide 5014 with acetone
oxime using potassium hydroxide in DMSO and then ally-
lating the resulting secondary alcohol 51 (Scheme 19). It is
worth pointing out that oxime 51 failed to undergo intra-
molecular photocycloaddition when directly irradiated with
254 nm UV light.
Irradiation of 52 using 254 nm UV light led to the forma-
tion of the linear meta photocycloadduct 53 and an impure
sample of the ortho-derived photocycloadduct 54 as the two
major products (Scheme 20), although traces of the angular
meta photocycloadduct 55 could be observed in the 1H NMR
spectrum of the crude photolysis residue.
Irradiation of the linear adduct 53 was then performed in
either cyclohexane or acetonitrile as the solvent under triplet
sensitized conditions using acetophenone (Scheme 21). In
cyclohexane this secondary photoreaction led to significant
decomposition via polymerization, while in acetonitrile the
linear adduct 53 simply photoequilibrated with the angular
form 55.
Two versions of the photosubstrate were prepared: one
with an oxybut-3-enyl chain (62) and the other with an
oxypent-4-enyl chain (63). Their synthesis began by ether-
ification of methyl salicylate 5715 (oil of wintergreen) with
either 4-bromobutene or 5-bromopentene, respectively. The
methyl esters 586c and 59 were then reduced with DIBAL and
the resulting primary alcohols 60 and 61 were allylated to
(13) Roscini, C.; Cubbage, K. L.; Berry, M.; Orr-Ewing, A. J.; Booker-
Milburn, K. I. Angew. Chem., Int. Ed. 2009, 48, 8176.
(14) Guy, A.; Doussot, J.; Ferroud, C.; Garreau, R.; Godefroy-
Falguieres, A. Synthesis 1992, 821.
(15) Smith, K.; Morris, I. K.; Owen, P. G. J. Chem. Soc., Perkin Trans. 1
1988, 77.
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SCHEME 23. Formation of Arenyl-Diene Photosubstrates 62 and 63a
aConditions: (a) 4-bromobutene or 5-bromopentene, K2CO3, acetone, reflux; (b) DIBAL, Et2O, 0 °C; (c) Bu4NHSO4, NaOH(aq), CH2Cl2, allyl
bromide.
SCHEME 24. Linear meta and ortho-Derived Photoadducts
Formed during Primary Photolysis Stages Involving
Arenyl-Diene Photosubstrates 62 and 63
SCHEME 26. The Conversion of Linear meta Photoadduct 64
€
into the Angular meta Photoadduct 69 and the Paterno-Buchi
Cycloadduct 70
SCHEME 27. Failed Attempts to Convert meta Photoadducts
64 and 66 into Double meta Cycloadducts 71 and 72
SCHEME 25. The Conversion of Linear meta Photoadduct 64
into the 1,2-Alkoxy Rearranged Product 68
afford the two arenyl-diene photosubstrates 62 and 63,
respectively (Scheme 23).
Direct irradiation of the oxybut-3-enyl analogue 62 with
254 nm UV light until it had all been consumed afforded the
linear meta photocycloadduct 64 and the ortho-derived
photocycloadduct 65. Similarly irradiation of the oxypent-
4-enyl variant 63 gave the linear meta photocycloadduct 66
and the ortho-derived photocycloadduct 67 (Scheme 24).
Secondary photolysis of the oxybut-3-enyl linear meta
photoadduct 64 without triplet sensitization in cyclohexane
resulted in decomposition and conversion to the 1,2-alkoxy
rearranged product 68 (c.f. compound 7). This could be
derived from a photoequilibration of linear adduct 64 to its
angular form 69, then a 1,2-translocation of the oxygen
linked alkenyl chain to afford 68 (Scheme 25).
place between acetone and the angular isomer 69 to afford
the oxetane 70. Again no 1,2-alkoxy rearranged product 68
was derived from this triplet-sensitized reaction and inter-
€
estingly there was no product derived from Paterno-Buchi
cycloaddition between acetone and the linear meta photo-
cycloadduct 64 (Scheme 26).
A similar series of secondary photolytic studies were
performed using the oxypent-4-enyl linear meta photoad-
duct 66 in the hope that a longer tether might favor the
formation of an appropriate conformation to allow second-
ary cycloaddition. However rapid decomposition of 66 hindered
subsequent purification procedures and disappointingly no
evidence could be established to support the formation of
double meta cycloaddition products 71 or 72 from either
the oxybut-3-enyl or the oxypent-4-enyl meta adducts 64 or
66 (Scheme 27).
Photolysis of the linear adduct 64 in the presence of
acetophenone with cyclohexane as the solvent only resulted
in interconversion between the linear (64) and angular (69)
forms; no 1,2-alkoxy rearranged product 68 was generated
during this procedure. Repeating this process with acetoni-
trile as the solvent achieved a similar result, albeit with less
decomposition of the photosubstrate. When photolysis of
the linear adduct 64 was performed in neat acetone to act as a
triplet sensitizer, photoequilibration to the angular form 69
Conclusion
The flexibility of the double [3 þ 2] photocycloaddition
reaction to assemble a range of ether and aza [5.5.5.5]
fenestrane structures has been demonstrated with the for-
mation of compounds 2,1 16,1 30, 31, 32, 33, and 49. Their
respective 1H and 13C NMR spectra are compared on pages
S267 and S268 of the Supporting Information. Thermolysis
properties of linear meta photoadduct 3 were investigated
occurred and a Paterno-Buchi cycloaddition process16 took
€
ꢁ
(16) (a) Paterno, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39-1, 341.
€
(b) Buchi, G.; Inman, C. G.; Lipinsky, E. S. J. Am. Chem. Soc. 1954, 76,
4327. (c) Bach, T. Synthesis 1998, 683.
J. Org. Chem. Vol. 76, No. 5, 2011 1301

Penkett et al.
JOCArticle
and resulted in a fragmentive elimination-addition reaction
to afford tricyclic acetal 11. The insertion of an additional
methylene group into the basic arenyl-diene skeleton failed
to afford the desired [5.5.5.6] fenestrane structure. The
presence of an oxime moiety in the aromatic photosubstrate
did not prevent the primary meta photocycloaddition reac-
tion from taking place; however, the highly substituted
compound 53 failed to undergo a secondary photocycload-
dition reaction to afford polyheterocyclic fenestrane 56. Also
investigations into the formation of criss-cross double meta
photocycloadducts 71 and 72 failed to achieve the desired
result. During the course of these investigations a Paterno-
The apparatus was cooled with water, and the solution was
irradiated for 32 h using a 6 W low-pressure mercury vapor lamp
(λmax = 254 nm) until NMR analysis showed the complete
consumption of starting material. The solvent was removed
under reduced pressure, and the resulting yellow residue was
subjected to flash column chromatography (100:1 silica, ethyl
acetate/petroleum ether 10:90) to afford linear meta adduct 27
(145 mg, 4.8%). A second separation (diethyl ether/pentane 4:94
to 20:80) gave linear meta photocycloadduct 26 (250 mg, 8.3%).
Angular adduct 28 (55 mg, 1.8%) and ortho derived adduct 29
(540 mg, 18%) were also isolated pure from the reaction
mixture. Other impure adducts that included further ortho
derivatives and degradation products from apparent Norrish-
type reactions also existed in the crude photolysis residue but
could not be obtained in a satisfactorily purified form.
€
Buchi cycloaddition reaction between acetone and an angular
meta photocycloadduct was discovered.
Compound 26. 1H NMR (500 MHz, CDCl3): δ 5.84 (1H,
dddd, J=6.7, 6.7, 10.4, 17.1 Hz); 5.66 (1H, dd, J = 2.4, 5.6 Hz);
5.56 (1H, ddd, J = 1.2, 2.7, 5.6 Hz); 5.03 (1H, d, J=17.1 Hz);
4.95 (1H, d, J = 10.4 Hz); 4.07 (1H, dd, J = 7.7, 8.9 Hz); 4.00
(1H, dd, J = 3.3, 9.4 Hz); 3.57 (1H, dd, J = 4.7, 9.0 Hz); 3.41
(3H, s); 3.40-41 (1H, m); 2.32-2.38 (1H, m); 2.20-2.28 (1H,
m); 2.14-2.16 (1H, m); 2.07-2.15 (1H, m); 1.94 (1H, ddd, J =
5.4, 9.2, 11.7 Hz); 1.87 (1H, dd, J = 6.7, 11.7 Hz); 1.63 (1H,
dddd, J = 5.1, 9.6, 10.0, 14.1 Hz); 1.46 (1H, dddd, J = 3.4, 6.3,
9.9, 14.1 Hz). 13C NMR (125 MHz, CDCl3): δ 138.5, 133.1,
127.9, 114.4, 88.3, 75.2, 71.9, 56.6, 56.2, 53.6, 44.2, 43.1, 37.0,
31.9, 29.9. IR (thin film, cm-1) 3055, 2935, 2855, 1640, 1586,
1450, 1401, 1356, 1340, 1325, 1305, 1246, 1231, 1193, 1170, 1133,
1097, 1071, 1008, 911, 864, 748, 734. HRMS (ESI) m/z calcd for
C15H20NaO2 [M þ Na]þ, 255.1361; found, 255.1347.
Experimental Section
Representative Procedures. Full experimental procedures and
spectroscopic data for all compounds can be found in the
Supporting Information. Some standard examples are provided
here.
Compound 11. The major linear meta photoadduct 31 (50 mg)
was dissolved in toluene-d8 (0.7 mL) and added to a resealable
Young’s tap NMR tube. This was sealed under a nitrogen
atmosphere and heated to 200 °C for approximately 1.75 h.
The major product was isolated by flash column chromatogra-
phy (40:1 SiO2; diethyl ether/pentane 10:90) yielding 11 (30 mg,
59%) as a colorless semisolid. 1H NMR (500 MHz, CDCl3): δ
6.19 (1H, d, J = 2.5 Hz); 5.83-5.92 (1H, m); 5.87 (1H, dd, J=
3.3, 6.4 Hz); 5.78 (1H, dd, J=3.1, 6.3 Hz); 5.25 (1H, dm, J =
17.2 Hz); 5.09 (1H, dm, J = 10.3 Hz); 4.41 (1H, dd, J = 8.3, 9.4
Hz); 3.93 (2H, dm, J = 5.4); 3.70 (1H, dd, J = 8.3, 12.9 Hz); 3.33
(1H, d, J = 3.1 Hz); 3.21 (3H, s); 2.92 (1H, ddddd, J = 2.5, 7.7,
9.4, 9.6, 12.9 Hz); 2.73 (1H, ddd, J = 2.7, 3.3, 3.6 Hz); 1.72 (1H,
ddd, J = 3.6, 7.7, 12.5 Hz); 1.49 (1H, ddd, J = 2.7, 9.6, 12.5 Hz).
13C NMR (125 MHz, CDCl3): δ 138.1, 134.9, 130.9, 130.3,
116.2, 114.5, 111.4, 76.0, 63.0, 48.7, 44.0, 43.7, 36.9, 28.4. IR
(thin film, cm-1) 3061, 2941, 2862, 1765, 1667, 1646, 1598, 1463,
1368, 1348, 1320, 1288, 1238, 1189, 1126, 1059, 1006, 949, 921,
787, 771, 704. HRMS (ESI) m/z calcd for C14H18NaO3 [M þ
Na]þ, 257.1154; found, 257.1150.
Compound 27. 1H NMR (500 MHz, CDCl3): δ 5.92 (1H,
dddd, J=5.6, 5.7, 10.4, 17.2 Hz); 5.71 (1H, dd, J=2.0, 5.7 Hz);
5.51 (1H, ddd, J = 1.3, 2.7, 5.6 Hz); 5.26 (1H, dddd, J = 1.6, 1.7,
1.7, 17.2 Hz); 5.14 (1H, dddd, J = 1.4, 1.4, 1.7, 10.4 Hz); 4.02
(1H, dddd, J = 1.5, 1.5, 5.5, 12.9 Hz); 3.93 (1H, dddd, J = 1.4,
1.5, 5.7, 12.9 Hz); 3.76 (1H, dd, J = 2.2, 4.3 Hz); 3.38 (3H, s);
3.24 (1H, dd, J = 2.7, 5.6 Hz); 2.47 (1H, m); 2.20-2.26 (1H, m);
2.04-2.11 (1H, m); 1.97-2.03 (1H, m); 1.82-1.89 (2H, m); 1.73
(1H, ddd, J = 5.5, 9.7, 11.7 Hz); 1.34 (1H, dddd, J = 2.9, 2.9,
7.5, 12.5 Hz). 13C NMR (125 MHz, CDCl3): δ 135.6, 132.6,
128.6, 116.4, 90.4, 78.5, 69.7, 56.9, 56.2, 52.5, 45.4, 40.2, 37.9,
33.1, 28.5. HRMS (ESI) m/z calcd for C15H20NaO2 [M þ Na]þ,
255.1361; found, 255.1348.
Compound 17. To a stirred solution of alcohol 2410 (2.92 g,
15.2 mmol) and allyl bromide (6.58 mL, 76.1 mmol) in dichlor-
omethane (10 mL) under a nitrogen atmosphere, was added
50% NaOH (25 mL) and tetrabutylammonium hydrogen sul-
fate (10.33 g, 30.4 mmol). This was allowed to stir for 3 days until
TLC showed complete conversion of the starting material. The
reaction was quenched with saturated ammonium chloride
solution (50 mL) and extracted with diethyl ether (2 ꢀ 50 mL).
The combined organic layers were dried over magnesium sul-
fate, the solvents were removed under reduced pressure, and the
resulting residue was purified by flash column chromatography
(diethyl ether/petrol 10:90) to yield the ether 17 (2.81 g, 80%) as
a yellow oil. Rf=0.63 (diethyl ether/petrol 10:90). 1H NMR (500
MHz, CDCl3): δ 7.41 (1H, br d, J=7.4 Hz); 7.24 (1H, br t, J =
7.8 Hz); 6.99 (1H, t, J = 7.4 Hz); 6.87 (1H, br d, J = 8.2 Hz);
5.81-5.98 (2H, m); 5.26 (1H, d, J = 17.2 Hz); 5.14 (1H, d, J =
10.4 Hz); 5.03 (1H, d, J = 17.2 Hz); 4.95 (1H, d, J = 10.2 Hz)
4.80 (1H, dd, J = 5.1, 7.7 Hz); 3.93 (1H, dd, J = 5.2, 12.7 Hz);
3.82 (3H, s); 3.79 (1H, dd, J = 5.9, 12.7 Hz); 2.09-2.28 (2H, m);
1.72-1.85 (2H, m). 13C NMR (125 MHz, CDCl3): δ 156.9,
138.7, 135.3, 130.9, 128.0, 126.7, 120.7, 116.3, 114.2, 110.3, 74.4,
69.8, 55.3, 36.1, 30.0. HRMS (ESI) m/z calcd for C15H20NaO2
[M þ Na]þ, 255.1361; found, 255.1364.
Compound 28. 1H NMR (500 MHz, CDCl3): δ 5.87-5.94
(1H, m); 5.74 (1H, dd, J = 1.2, 5.7 Hz); 5.55 (1H, dd, J = 2.4, 5.7
Hz); 5.27 (1H, d, J = 17.2 Hz); 5.14, (1H, d, J = 10.4 Hz); 4.13
(1H, dd, J = 4.1, 7.1 Hz); 3.96-4.03 (2H, m); 3.32 (3H, s);
2.24-2.31 (2H, m); 2.19 (1H, d, J = 8.5); 2.08 (1H, dd, J = 6.3,
8.5 Hz); 1.71 (1H, dd, J = 6.1, 8.8, 9.3 Hz); 1.61-1.68 (2H, m);
1.52-1.57 (1H, m); 1.46 (1H, dd, J = 6.2, 13.6 Hz). 13C NMR
(125 MHz, CDCl3): δ 135.2, 133.7, 124.0, 116.2, 91.0, 78.9, 71.7,
70.7, 57.0, 56.7, 37.1, 35.9, 34.7, 28.1, 26.8. IR (thin film, cm-1
)
2935, 1646, 1584, 1448, 1379, 1210, 1157, 1089, 1005, 920, 760,
700. HRMS (ESI) m/z calcd for C15H20NaO2 [M þ Na]þ,
255.1361; found, 255.1354.
1
Compound 29. H NMR (500 MHz, CDCl3): δ 6.13 (1H, d,
J = 2.7 Hz); 6.06 (1H, d, J = 2.7 Hz); 5.91 (1H, dddd, J = 5.7,
5.7, 10.4, 17.2 Hz); 5.82 (1H, dd, J = 2.8, 6.1 Hz); 5.26 (1H, d,
J = 17.2 Hz); 5.14 (1H, d, J = 10.4 Hz); 4.20 (1H, dddd, J=5.1,
5.3 Hz); 3.95 (1H, dddd, J = 1.5, 1.5, 5.6, 12.8 Hz); 3.91 (1H,
dddd, J = 1.4, 1.5, 5.9, 12.8 Hz); 3.29-3.36 (1H, m); 3.32 (3H,
s); 2.33-2.40 (1H, m); 2.08-2.15 (1H, m); 2.04 (1H, dd, J = 5.3,
12.4 Hz); 1.87-1.93 (1H, m); 1.68 (1H, dddd, J = 4.8, 7.2, 7.2,
12.2 Hz); 1.30 (1H, dddd, J = 7.3, 7.3 7.4, 12.6 Hz); 1.15 (1H, t,
J = 12.5 Hz); 13C NMR (125 MHz, CDCl3): δ 149.5, 138.4,
136.3, 135.4, 121.5, 116.7, 85.0, 81.3, 69.1, 51.8, 46.9, 37.1,
34.4, 31.8, 29.1. IR (thin film, cm-1) 3075, 3043, 2975, 2931,
2846, 2244, 1826, 1679, 1640, 1586, 1563, 1449, 1377, 1342, 1292,
Synthesis of Compounds 26, 27, 28, and 29. A solution of ether
17 (3.00 g, 12.9 mmol) in dry cyclohexane (150 mL) was degassed
with nitrogen for 15 min in a quartz immersion-well photoreactor.
1302 J. Org. Chem. Vol. 76, No. 5, 2011

Penkett et al.
JOCArticle
1257, 1208, 1172, 1098, 1021, 989, 911, 830, 767, 730. HRMS
(ESI) m/z calcd for C15H20NaO2 [M þ Na]þ, 255.1361; found,
255.1356.
1492, 1456, 1432, 1389, 1289, 1240, 1196, 1114, 1045, 917, 752.
HRMS (ESI) m/z calcd for C11H14NaO2 [M þ Na]þ, 201.0891;
found, 201.0884.
Compound 30. The linear meta adduct 26 (81 mg, 0.349 mmol)
and acetophenone (62.8 mg, 0.523 mmol) were dissolved in dry
cyclohexane (200 mL) in a quartz immersion-well photoreactor.
Nitrogen was bubbled through the solution for 20 min in order
to remove dissolved oxygen. The mixture was then irradiated for
11 h using a 6 W low pressure mercury vapor lamp. Cyclohexane
was removed under reduced pressure, and the resulting residue
was subjected to flash column chromatography (100:1 silica;
ether/dichloromethane/pentane 10:5:85); to yield the double [3
þ 2] product 30 as a pale yellow oil (22 mg, 27%). Rf = 0.22
(diethyl ether/dichloromethane/pentane 10:5:85). 1H NMR
(500 MHz, CDCl3): δ 5.67 (1H, ddd, J = 1.6, 2.5, 6.0 Hz);
5.46 (1H, ddd, J = 1.4, 2.6, 6.0 Hz); 4.53 (1H, d, J = 7.9 Hz);
3.65 (1H, dd, J = 4.5, 8.8 Hz); 3.52 (1H, d, J = 8.8 Hz); 3.24 (1H,
dddd, J = 1.4, 2.5, 7.9, 8.5 Hz); 3.21 (3H, s); 3.11 (1H, dm, J =
10.1 Hz); 2.29 (1H, ddd, J = 4.6, 8.1, 11.0 Hz); 2.14-2.26 (2H,
m); 1.96 (1H, ddd, J = 5.4, 7.9, 11.2 Hz); 1.87 (2H, dd, J = 6.9,
14.5 Hz); 1.75 (1H, ddd, J = 10.2, 10.9, 13.1 Hz); 1.64 (1H, ddd,
J = 1.3, 8.0, 13.0 Hz); 1.51 (1H, ddd, J = 5.0, 7.3, 11.5 Hz); 1.20
(1H, dddd, J = 7.1, 11.4, 11.4, 13.5 Hz); 1.06 (1H, ddd, J = 8.5,
11.2, 13.5 Hz). 13C NMR (125 MHz, CDCl3): δ 133.4, 132.6,
102.4, 77.3, 77.2, 72.4, 60.0, 53.4, 51.9, 48.2, 43.6, 40.0, 36.6,
31.5, 23.3. HRMS (ESI) m/z calcd for C15H20NaO2 [M þ Na]þ,
255.1361; found, 255.1356.
Compound 31. The linear meta adduct 27 (35 mg, 0.151 mmol)
and acetophenone (27.2 mg, 0.226 mmol) were dissolved in dry
cyclohexane (200 mL) in a quartz immersion-well photoreactor.
Nitrogen was bubbled through the solution for 20 min in order
to remove dissolved oxygen. The mixture was then irradiated for
17 h using a 6 W low pressure mercury vapor lamp. Cyclohexane
was removed under reduced pressure, and the resulting residue
was subjected to flash column chromatography (100:1 silica;
ether/pentane 20:80) to yield the double [3 þ 2] product 31 as a
yellow oil (11 mg, 31%). Rf=0.29 (diethyl ether/pentane 20:80);
1H NMR (500 MHz, CDCl3): δ 5.65 (1H, dm, J = 5.9 Hz); 5.47
(1H, dm, J = 5.8 Hz); 4.28 (1H, br. s.); 3.67 (1H, t, J = 6.7 Hz);
3.35 (1H, t, J = 8.2 Hz); 3.21 (1H, dd, J = 7.1, 12.1 Hz); 3.19
(3H, s); 3.10 (1H, dm, J = 10.0 Hz); 2.81-2.89 (1H, m);
2.26-2.32 (1H, m); 1.95 (1H, ddd, J = 5.3, 7.7, 11.2 Hz);
1.78-1.89 (2H, m); 1.68-1.76 (1H, m); 1.62 (1H, dd, J = 8.3,
13.3 Hz); 1.52-1.57 (1H, m); 1.42 (1H, dd, J = 5.7, 12.4 Hz);
1.16 (1H, ddd, J = 8.9, 11.3, 13.8 Hz). 13C NMR (125 MHz,
CDCl3): δ 133.7, 132.0, 103.5, 80.3, 76.8, 66.9, 62.1, 55.1, 52.0,
48.6, 41.4, 36.3, 32.6, 31.3, 28.9. HRMS (ESI) m/z calcd for
C15H20NaO2 [M þ Na]þ, 255.1361; found, 255.1356.
Compound 62. To a stirred solution of alcohol 60 (2.04 g, 11.5
mmol) and allyl bromide (4.96 mL, 57.3 mmol) in dichloro-
methane (10 mL) under a nitrogen atmosphere at 0 °C, was
added 50% NaOH (30 mL) and tetrabutylammonium hydrogen
sulfate (3.9 g, 11.5 mmol). This was allowed to warm to ambient
temperature and to stir for 24 h until TLC showed complete
conversion of the starting material. The reaction was quenched
with saturated ammonium chloride solution (50 mL) and ex-
tracted with diethyl ether (2 ꢀ 50 mL). The combined organic
layers were dried over magnesium sulfate, the solvents were
removed under reduced pressure and the resulting residue was
purified by flash column chromatography (ethyl acetate/petrol
3:97) to yield the ether 62 (2.4 g, 96%) as a pale yellow oil. Rf=
0.39 (diethyl ether/hexane 20:80). 1H NMR (500 MHz, CDCl3):
δ 7.41 (1H, dd, J = 1.8, 7.5 Hz); 7.24 (1H, td, J = 1.8, 7.8 Hz);
6.96 (1H, td, J = 1.0, 7.4 Hz); 6.85 (1H, dd, J = 1.0, 8.1 Hz);
5.95-6.04 (1H, ddt, J = 5.6, 10.5, 17.2 Hz); 5.88-5.97 (1H, ddt,
J = 6.7, 10.2, 17.0 Hz); 5.34 (1H, dm, J = 17.2 Hz); 5.21 (1H,
dm, J = 10.2 Hz); 5.18 (1H, dm, J 17.1 Hz); 5.11 (1H, dm, J =
10.2 Hz); 4.58 (2H, s); 4.09 (2H, ddd, J = 1.4, 1.5, 5.6 Hz); 4.04
(2H, t, J = 6.6 Hz); 2.54-2.59 (2H, m). 13C NMR (125 MHz,
CDCl3): δ 156.4, 135.1, 134.6, 128.9, 128.5, 120.5, 116.9, 116.7,
111.2, 71.5, 67.3, 66.9, 33.7. IR (thin film, cm-1) 2627, 2848,
1641, 1433, 1374, 1344, 1292, 1258, 1156, 1094, 1057, 914, 883,
820, 758, 743. HRMS (ESI) m/z calcd for C14H18NaO2 [M þ
Na]þ, 241.1204; found, 241.1199.
Synthesis of Compounds 64 and 65. A solution of ether 62 (2.10
g, 9.63 mmol) in dry cyclohexane (400 mL) was degassed with
nitrogen for 15 min in a quartz immersion-well photoreactor.
The apparatus was cooled with water and the solution was
irradiated for 18 h using a 16 W low-pressure mercury vapor
lamp (λmax=254 nm) until NMR analysis showed the complete
consumption of starting material. The solvent was removed
under reduced pressure, and the resulting orange residue was
subjected to flash column chromatography (100:1 silica, di-
chloromethane/diethyl ether/petrol 5:10:85) to afford meta ad-
duct 64 (280 mg, 13%) and ortho-derived adduct 65 (301 mg,
14%) both with minor coeluting impurities.
Compound 64. Rf = 0.39 (dichloromethane/diethyl ether/
petrol 5:10:85). 1H NMR (500 MHz, CDCl3): δ 5.81 (1H, ddt,
J = 6.7, 10.2, 17.1 Hz); 5.69 (1H, dd, J = 2.3, 5.8 Hz); 5.56 (1H,
dm, J = 5.8 Hz); 5.09 (1H, dm, J = 17.1 Hz); 5.03 (1H, dm, J =
10.2 Hz); 3.90 (1H, d, J = 9.1 Hz); 3.89 (1H, dd, J = 7.8, 8.9 Hz);
3.70 (1H, dd, J = 3.5, 8.9 Hz); 3.69 (1H, d, J = 9.1 Hz); 3.63 (1H,
dt, J = 6.8, 9.2 Hz); 3.57 (1H, dt, J = 6.8, 9.2 Hz); 3.37 (1H, dd,
J = 2.7, 5.0 Hz); 2.34 (2H, q, J = 6.8 Hz); 2.25-2.31 (1H, m);
2.21 (1H, br. s); 1.96 (1H, dd, J = 5.3, 9.4 Hz); 1.92 (1H, dd, J =
6.2, 10.6 Hz). 13C NMR (125 MHz, CDCl3): δ 135.0, 132.8,
128.1, 116.4, 87.7, 73.4, 68.7, 66.1, 53.8, 52.6, 44.7, 42.4, 36.8,
34.4. IR (thin film, cm-1) 3055, 2930, 2851, 1658, 1641, 1586,
1465, 1456, 1430, 1376, 1330, 1277, 1246, 1188, 1169, 1138, 1077,
1057, 1015, 909, 860, 743. HRMS (ESI) m/z calcd for C14H18-
NaO2 [M þ Na]þ, 241.1204; found, 241.1198.
Compound 60. Ester 586c (2.8 g, 13.6 mmol) was dissolved in
diethyl ether (50 mL) under a nitrogen atmosphere and cooled to
0 °C. DIBAL (1 M, 40.8 mL, 40.8 mmol) was added dropwise via
syringe over 30 min. The reaction was stirred until analysis by
TLC showed none of the ester remained. With the temperature
maintained at 0 °C, the reaction was diluted with diethyl ether
(100 mL) followed by the cautious addition of water (100 mL).
The two layers were partitioned in a separating funnel; the
organic layer was washed with brine (2 ꢀ 50 mL) and dried
over anhydrous magnesium sulfate. The ether was removed
under reduced pressure to yield alcohol 60 (2.04 g, 84%) as a
colorless oil that was used without further purification. Rf=0.11
(diethyl ether/petrol 10:90). 1H NMR (500 MHz, CDCl3): δ
7.24-7.28 (2H, m); 6.94 (1H, td, J = 1.1, 7.4 Hz); 6.88 (1H, dd,
J = 1.0, 8.5 Hz); 5.86-5.95 (1H, ddt, J = 6.8, 10.2, 17.0 Hz);
5.22 (1H, dm, J = 17.0 Hz); 5.16 (1H, dm, J = 10.2 Hz); 4.68
(2H, br. s); 4.09 (2H, t, J = 6.3 Hz); 2.56-2.61 (2H, m);
2.52-2.58 (1H, br. s). 13C NMR (125 MHz, CDCl3): δ 156.8,
134.6, 129.3, 128.8, 128.7, 120.7, 117.4, 111.0, 66.8, 62.3, 33.7.
IR (thin film, cm-1) 3392, 3076, 2926, 2873, 1642, 1603, 1590,
Compound 65. Rf = 0.30 (dichloromethane/diethyl ether/
1
petrol 5:10:85). H NMR (500 MHz, CDCl3): δ 6.15 (1H, dm,
J = 1.9 Hz); 6.02 (1H, dm, J = 1.9 Hz); 5.75-5.84 (1H, m); 5.60
(1H, br. s); 5.06 (1H, dm, J = 17.1 Hz); 5.00 (1H, dm, J = 10.2
Hz); 4.36 (1H, d, J = 13.4 Hz); 4.25 (1H, d, J = 13.4 Hz); 4.18
(1H, t, J = 8.3 Hz); 3.50 (2H, t, J = 6.9 Hz); 3.37 (1H, t, J = 8.4
Hz); 3.30 (1H, d, J = 6.0 Hz); 2.47-2.56 (1H, m); 2.28 (2H, q,
J = 7.0 Hz); 2.09 (1H, dd, J = 5.2, 12.3 Hz); 1.25 (1H, t, J =
12.3); 13C NMR (125 MHz, CDCl3): δ 145.5, 138.1, 136.6, 135.2,
116.2, 115.2, 84.7, 73.8, 63.5, 47.4, 37.0, 34.9, 33.5. IR (thin film,
cm-1) 2926, 2847, 1640, 1586, 1459, 1474, 1434, 1374, 1344,
1291, 1157, 1097, 1058, 1029, 994, 918, 821, 785, 760, 721, 693,
J. Org. Chem. Vol. 76, No. 5, 2011 1303

Penkett et al.
JOCArticle
652. HRMS (ESI) m/z calcd for C14H18NaO2 [M þ Na]þ,
Compound 69. Rf = 0.34 (diethyl ether/hexane 20:80). 1H
NMR (500 MHz, CDCl3): δ 5.81 (1H, ddt, J = 6.9, 10.3, 17.0
Hz); 5.63 (1H, dd, J = 2.3, 5.6 Hz); 5.55 (1H, d, J = 5.6 Hz); 5.08
(1H, dm, J = 17.0 Hz); 5.04 (1H, dm, J = 10.3 Hz); 4.23 (1H, d,
J = 8.9 Hz); 3.85 (1H, dd, J = 7.9, 8.0 Hz); 3.81 (1H, d, J = 8.9
Hz); 3.68 (1H, dd, J = 8.2, 10.7 Hz); 3.50-3.60 (2H, m);
2.42-2.47 (1H, m); 2.31-2.37 (2H, m); 2.16-2.24 (2H, m);
1.81 (1H, dd, J = 5.8, 14.0 Hz); 1.58 (1H, dd, J = 6.4, 14.0 Hz).
13C NMR (125 MHz, CDCl3): δ 134.9, 133.2, 125.9, 116.6, 89.3,
70.0, 69.3, 68.9, 68.2, 58.1, 37.4, 36.9, 34.5, 23.6. HRMS (ESI) m/
z calcd for C14H18NaO2 [M þ Na]þ, 241.1204; found, 241.1197.
Compound 70. Rf = 0.29 (diethyl ether/hexane, 40:60) 1H
NMR (500 MHz, CDCl3): δ 5.85 (1H, ddt, J = 6.8, 10.2, 17.2
Hz); 5.09 (1H, dm, J = 17.2 Hz); 5.03 (1H, dm, J = 10.2 Hz);
4.69 (1H, dm, J = 4.2 Hz); 4.26 (1H, d, J = 9.3 Hz); 4.01 (1H, t,
J = 8.1 Hz); 3.83 (1H, d, J = 9.3 Hz); 3.76 (1H, ddd, J = 6.8,
6.8, 8.9 Hz); 3.64 (1H, ddd, J = 7.0, 7.0, 8.9 Hz); 3.47 (1H, dd,
J = 8.3, 10.5 Hz); 2.48 (1H, d, J = 4.1 Hz); 2.37 (2H, q, J = 6.9
Hz); 2.21 (1H, ddd, J = 7.3, 7.3, 10.3 Hz); 2.03 (1H, d, J = 9.8
Hz); 1.97 (1H, dd, J = 6.0, 9.8 Hz); 1.72 (1H, dd, J = 6.0, 14.1
Hz); 1.51 (3H, s); 1.38 (3H, s); 1.37 (1H, ddm, J = 6.7, 14.1 Hz).
13C NMR (125 MHz, CDCl3): δ 135.1, 116.5, 89.1, 83.3, 82.1,
72.8, 69.1, 68.5, 68.2, 53.0, 45.4, 34.6, 33.9, 31.6, 28.9 24.5, 23.1.
HRMS (ESI) m/z calcd for C17H24NaO3 [M þ Na]þ, 299.1623;
found, 299.1614.
241.1204; found, 241.1198.
Compound 68. A solution of linear meta adduct 64 (100 mg,
0.460 mmol) in dry cyclohexane (400 mL) was degassed with
nitrogen for 15 min in a quartz immersion-well photoreactor.
The apparatus was cooled with water, and the solution was
irradiated for 48 h using a 16 W low-pressure mercury vapor
lamp (λmax=254 nm) until NMR analysis showed the complete
consumption of starting material. The solvent was removed
under reduced pressure, and the resulting residue was subjected
to flash column chromatography (100:1 SiO2, diethyl ether/
hexane 20:80) to afford 1,2-alkenyloxy migration adduct 68
(12.0 mg, 12%) alongside other isomers that could not be
obtained in a satisfactorily purified form. Rf = 0.36 (diethyl
ether/hexane, 20:80). 1H NMR (500 MHz, CDCl3): δ 6.20 (1H,
d, J = 5.9 Hz); 5.96 (1H, dd, J = 2.4, 5.9 Hz); 5.78 (1H, dddd,
J = 6.9, 6.9, 10.2, 17.2 Hz); 5.61 (1H, br. s.); 5.06 (1H, dm, J =
17.2 Hz); 5.00 (1H, dm, J = 10.2 Hz); 4.49 (1H, d, J = 2.4 Hz);
3.90 (1H, d, J = 9.1 Hz); 3.87 (1H, d, J = 9.4 Hz); 3.67 (1H, dd,
J = 4.4, 9.0 Hz); 3.58 (1H, ddd, J = 7.1, 7.1, 9.0 Hz); 3.42-3.47
(1H, m); 3.42 (1H, d, J = 9.4 Hz); 2.75-2.84 (2H, m); 2.59 (1H,
ddd, J = 1.7, 5.0, 15.9 Hz); 2.55 (2H, m). 13C NMR (125 MHz,
CDCl3): δ 148.7, 140.9, 135.2, 133.3, 125.5, 116.3, 76.9, 76.9,
74.8, 70.4, 68.3, 47.6, 42.8, 34.4. IR (thin film, cm-1) 2926, 2847,
1640, 1586, 1459, 1474, 1434, 1374, 1344, 1291, 1157, 1097, 1058,
1029, 994, 918, 821, 785, 760, 721, 693, 652. HRMS (ESI) m/z
calcd for C14H18NaO2 [M þ Na]þ, 241.1204; found, 241.1198.
Synthesis of Compounds 69 and 70. A solution of linear meta
adduct 64 (50.0 mg, 0.229 mmol) in acetone (150 mL) was
degassed with nitrogen for 15 min in a quartz immersion-well
photoreactor. The apparatus was cooled with water, and the
solution was irradiated for 3 h using a 6 W low-pressure mercury
vapor lamp (λmax = 254 nm) until NMR analysis showed the
complete consumption of starting material. The solvent was
removed under reduced pressure, and the resulting residue was
subjected to flash column chromatography (ether/hexane 20:80
to 40:60) to afford angular meta adduct 69 (9 mg, 18%) and
Acknowledgment. We thank the EPSRC and the Nuffield
Foundation for financial assistance and Iain Day for NMR
support. C.S.P. would like to express his gratitude to Philip
Parsons, Jeff Winkler, and Paul Wender for their advice and
support.
Supporting Information Available: Complete experimental
procedures, full characterization including H and 13C NMR
1
spectra and where relevant COSY or DQF-COSY, multiplicity-
edited HSQC, standard HMBC and ROESY correlation spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
€
Paterno-Buchi adduct 70 (12.0mg, 24%) alongsideother isomers
that could not be obtained in a satisfactorily purified form.
1304 J. Org. Chem. Vol. 76, No. 5, 2011