A natural light induced regioselective 6π-electrocyclisation-oxidative aromatisation reaction: Experimental and theoretical insights

Article abstract of DOI:10.1039/b811284c

Stoichiometric intermolecular Pauson-Khand reactions of 4-(phenylethynyl)-6-methyl-2-pyrones with norbornene and dicobalt(0)octacarbonyl provide cyclopentenone products that undergo a facile 6π-electrocyclisation- oxidative aromatisation transformation in the presence of natural light and oxygen, affording functionalised benzo[h]indeno[1,2-f]isochromene type products. The results are rationalised by theoretical studies, which confirm that the electrocyclisation process is favoured at C3 in the 2-pyrone ring system. The identity and precise arrangement of the 'trienyl' substituents control whether the electrocyclisation occurs in natural light.

Full text of DOI:10.1039/b811284c

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A natural light induced regioselective 6p-electrocyclisation–oxidative
aromatisation reaction: experimental and theoretical insights†
Benjamin E. Moulton,a Hao Dong,b Ciara T. O’Brien,a Simon B. Duckett,a Zhenyang Lin*‡b and
Ian J. S. Fairlamb*‡a
Received 2nd July 2008, Accepted 12th September 2008
First published as an Advance Article on the web 30th October 2008
DOI: 10.1039/b811284c
Stoichiometric intermolecular Pauson–Khand reactions of 4-(phenylethynyl)-6-methyl-2-pyrones with
norbornene and dicobalt(0)octacarbonyl provide cyclopentenone products that undergo a facile
6p-electrocyclisation–oxidative aromatisation transformation in the presence of natural light and
oxygen, affording functionalised benzo[h]indeno[1,2-f ]isochromene type products. The results are
rationalised by theoretical studies, which confirm that the electrocyclisation process is favoured at C3 in
the 2-pyrone ring system. The identity and precise arrangement of the ‘trienyl’ substituents control
whether the electrocyclisation occurs in natural light.
conjugated triene systems. Those found at vital junctures in
biomimetic processes yield fascinating structures of significant
interest.6
Introduction
Photochemically induced 6p-electrocyclisations of diarylethenes
provide an important route into dihydrophenanthrenes
(Scheme 1).1 For certain types of aryl and heteroaryl moi-
eties, the transformation has been used extensively to provide
photochromic materials2 and natural product targets.3 The in-
termediate dihydrophenanthrenes usually undergo cyclorever-
sion, but in certain cases can be isolated.4 The presence of
an oxidant, e.g. O2 or I2, allows thermodynamically favoured
aromatic derivatives to be formed from the dihydrophenan-
threne intermediates via the formal loss of H2, e.g. trapped as
H2O. Whilst many of these photochemical processes require high
energy UV irradiation, there are examples in the literature where
natural light5 can trigger certain 6p-electrocyclisations in highly
During the course of synthetic and biochemical studies on
2-pyrones,7,8 specifically the 4-(phenylethynyl)-2-pyrone 1a,9 we
became aware of a regioselective 6p-electrocyclisation–oxidative
aromatisation reaction (2a→4a) taking place in natural light
(Fig. 1). In this paper, we report the experimental results from
this study. In addition, theoretical results are presented to support
the experimental findings and offer an explanation for the
regiochemical outcome observed during the electrocyclisation.10
Scheme 1 2-Pyrones and derivatives.
aDepartment of Chemistry, University of York, Heslington, York, UK.
E-mail: ijsf1@york.ac.uk; Fax: +44 (0)1904; Tel: +44 (0)1904 434091
bDepartment of Chemistry, The Hong Kong University of Science and
Technology, Clear Water Bay, Kowloon, Hong Kong, P. R. China. E-mail:
chzlin@ust.hk
Fig. 1 Alkynylated 2-pyrone 1a and cyclisation products.
† Electronic supplementary information (ESI) available: X-Ray diffraction
data, refinement information and cartesian coordinates. CCDC reference
number 624078. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b811284c
‡ Joint corresponding authors. For details concerning the theoretical
calculations contact Z.L., and the experimental studies I.J.S.F.
Results and discussion
Our initial interest in this area derives from investigations on the
stoichiometric intermolecular Pauson–Khand (PK) reaction11 of
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4523–4532 | 4523
©

View Article Online
the internal alkyne 1a,12 norbornene and CO {from Co2(CO)8}.
The reaction can, in principle, generate two regioisomeric prod-
ucts, 2a and 2a¢ (Scheme 2). Through consideration of the
apparent polarisation effects across the alkyne bond in 1a, and
making the assumption that 2-pyrone and phenyl are sterically
near equivalent, it was predicted13 that the major regioisomeric
product would possess the phenyl group at the a-position and the
electron-deficient 2-pyrone at the b-position in the newly formed
cyclopentenone ring. The reaction is very clean when conducted
in a microwave,14 producing both regioisomers in a 3.7:1 ratio
and 89% overall yield (separable by chromatography on silica-
gel). However, the structural assignments of the two isomeric
1
products could not be definitively proven by simple H and 13C
NMR spectroscopy. It is interesting to note that this specific
example represents the first intermolecular PK reaction of any
alkyne containing a 2-pyrone moiety.15
Fig. 2 Potential regioisomeric products (line in bold depicts the position
of the new bond).
Scheme 2 Pauson–Khand reaction of 1a with norbornene and Co2(CO)8.
It emerged that the major regioisomeric product from the PK
reaction of 1a with norbornene and Co2(CO)8 was being slowly
converted to a new compound on standing in CDCl3. At this
stage, no special precaution was taken to protect the sample
from O2 or natural light. Using purified (dried and degassed)
CDCl3, or exposing the product to O2 in the dark, resulted in
no observable reaction. However, on exposure to both natural
light and O2 the reaction proceeded. This information, and
the combined spectroscopic and spectrometric evidence, pointed
to a photochemical 6p-electrocyclisation–oxidative aromatisation
process taking place. The structure of the product was expected
to be one of four regioisomers (Fig. 2); the 6p-electrocyclisation
can in principle take place at C3 or C5 in the 2-pyrone ring system
from either regioisomer 2a (to give either 4a or 4a¢) or 2a¢ (to
give either 4ab or 4ab¢). Pleasingly, 4a crystallised from a CDCl3
solution of the major isomer from the PK reaction, allowing its
structure to be determined by X-ray diffraction. This confirmed
that a regioselective 6p-electrocyclisation–oxidative aromatisation
reaction had occurred (Fig. 3). The structure determination also
confirmed the major regioisomer formed in the PK reaction
was 2a. The minor regioisomer 2a¢ does not undergo such
a facile 6p-electrocyclisation–oxidative aromatisation reaction,
being more stable in CDCl3 solution in the presence of natural light
and O2.
Fig. 3 X-Ray crystal structure of compound 4a shown in ORTEP
(arbitrary numbering used). Thermal ellipsoids are at 50% probability.
Thermal versus photochemical activation: origin of the
regioselectivity in the 6p-electrocyclisation process
To validate that the reaction was activated by natural light and not
by a thermal process, and wishing to establish the underpinning
reason for C3over C5 electrocyclisation, B3LYP density functional
theory calculations were carried out. Geometry optimisation on
2a gives two local minima, corresponding to conformers I and II
(Scheme 3). The two structures are related by a simple rotation
of the 6-methyl-2-pyrone group about the C4–C7 single bond
and have similar stabilities. Conformer I is less stable by only
1.2 kcal/mol than II. Interestingly, attempts at the optimisation
of structure III were not successful and resulted instead in the
identification of g-keto-ketene intermediate V. There are two
pathways (III→V or III→IV→V, as indicated in Scheme 3).
Structure V is 44.0 kcal/mol higher in energy than 2a, and
is therefore highly unstable and energetically inaccessible. The
result is consistent with the experimental observation that the
4524 | Org. Biomol. Chem., 2008, 6, 4523–4532
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Scheme 3 Mechanism to explain the selective formation of regioisomer 4a. Note: arbitrary atom numbering used.
C5 electrocyclisation does not occur; III is not a species that
corresponds to a stationary point on the potential energy surface.
For the C3 6p-electrocyclisation reaction, two intermediates,
3a and 3a¢, can be obtained through conrotatory and disrotatory
cyclisations, respectively. Due to the breaking of conjugation, the
two intermediates are higher in energy by 21.5 and 32.7 kcal/mol,
respectively, than reactant 2a (Fig. 4). Furthermore, structure 3a¢
is less stable than 3a as it is more strained.
On the basis of the highest occupied molecular orbital (HOMO)
of 2a (Fig. 5), the cyclisation is relevant to a 6p-electron system
and we expect that the disrotatory cyclisation is symmetry-allowed
while the conrotatory cyclisation is symmetry-forbidden.1 Indeed,
we were able to locate the transition state TSI-3a¢ connecting I
and 3a¢, which corresponds to the symmetry-allowed disrotatory
cyclisation, and failed to locate the transition state TSI-3a con-
necting I and 3a, which corresponds to the symmetry-forbidden
conrotatory cyclisation. The calculations show that the symmetry-
allowed disrotatory cyclisation has a barrier of 43.5 kcal/mol and
gives the relatively less stable intermediate 3a¢. Therefore, in view
of the inaccessibly high barrier and the very high instability of 3a¢,
it is clear that the symmetry-allowed disrotatory cyclisation giving
intermediate 3a¢ is not responsible for the experimentally observed
reaction that eventually leads to the formation of 4a. Because of
the symmetry-forbidden nature, and the fact that we failed to
locate the corresponding transition state, a thermal conrotatory
cyclisation giving intermediate 3a can be ruled out.
Under the experimental conditions, it may be postulated that
trace quantities of HCl (DCl) in the CDCl3 solvent could
have promoted the electrocyclisation through protonation of the
carbonyl of the 2-pyrone fragment of 2a (Scheme 4). However,
the calculations do not support such a possibility. The calculated
energies of 2a_H+, 3a¢_H+ and 3a_H+ show that 3a¢_H+ and
3a_H+ are higher in energy by 46.6 and 35.6 kcal/mol, respectively,
than 2a_H+. The protonation increases the energy gaps between
the intermediates and 2a. Experimentally, the reaction proceeds
in C6H6, as well as CHCl3, ruling out trace acid as a reaction
promoter.
In keeping with the Woodward–Hoffman rules,16 for a 6p-
electron system, a conrotatory cyclisation is brought about by
light.17 Given both the experimental observations and the theoret-
ical insight, it is proposed that the visible light in the laboratory
initiates the conrotatory cyclisation to give the relatively more
stable intermediate 3a, followed by hydrogen elimination in the
presence of O2 to give 4a (and H2O). Analogous ring-open systems
convert to the corresponding ring-closed forms upon UV-visible
irradiation.18
The first excited state of 2a was calculated using the time-
dependent density functional theory (TDDFT) method and can
be accessed by absorption of light at 396 nm. The solvent (CDCl3)
effect was found to reduce the energy gap between the ground
state and the first excited state, suggesting that 2a can be excited
by absorption of visible light. The small energy gap between the
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4523–4532 | 4525
©

View Article Online
Scheme 4 Probing the potential role of trace acid.
oxygen vide supra.19,1 Therefore it is proposed that the oxidant
rapidly reacts with intermediate 3a to give 4a exclusively (in natural
light).
In order to accelerate the reaction, a solution of 2a in CDCl3 was
photolysed using a standard UV lamp with a filter at 400 nm, in a
reaction vessel open to air. After 6 h, the reaction was essentially
complete (~quantitative conv.; >90% purity). A small quantity
1
of an uncharacterised side-product was evident in the H NMR
spectra, which appears to be formed towards the latter stages of
the reaction (and on prolonged exposure to light). The identical
reaction in benzene gave a similar yield of 4a, proceeding in 3 h.
Iodine proved a superior oxidant in benzene, yielding a purer
product, although the reaction time increased to 6 h. For this
latter reaction, the evolution of 4a was monitored over time by
1H NMR spectroscopy (Scheme 5). The disappearance of the C3
and C5 protons of 2a is evident (~ d 5.2 and 6.2 ppm), as is the
emergence of a new signal (~ d 6.0) corresponding to the C5 proton
of the new product. The appearance of highly deshielded aromatic
protons at ~ d 9.7 and 10.2 ppm confirms the formation of 4a.
In an effort to detect intermediate 3a, preliminary in situ
photolysis experiments (325 nm He–Cd 27 mW continuous wave
laser coupled directly to a 400 MHz NMR spectrometer) were
carried out. Interestingly, at this higher energy, electrocyclisation–
oxidative aromatisation occurs slowly in dry and degassed
CDCl3.20 It should be noted that other uncharacterised products
are formed in these reactions which do not derive from secondary
reactions of 4a. The identical reaction run in the presence of O2
affords 4a at a faster rate than the reaction run in its absence (for
which uncharacterised side-products also result).
Fig. 4 B3LYP-optimised structures. The bond distances are given in
angstroms.
Substituent effects in the aryl ring system
We envisaged that substituents on the aryl ring system would
significantly affect the rate of the 6p-electrocyclisation–oxidative
aromatisation process. Two further PK reactions of alkynyl 2-
pyrones 1b and 1c were explored. Both 1b and 1c were prepared
by Sonogashira cross-coupling of 4-bromo-6-methyl-2-pyrone8y
with the requisite terminal acetylene under standard conditions
(Scheme 6). The PK reactions of both 1b and 1c with norbornene
and Co2(CO)8 were then conducted using the previously developed
Fig. 5 The highest occupied molecular orbital (HOMO) of 2a from
conformer I.
ground state and the first excited state of 2a is related to the
extensive conjugation in 2a.
More generally, dihydrophenanthrene irreversibly converts to
phenanthrene in the presence of air, by hydrogen-elimination with
4526 | Org. Biomol. Chem., 2008, 6, 4523–4532
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Scheme 5 6-p-electrocyclisation–oxidative aromatisation of 2a→4a.21 Note: arbitrary atom numbering used.
Scheme 7 6p-Electrocyclisation–oxidative aromatisation of 2b and 2c.
From the data collected in Table 1, it is clear that 2c is
undergoing a considerably faster electrocyclisation–oxidative aro-
matisation reaction than 2a and 2b. The slowest reaction is
that involving 2b, allowing a reactivity order to be established:
p-OMe (2c) > H (2a) > p-Cl (2b). The increased reactivity
of 2c is attributed to the meta- or ortho-meta-effect (position
of the substituents relative to the new C–C bond).22 In this
example, the electron-releasing methoxy group would be expected
to stabilise the first excited state and accelerate the rate of the
6p-electrocyclisation process. The precise location of the sub-
stituents in 2a–c appears to greatly assist the 6p-electrocyclisation–
oxidative aromatisation process in natural light, as indicated by
the fact that 2a¢, 2b¢ and 2c¢ do not participate in such a facile
reaction.
Scheme 6 Aryl-substituent effects in PK reactions.
Table 1 Comparison of the relative rates of electrocyclisation–
aromatisation for 2a–ca
microwave conditions. The presence of p-chloro or p-methoxy
groups on the aryl ring does not significantly affect the overall
regioselectivity. A comparison of the spectroscopic data for both
regioisomers resulting from the PK reactions of 1b and 1c confirm
that the major regioisomers are 2b and 2c, respectively.
To determine the relative rates of the electrocyclisation–
aromatisation reactions for 2a–c, CDCl3 solutions of each com-
pound were simultaneously exposed to sunlight for one hour
(identical conditions), after which time the relative ratios of the
starting compounds to products 4a–c were determined by 1H
NMR spectroscopy (Table 1 and Scheme 7).
% Ratiob
Reaction
t = 0
t = 60 min
Relative % increase
2a → 4a
2b → 4b
2c → 4c
96.9 : 3.1
97.0 : 3.0
95.4 : 4.6
93.1 : 6.9
95.9 : 4.1
80.0 : 20.0
3.8
1.1
15.4
a Concentration of reagents 2a–c (75 mM in CDCl3) exposed to sunlight
for 1 h. b Percentage ratios given as starting material:product as determined
by 1H NMR spectroscopy (400 MHz).
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4523–4532 | 4527
©

View Article Online
It is also noted that compound 5, formed by a double-arylation
of 1a by the reaction conditions reported by Larock and Zhou,23
is stable in the presence of natural light and O2 (Scheme 8).
Irradiation (filter at 400 nm) of 5 in CDCl3 in an NMR tube
open to air at 25 ◦C resulted in a slow electrocyclisation–
oxidative aromatisation reaction to give a product which based
on 1H NMR spectroscopic evidence (500 MHz, see ESI† for
further discussion) is postulated to be 6 (58% relative conversion
after 20 h).
used.26 All calculations were carried out with the Gaussian 03
software package.27
General synthetic details
Solvents were dried where necessary using standard procedures
prior to use and stored under an argon atmosphere. DCE refers to
1,2-dichloroethane. Nitrogen gas was oxygen-free and was dried
immediately prior to use by passage through an 80 cm column
containing sodium hydroxide pellets andsilica. Argongas was used
directly via balloon transfer or on a Schlenk line. TLC analysis was
performed routinely using Merck 5554 aluminum backed silica
plates. Compounds were visualized using UV light (254 nm) and
1
a basic aqueous solution of potassium permanganate. H NMR
spectra were recorded at either 400 MHz using a JEOL ECX
400 spectrometer, with 13C NMR spectra recorded on the same
instrument at 100 MHz (1H decoupled); or at 500 MHz on a
Bruker AV 500 spectrometer, with 13C NMR spectra recorded
on the same instrument at 125 MHz (1H decoupled). Chemical
shifts are reported in parts per million (d) relative to CHCl3
at d 7.24 (1H) or 77.0 (13C). Coupling constants (J values) are
reported in hertz (Hz), and spin multiplicities are indicated by the
following symbols: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), br (broad). Photolysis was performed using a
Philips HPK 125 W medium pressure mercury lamp. 4-Bromo-
6-methyl-2-pyrone and 4-(phenylethynyl)-6-methyl-2-pyrone (1a)
were prepared as previously reported.8f,y
In situ photolysis
Compound 2a (5 mg, 0.015 mmol) was dissolved in dry and
degassed CDCl3 (0.5 mL) and added to a Youngs type NMR
tube (prepared in a dry-box; O2 <0.1 ppm). The sample was then
1
photolysed and H NMR spectra obtained approximately every
Scheme 8 Synthesis of vinyl-2-pyrone 5 and electrocyclisation–aromati-
sation to give 6.
10 minutes. This was conducted using a modified NMR probe
equipped for in situ photolysis, for which a general method has
been described previously.28 A Kimmon IK3202R-D 325 nm He–
Cd 27 mW continuous wave (CW) laser was used as the light
source.
Conclusions
The major PK regioisomeric products 2a–c readily undergo
a photochemically-induced 6p-electrocyclisation–oxidative aro-
matisation reaction to reveal functionalised benzo[h]indeno[1,2-
f ]isochromene type products 4a–c, respectively. The precise
arrangement of the substituents in 2a–c appears to facilitate
the photochemically-induced electrocyclisation process in natural
light.
General method for the preparation of 1b and 1c using Sonogashira
cross-coupling
To a degassed Schlenk flask, 4-bromo-6-methyl-2-pyrone (1 eq.),
arylacetylene (1.1 eq.), PdCl2(PPh3)2 (1 mol%), CuI (3 mol%), dry
acetonitrile (1.5 mL/mmol) and dry triethylamine (1.5 eq.) were
added and the reaction heated at 60 ◦C for 16 h. The reaction
mixture was cooled, washed with H2O, extracted with CH2Cl2,
dried over MgSO4 and filtered. The solvent was removed in vacuo
and the crude material subjected to chromatography on silica-
gel using an EtOAc/hexane eluent (0/1 to 1/5, v/v) to give the
products (characterisation data given below).
Experimental
Computational studies by DFT
Density functional theory (DFT) calculations at the B3LYP level24
were performed to calculate the structures of the isomers and the
transition states. Frequency calculations were also performed to
confirm the characteristics of the calculated structures as minima
or transition states. Calculations of intrinsic reaction coordinates
(IRC)25 were also performed on transition states to confirm
that such structures are indeed connecting two minima. Time-
dependent density functional theory was used to calculate the
energy of the first excited state. The standard 6–31G basis set was
4-(4-Chlorophenylethynyl)-6-methyl-2-pyrone (1b)
Synthesised following the general Sonogashira procedure, with
4-bromo-6-methyl-2-pyrone (504 mg, 2.7 mmol) and 1-ethynyl-4-
chlorobenzene (400 mg, 2.9 mmol), to afford the title compound as
a yellow solid (495 mg, 76%); M.p. = 134–136 ◦C; dH (400 MHz,
CDCl3) 2.25 (3H, dd, J = 0.7, 0.9 Hz), 6.03 (1H, dq, J = 0.9,
4528 | Org. Biomol. Chem., 2008, 6, 4523–4532
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
1.4 Hz), 6.28 (1H, dq, J = 0.7, 1.4 Hz), 7.36 (2H, d, J =
8.7 Hz), 7.45 (2H, d, J = 8.7 Hz); dC (100.5 MHz, CDCl3)
19.9 (CH3), 86.2 (4◦), 97.2 (4◦), 105.2 (CH), 114.6 (CH), 119.7
(4◦), 129.0 (CH), 133.3 (CH), 136.2 (4◦), 138.5 (4◦), 162.07 (4◦),
162.10 (4◦); nmax (CH2Cl2, cm-1) 2211, 1744, 1726, 1636, 1540,
1441, 1316, 1094, 1015; LR(ESI-MS): m/z 245/247 (Cl35/Cl37
MH+, 9%), 267/269 (Cl35/Cl37 MNa+, 100); HR(ESI-MS): m/z
calcd for C14H9ClNaO2 [M + Na]+: 267.0183, found 267.0182
(0.6 ppm).
MS): m/z calcd for C22H21O3 [M + H]+: 333.1485, found 333.1496
(3.3 ppm).
(3aSR,4RS,7SR,7aRS)-6-Methyl-4-(1-oxo-3-phenyl-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-2-yl)-
2H-pyran-2-one (2a¢)
M.p. = 149–152 ◦C; dH (500 MHz, CDCl3) 1.03 (1H, d, J =
10.7 Hz), 1.11 (1H, d, J = 10.7 Hz), 1.38–1.42 (2H, m), 1.64–1.68
(2H, m), 2.09 (1H, m), 2.16 (3H, dd, J = 0.7, 0.9 Hz), 2.50 (1H, d,
J = 5.5 Hz), 2.58 (1H, m), 3.20 (1H, d, J = 5.5 Hz), 5.75 (1H, dq,
J = 0.9, 1.4 Hz), 6.08 (1H, dq, J = 0.7, 1.4 Hz), 7.34–7.44 (m, 5H;
Ph); dC (100.5 MHz, CDCl3) 20.0 (CH3), 28.6 (CH2), 28.9 (CH2),
31.6 (CH2), 38.4 (CH), 39.6 (CH), 51.4 (CH), 54.3 (CH), 104.7
(CH), 112.5 (CH), 128.3 (CH), 128.9 (CH), 130.7 (CH), 133.9
(4◦), 138.3 (4◦), 148.4 (4◦), 161.8 (4◦), 162.9 (4◦), 174.2 (4◦), 206.4
(4◦); nmax (CH2Cl2, cm-1) 2964, 2877, 1720, 1698, 1639, 1607, 1548,
4-(4-Methoxyphenylethynyl)-6-methyl-2-pyrone (1c)
Synthesised following the general Sonogashira procedure, with
4-bromo-6-methyl-2-pyrone (325 mg, 1.7 mmol) and 1-ethynyl-4-
methoxybenzene (250 mg, 1.9 mmol), to afford the title compound
as a cream solid (376 mg, 91%); M.p. = 125–128 ◦C; dH (400 MHz,
CDCl3) 2.23–2.25 (3H, m), 3.84 (3H, s), 6.02–6.03 (1H, m), 6.24–
6.25 (1H, m), 6.89 (2H, d, J = 8.9 Hz), 7.46 (2H, d, J = 8.9 Hz);
dC (100.5 MHz, CDCl3) 19.8 (CH3), 55.4 (CH3), 84.7 (4◦), 99.4
(4◦), 105.5 (CH), 113.2 (4◦), 113.6 (CH), 114.3 (CH), 133.9 (CH),
139.3 (4◦), 160.9 (4◦), 161.7 (4◦), 162.4 (4◦); nmax (CH2Cl2, cm-1)
2204, 1725, 1637, 1605, 1539, 1509, 1444, 1317, 1295, 1212, 1174,
1139, 1110, 1030; LR(ESI-MS): m/z 241 (MH+, 100%); HR(ESI-
MS): m/z calcd for C15H13O3 [M + H]+: 241.0859, found 241.0863
(1.4 ppm).
1445; LR(ESI-MS): m/z 291 (MH2 - CO2 , 8%), 333 (MH+, 100),
+
355 (MNa+, 13); HR(ESI-MS): m/z calcd for C22H21O3 [M + H]+:
333.1485, found 333.1495 (3.0 ppm).
Other characterisation data (from reactions using 0.5 mmol of
either 1b or 1c):
(3aSR,4RS,7SR,7aRS)-4-[2-(4-Chlorophenyl)-1-oxo-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-3-yl]-6-methyl-
2H-pyran-2-one (2b)
General method for the Pauson–Khand reactions of 1a–c
(Based on 1a.) To a microwave tube containing 1a (105 mg,
0.5 mmol) was added Co2(CO)8 (171 mg, 0.5 mmol) and DCE
(2 mL). The mixture was stirred at room temperature for 1 h.
Norbornene (235 mg, 2.5 mmol) was added and the reaction
heated in the microwave (100 W) at 90 ◦C for between 60
and 80 min (loss of the intermediate alkynyl–Co2(CO)6 complex
was monitored by TLC analysis). On completion of the reac-
tion, the solvent was removed in vacuo and the crude material
subjected to column chromatography on silica-gel using an
EtOAc/hexane eluent (1/99 to 1/5, v/v) to give the two regioi-
someric products 2a (117 mg, 70%) and 2a¢ (33 mg, 19%) as white
solids.
Cream solid (122 mg, 67%); M.p. = 194–199 ◦C (decomposes); dH
(500 MHz, CDCl3) 1.09 (2H, s), 1.36–1.41 (2H, m), 1.61–1.76 (2H,
m), 2.15 (3H, s), 2.21 (1H, m), 2.48 (1H, d, J = 5.5 Hz), 2.59 (1H,
m), 2.98 (1H, d, J = 5.5 Hz), 5.62 (1H, s), 6.20 (1H, s), 7.18 (2H, d,
J = 8.5 Hz), 7.33 (2H, d, J = 8.5 Hz); dC (125 MHz, CDCl3) 20.1
(CH3), 28.5 (CH2), 28.8 (CH2), 31.6 (CH2), 38.0 (CH), 39.6 (CH),
50.2 (CH), 53.9 (CH), 103.1 (CH), 111.4 (CH), 128.5 (4◦), 128.8
(CH), 130.4 (CH), 135.1 (4◦), 144.6 (4◦), 151.1 (4◦), 162.3 (4◦),
162.6 (4◦), 164.0 (4◦), 207.3 (4◦); nmax (CH2Cl2, cm-1) 2964, 2876,
1725, 1702, 1638, 1543, 1490, 1311, 1298, 1230, 1198, 1091, 1016;
LR(ESI-MS): m/z 367 (MH+, 100%); HR(ESI-MS): m/z calcd
for C22H20ClO3 [M + H]+: 367.1095, found 367.1088 (1.9 ppm).
(3aSR,4RS,7SR,7aRS)-6-Methyl-4-(1-oxo-2-phenyl-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-3-yl)-
2H-pyran-2-one (2a)
(3aSR,4RS,7SR,7aRS)-4-[3-(4-Chlorophenyl)-1-oxo-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-2-yl]-6-methyl-
2H-pyran-2-one (2b¢)
M.p. = 117–120 ◦C (decomposes); dH (500 MHz, CDCl3) 1.08
(1H, d, J = 10.8 Hz), 1.13 (1H, d, J = 10.8 Hz), 1.37–1.42
(2H, m), 1.63–1.74 (2H, m), 2.10 (3H, dd, J = 0.8, 0.8 Hz), 2.20
(1H, m), 2.49 (1H, d, J = 5.5 Hz), 2.60 (1H, m), 2.99 (1H, d,
J = 5.5 Hz), 5.60 (1H, br s), 6.22 (1H, br s), 7.20–7.22 (2H,
m), 7.34–7.36 (3H, m); dH (500 MHz, C6D6) 0.68–1.42 (6H, m),
1.61 (3H, br s), 1.84 (1H, br s), 2.09 (1H, br s), 2.34 (1H, br s),
2.56 (1H, br s), 5.18 (1H, br s), 6.17 (1H, br s), 7.01–7.52 (5H,
m); dC (125 MHz, CDCl3) 20.0 (CH3), 28.5 (CH2), 28.9 (CH2),
31.6 (CH2), 38.1 (CH), 39.6 (CH), 50.0 (CH), 53.9 (CH), 103.4
(CH), 111.4 (CH), 128.5 (CH), 128.9 (CH), 129.0 (CH), 130.3
(4◦), 146.1 (4◦), 151.3 (4◦), 162.1 (4◦), 162.5 (4◦), 163.4 (4◦), 207.6
(4◦); nmax (CH2Cl2, cm-1) 2961, 1722, 1700, 1637, 1541, 1445, 1308;
LR(ESI-MS): m/z 333 (MH+, 100%), 355 (MNa+, 13); HR(ESI-
◦
White solid (42 mg, 23%); M.p. = 144–147 C (decomposes); dH
(500 MHz, CDCl3) 1.07 (1H, d, J = 10.7 Hz), 1.09 (1H, d, J =
10.7 Hz), 1.37–1.42 (2H, m), 1.63–1.71 (2H, m), 2.08 (1H, m),
2.18 (3H, s), 2.50 (1H, d, J = 5.5 Hz), 2.59 (1H, m), 3.16 (1H, d,
J = 5.5 Hz), 5.73 (1H, s), 6.07 (1H, s), 7.31 (2H, d, J = 8.5 Hz),
7.39 (2H, d, J = 8.5 Hz); dC (125 MHz, CDCl3) 20.1 (CH3), 28.6
(CH2), 28.9 (CH2), 31.7 (CH2), 38.5 (CH), 39.7 (CH), 51.3 (CH),
54.3 (CH), 104.4 (CH), 112.6 (CH), 129.3 (CH), 129.6 (CH), 132.2
(4◦), 137.0 (4◦), 138.7 (4◦), 148.0 (4◦), 162.2 (4◦), 162.6 (4◦), 172.2
(4◦), 206.0 (4◦); nmax (CH2Cl2, cm-1) 2964, 2877, 1721, 1698, 1639,
1610, 1592, 1547, 1491, 1402, 1332, 1095; LR(ESI-MS): m/z 367
(MH+, 100%); HR(ESI-MS): m/z calcd for C22H20ClO3 [M + H]+:
367.1095, found 367.1092 (0.8 ppm).
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4523–4532 | 4529
©

View Article Online
(3aSR,4RS,7SR,7aRS)-4-[2-(4-Methoxyphenyl)-1-oxo-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-3-yl]-6-methyl-
2H-pyran-2-one (2c)
m), 6.64 (1H, s), 7.69–7.79 (2H, m), 9.30 (1H, d, J = 7.6 Hz),
9.70 (1H, d, J = 8.1 Hz); dH (500 MHz, C6D6) 0.57 (1H, d, J =
10.8 Hz), 0.65 (1H, d, J = 10.8 Hz), 1.06–1.16 (2H, m), 1.30–1.44
(2H, m), 1.75 (3H, s), 2.09 (1H, m), 2.32 (1H, d, J = 5.7 Hz), 2.58
(1H, d, J = 5.7 Hz), 2.62 (1H, m), 5.98 (1H, s), 7.43 (1H, m), 7.51
(1H, m), 9.71 (1H, d, J = 8.2 Hz), 10.15 (1H, d, J = 8.7 Hz);
dC (100.5 MHz, CDCl3) 20.0 (CH3), 28.4 (CH2), 29.4 (CH2), 32.0
(CH2), 39.8 (CH), 40.3 (CH), 46.2 (CH), 56.5 (CH), 100.5 (CH),
117.3 (4◦), 124.2 (CH), 126.5 (CH), 127.7 (4◦), 128.6 (CH), 129.3
(CH), 131.2 (4◦), 137.2 (4◦), 137.9 (4◦), 153.7 (4◦), 157.7 (4◦), 161.6
(4◦), 209.1 (4◦); nmax (CH2Cl2, cm-1) 2963, 2876, 1724, 1701, 1655,
1612, 1592, 1560, 1509, 1443, 1385, 1351, 1229; LR(CI-MS): m/z
331 (MH+, 100%); HR(CI-MS): m/z calcd for C22H19O3 [M + H]+:
331.13342, found 331.13254 (2.6 ppm).
Yellow solid (110 mg, 65%); M.p. = 97–101 ◦C (decomposes);
dH (500 MHz, CDCl3) 1.06 (1H, d, J = 10.7 Hz), 1.10 (1H, d,
J = 10.7 Hz), 1.34–1.41 (2H, m), 1.61–1.74 (2H, m), 2.12 (3H,
s), 2.20 (1H, m), 2.46 (1H, d, J = 5.5 Hz), 2.59 (1H, m), 2.95
(1H, d, J = 5.5 Hz), 3.81 (3H, s), 5.65 (1H, s), 6.23 (1H, s),
6.87 (2H, d, J = 1.9, 8.8 Hz), 7.18 (2H, dd, J = 1.9, 8.8 Hz);
dC (125 MHz, CDCl3) 20.0 (CH3), 28.6 (CH2), 28.9 (CH2), 31.6
(CH2), 38.1 (CH), 39.6 (CH), 49.9 (CH), 53.9 (CH), 55.3 (CH3),
103.5 (CH), 111.3 (CH), 114.0 (CH), 122.4 (4◦), 130.5 (CH), 145.3
(4◦), 151.7 (4◦), 160.1 (4◦), 162.1 (4◦), 162.1 (4◦), 162.6 (4◦), 208.0
(4◦); nmax (CH2Cl2, cm-1) 2962, 2876, 2840, 1719, 1700, 1637, 1605,
1543, 1510, 1198, 1177, 1159, 1033; LR(ESI-MS): m/z 363 (MH+,
100%); HR(ESI-MS): m/z calcd for C23H23O4 [M + H]+: 363.1591,
found 363.1601 (2.7 ppm).
(9aRS,10SR,13RS,13aSR)-6-Chloro-2-methyl-
4,9,9a,10,11,12,13,13a-octahydro-10,13-
methanobenzo[h]indeno[1,2-f ]isochromene-4,9-dione (4b)
M.p. = 186–187 ◦C (decomposes); dH (400 MHz, CDCl3) 0.84
(1H, d, J = 10.9 Hz), 1.03 (1H, d, J = 10.9 Hz), 1.49 (1H, m),
1.62 (1H, m), 1.74 (1H, m), 1.84 (1H, m), 2.47 (3H, d, J = 0.9 Hz),
2.55 (1H, m), 2.70–2.74 (2H, m), 3.28 (1H, d, J = 5.8 Hz), 6.65
(1H, m), 7.66 (1H, dd, J = 2.2, 9.0 Hz), 9.24 (1H, d, J = 9.0 Hz),
9.76 (1H, d, J = 2.2 Hz); dC (100.5 MHz, CDCl3) 22.6 (CH3), 28.4
(CH2), 29.4 (CH2), 32.1 (CH2), 39.8 (CH), 40.4 (CH), 46.2 (CH),
56.5 (CH), 100.5 (CH), 116.4 (4◦), 125.6 (CH), 125.8 (CH), 126.0
(4◦), 129.2 (CH), 132.1 (4◦), 136.0 (4◦), 137.8 (4◦), 138.1 (4◦), 153.7
(4◦), 158.5 (4◦), 161.3 (4◦), 208.8 (4◦); nmax (CH2Cl2, cm-1) 2963,
2929, 2877, 1723, 1701, 1653, 1608, 1503, 1363, 1346, 1156, 1197;
LR(ESI-MS): m/z 365 (MH+, 100%), 387 (MNa+, 10); HR(ESI-
MS): m/z calcd for C22H18O3 [M + H]+: 365.0939, found 365.0938
(0.3 ppm).
(3aSR,4RS,7SR,7aRS)-4-[3-(4-Methoxyphenyl)-1-oxo-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-2-yl]-6-methyl-
2H-pyran-2-one (2c¢)
Yellow solid (31 mg, 17%); M.p. = 172–174 ◦C (decomposes); dH
(500 MHz, CDCl3) 1.01 (1H, d, J = 10.7 Hz), 1.09 (1H, d, J =
10.7 Hz), 1.37–1.44 (2H, m), 1.65–1.68 (2H, m), 2.12 (1H, m),
2.17 (3H, s), 2.48 (1H, d, J = 5.5 Hz), 2.57 (1H, m), 3.18 (1H,
d, J = 5.5 Hz), 3.85 (3H, s), 5.76 (1H, br s), 6.13 (1H, br s),
6.91 (2H, dd, J = 1.9, 8.7 Hz), 7.37 (2H, dd, J = 1.9, 8.7 Hz); dC
(125 MHz, CDCl3) 20.0 (CH3), 28.7 (CH2), 29.0 (CH2), 31.7 (CH2),
38.9 (CH), 39.5 (CH), 50.9 (CH), 54.3 (CH), 55.4 (CH3), 104.8
(CH), 112.5 (CH), 114.3 (CH), 125.9 (4◦), 130.5 (CH), 136.7 (4◦),
149.1 (4◦), 161.8 (4◦), 161.9 (4◦), 162.9 (4◦), 173.1 (4◦), 206.1 (4◦);
n
max (CH2Cl2, cm-1) 2963, 2877, 1720, 1694, 1511, 1404, 1336, 1160,
1031; LR(ESI-MS): m/z 363 (MH+, 100%); HR(ESI-MS): m/z
(9aRS,10SR,13RS,13aSR)-6-Methoxy-2-methyl-
4,9,9a,10,11,12,13,13a-octahydro-10,13-methanobenzo[h]indeno
[1,2-f ]isochromene-4,9-dione (4c)
calcd for C23H23O4 [M + H]+: 363.1591, found 363.1601 (2.7 ppm).
General procedure for electrocyclisation–oxidative aromatisation
(NMR studies)
M.p. = 173–177 ◦C (decomposes); dH (400 MHz, CDCl3) 0.85
(1H, d, J = 10.8 Hz), 1.00 (1H, d, J = 10.8 Hz), 1.48 (1H, m),
1.59 (1H, m), 1.72 (1H, m), 1.82 (1H, m), 2.46 (3H, d, J = 0.9 Hz),
2.54 (1H, m), 2.68 (1H, d, J = 5.7 Hz), 2.71 (1H, m), 3.26 (1H, d,
J = 5.7 Hz), 4.02 (3H, s), 6.63 (1H, q, J = 1.0 Hz), 7.35 (1H, dd,
J = 2.7, 9.2), 9.20 (1H, d, J = 9.2 Hz), 9.21 (1H, d, J = 2.7 Hz);
dC (100.5 MHz, CDCl3) 20.0 (CH3), 28.4 (CH2), 29.3 (CH2), 32.1
(CH2), 39.8 (CH), 40.3 (CH), 46.0 (CH), 55.5 (CH3), 56.6 (CH),
100.7 (CH), 106.3 (CH), 116.3 (4◦), 120.0 (CH), 122.8 (4◦), 125.5
(CH), 133.4 (4◦), 137.7 (4◦), 137.8 (4◦), 150.6 (4◦), 157.5 (4◦), 160.4
(4◦), 162.0 (4◦), 209.3 (4◦); nmax (CH2Cl2, cm-1) 2963, 2876, 1716,
1699, 1657, 1615, 1596, 1516, 1466, 1353, 1236, 1204, 1116, 1082,
1033, 1003; LR(ESI-MS): m/z 361 (MH+, 100%), 383 (MNa+, 15);
HR(ESI-MS): m/z calcd for C23H21O4 [M + H]+: 361.1434, found
361.1438 (1.0 ppm).
In a clean, dry NMR tube, 2a (10 mg, 0.03 mmol) was dissolved
in CDCl3 (0.4 mL) under an atmosphere of air. Alternatively, the
sample was dissolved in C6D6 (0.4 mL) and I2 (1 eq.) was added.
The tube was then placed in front of a 400 nm filter and the mixture
photolysed, with 1H NMR spectra recorded at 10, 20, 60 180 and
360 minute intervals, until the complete disappearance of 2a was
observed.
The comparison of the relative rates of electrocyclisation–
aromatisation for 2a–c were conducted in a similar manner to that
detailed above except in sunlight for 1 h. Conversion to products
4a–c was determined by 1H NMR spectroscopy (samples protected
from light after 1 h, prior to NMR spectroscopic analysis).
(9aRS,10SR,13RS,13aSR)-2-Methyl-4,9,9a,10,11,12,13,13a-
octahydro-10,13-methanobenzo[h]indeno[1,2-f ]isochromene-4,9-
dione (4a)
6-Methyl-4-(1,2,2-triphenylvinyl)-2-pyrone (5)
1a (106 mg, 0.5 mmol), iodobenzene (0.112 mL, 1 mmol), phenyl-
boronic acid (184 mg, 1.5 mmol), sodium hydrogen carbonate
(84 mg, 1 mmol), DMF (15 mL) and H2O (4 mL) were added
to a degassed Schlenk flask and stirred at 100 ◦C for 10 min.
M.p. = 225–229 ◦C; dH (500 MHz, CDCl3) 0.88 (1H, d, J =
10.8 Hz), 1.01 (1H, d, J = 10.8 Hz), 1.45–1.64 (2H, m), 1.68–1.85
(2H, m), 2.46 (3H, s), 2.54 (1H, m), 2.65–2.75 (2H, m), 3.27 (1H,
4530 | Org. Biomol. Chem., 2008, 6, 4523–4532
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
PdCl2(MeCN)2 (2 mg, 0.005 mmol) in DMF (1 mL) was then
injected into the mixture and the reaction was stirred for a further
24 h at 100 ◦C. The reaction mixture was cooled, quenched with
saturated NaCl solution (30 mL) and the aqueous layer was
extracted CH2Cl2 (3 ¥ 10 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and the solvent removed in
vacuo. Isolation of the product by chromatography on a silica-gel
column using pet. ether/EtOAc as eluent (95/5, v/v) gave the title
compound (142 mg, 78%) as a yellow solid; M.p. = 235–238 ◦C; dH
(400 MHz, CDCl3) 2.05 (3H, dd, J = 0.7, 0.9 Hz), 5.59 (1H, dq,
J = 0.9, 1.5 Hz), 5.83 (1H, dq, J = 0.7, 1.5 Hz), 6.93–6.96 (2H,
m), 7.01–7.04 (2H, m), 7.07–7.17 (8H, m), 7.23–7.27 (3H, m); dC
(400 MHz, CDCl3) 19.8 (CH3), 106.2 (CH), 113.9 (CH), 127.4
(CH), 127.7 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 130.5
(CH), 131.0 (CH), 131.1 (CH), 136.6 (4◦), 140.5 (4◦), 141.96 (4◦),
141.98 (4◦), 153.3 (4◦), 159.4 (4◦), 160.5 (4◦), 163.4 (4◦)—one CH
signal not observed; nmax (CH2Cl2, cm-1) 1709, 1634, 1548, 1493,
1445, 1383, 1314, 1097, 1076, 1029; LR(ESI-MS): m/z 365 (MH+,
100%); HR(ESI-MS): m/z calcd for C26H21O2 [M + H]+: 365.1536,
found 365.1541 (1.0 ppm).
Photochemistry and Photobiology, CRC Press, Boca Raton, FL, 2004,
Chapter 4.
6 For an excellent overview of this area, see: C. M. Beaudry, J. P. Malerich
and D. Trauner, Chem. Rev., 2005, 105, 4757.
7 For reviews, see: (a) G. P. McGlacken and I. J. S. Fairlamb, Nat. Prod.
Rep., 2005, 22, 369; (b) J. M. Dickinson, Nat. Prod. Rep., 1993, 10, 71.
8 (a) I. J. S. Fairlamb, L. R. Marrison, J. M. Dickinson, F.-J. Lu and
J.-P. Schmidt, Bioorg. Med. Chem., 2004, 12, 4285; (b) L. R. Marrison,
J. M. Dickinson and I. J. S. Fairlamb, Bioorg. Med. Chem. Lett., 2003,
13, 2667; (c) J. C. Collings, A. C. Parsons, L. Porre`s, A. Beeby, A. S.
Batsanov, J. A. K. Howard, D. P. Lydon, P. J. Low, I. J. S. Fairlamb
and T. B. Marder, Chem. Commun., 2005, 2666; (d) L. R. Marrison,
J. M. Dickinson and I. J. S. Fairlamb, Bioorg. Med. Chem. Lett., 2002,
12, 3509; (e) L. R. Marrison, J. M. Dickinson, R. Ahmed and I. J. S.
Fairlamb, Tetrahedron Lett., 2002, 43, 8853; (f) I. J. S. Fairlamb, F.-J.
Lu and J.-P. Schmidt, Synthesis, 2003, 2564; (g) I. J. S. Fairlamb, S. M.
Syva¨nne and A. C. Whitwood, Synlett, 2003, 1693; (h) I. J. S. Fairlamb,
J. M. Lynam, I. E. Taylor and A. C. Whitwood, Organometallics, 2004,
23, 4964. For representative studies on 2-pyrones by other groups, see;
(i) X. Shi, W. S. Leal, Z. Liu, E. Schrader and J. Meinwald, Tetrahedron
Lett., 1995, 36, 71; (j) W. S. Leal, X. Shi, D. Liang, C. Schal and
J. Meinwald, Proc. Natl. Acad. Sci. U.S.A., 1995, 92, 1033; (k) M.
Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina and R. Rossi,
Eur. J. Org. Chem., 2002, 1063; (l) F. Bellina, M. Biagetti, A. Carpita
and R. Rossi, Tetrahedron, 2001, 57, 2857; (m) M. Biagetti, F. Bellina,
A. Carpita and R. Rossi, Tetrahedron Lett., 2003, 44, 607; (n) F. Bellina,
A. Carpita, L. Mannocci and R. Rossi, Eur. J. Org. Chem., 2004, 2610;
(o) S. Cerezo, M. Moreno-Man˜as and R. Pleixats, Tetrahedron, 1998,
54, 7813; (p) G. H. Posner, W. Harrison and D. G. Wettlaufer, J. Org.
Chem., 1985, 50, 5041; (q) G. H. Posner and W. Harrison, J. Organomet.
Chem., 1985, 285, C27; (r) W. S. Kim, H. J. Kim and C. G. Cho,
Tetrahedron Lett., 2002, 43, 9015; (s) W. S. Kim, H. J. Kim and C. G.
Cho, J. Am. Chem. Soc., 2003, 125, 1428; (t) J. H. Lee, J. S. Park and
C. G. Cho, Org. Lett., 2002, 4, 1171; (u) K. M. Ryu, A. K. Gupta, J. W.
Han, C. H. Oh and C. G. Cho, Synlett, 2004, 2197; (v) J. H. Lee and
C. G. Cho, Tetrahedron Lett., 2003, 44, 65; (w) J. H. Lee, W. S. Kim,
Y. Y. Lee and C. G. Cho, Tetrahedron Lett., 2002, 43, 5779; (x) K. Ryu,
Y. S. Cho, S. Jung and C. G. Cho, Org. Lett., 2006, 8, 3343; (y) M.
Cervera, M. Moreno-Manas and R. Pleixats, Tetrahedron, 1990, 46,
7885.
Electrocyclisation–oxidative aromatisation of
6-methyl-4-(1,2,2-triphenylvinyl)-2-pyrone (5)
In a clean, dry NMR tube, 5 (15 mg, 0.04 mmol) was dissolved in
CDCl3 (0.4 mL) under an atmosphere of air. The tube was then
placed in front of a 400 nm filter and the mixture photolysed for
20 h. Selected 1H NMR spectroscopic data, including discussion,
is provided in the ESI.†
Acknowledgements
9 Internal alkynes containing the 2-pyrone motif can be prepared using
classical Sonogashira cross-coupling, see ref.8f and the experimental
section.
10 So far as we have been able to determine, there is only one other example
of a 6p-electrocyclisation–oxidative aromatisation reaction involving
a 2-pyrone substrate, namely N-methyl-6-oxo-N-phenyl-6H-pyran-
3-carboxamide, which reveals a lactam (6-methyl-6H-pyrano[3,2-
c]quinoline-2,5-dione) regioselectively in 30% yield in the presence of I2
as the oxidant, see: I. Ninomiya, T. Kiguchi and T. Naito, Heterocycles,
1978, 9, 1023.
This work has been supported by the EPSRC (DTA award to
B.E.M.) and the Royal Society (U.R.F. to I.J.S.F.). We are grateful
to Mr. R. A. Jennings for assistance with the preparation of
compounds 5 and 6. AstraZeneca are thanked for an unrestricted
research award. The referees are thanked for their constructive
critical comments concerning this paper.
11 For recent reviews, see: (a) K. H. Park and Y. K. Chung, Synlett, 2005,
545; (b) M. Rodriguez Rivero, J. Adrio and J. C. Carretero, Synlett,
2005, 26; (c) S. E. Gibson and A. Stevenazzi, Angew. Chem. Int. Ed.,
2003, 42, 1800.
Notes and references
1 F. B. Mallory and C. W. Mallory, Org. React., 1984, 30, 1.
12 On a general note, there appears to be limited unsymmetrical di-
arylethynes that undergo efficient intermolecular PK reactions, see:
(a) S. E. Gibson and N. Mainolfi, Angew. Chem. Int. Ed., 2005, 44,
3022; (b) S. Laschat, A. Becheanu, T. Bell and A. Baro, Synlett, 2005,
2547.
2 (a) M. Takeshita and M. Irie, J. Org. Chem., 1998, 63, 6643; (b) J. P.
Soumillion, J. Weiler, X. De Man, R. Touillaux, J. P. Declercq and B.
Tinant, Tetrahedron Lett., 1989, 30, 4509; (c) S. Shinkai, Pure Appl.
Chem., 1987, 59, 425; (d) M. Irie, Pure Appl. Chem., 1996, 68, 1367;
(e) M. Irie, Chem. Rev., 2000, 100, 1685.
13 (a) F. Robert, A. Milet, Y. Gimbert, D. Konya and A. E. Greene, J. Am.
Chem. Soc., 2001, 123, 5396; (b) T. J. M. de Bruin, A. Milet, F. Robert,
Y. Gimbert and A. E. Greene, J. Am. Chem. Soc., 2001, 123, 7184.
14 Stoichiometric intermolecular PK reactions involving internal alkyne
substrates are assisted by microwave heating. Note: the regioisomeric
distribution is similar using conventional heating. For the use of
microwave heating in PK reactions, see: M. Iqbal, N. Vyse, J. Dauvergne
and P. Evans, Tetrahedron Lett., 2002, 43, 7859.
15 The stoichiometric intermolecular PK reactions of a library of (2-
phenylethynyl)heteroaromatic compounds with norbornene, and their
regiochemical consequences, will be reported in due course. B. E. Moul-
ton, J. M. Lynam, A. F. Lee, A. C. Whitwood, and I. J. S. Fairlamb,
unpublished results.
3 For recent trienyl 6p-electrocyclisations, see: (a) A. Fu¨rstner, M. M.
Domostoj and B. Scheiper, J. Am. Chem. Soc., 2006, 128, 8087; (b) A.
Fu¨rstner, M. M. Domostoj and B. Scheiper, J. Am. Chem. Soc., 2005,
127, 11620; (c) without oxidation, C. M. Beaudry and D. Trauner, Org.
Lett., 2005, 7, 4475; (d) J. E. Barbarow, A. K. Miller and D. Trauner,
Org. Lett., 2005, 7, 2901. For related aza-6p-electrocyclisations, see:
M. L. Meketa and S. M. Weinreb, Org. Lett., 2007, 9, 953; M. L.
Meketa, S. M. Weinreb, Y. Nakao and N. Fusetani, J. Org. Chem., 2007,
72, 4892. For related oxa-6p-electrocyclisations, see: A. S. Kleinke, C.
Li, N. Rabasso and J. A. Porco, Jr., Org. Lett., 2006, 8, 2847.
4 K. Matsuda and M. Irie, Chem. Lett., 2006, 35, 1204.
5 (a) A. Astarita, M. DellaGreca, M. R. Iesce, S. Montanaro, L. Previtera
and F. Temussi, J. Photochem. Photobiol. A: Chem., 2007, 187, 263;
(b) M. Cermola, M. DellaGreca, M. R. Iesce, S. Montanaro, L.
Previtera and F. Temussi, Tetrahedron, 2006, 62, 7390; (c) A. Albini,
and M. Fagnoni, in: W. Horspool, and F. Lenci, (Eds.), (Organic
16 R. B. Woodward, and R. Hoffmann, The Conservation of Orbital
SymmetryVerlag Chemie, GmbH, Weinheim, 1970, p. 38.
17 Y. Nakayama and M. Irie, J. Org. Chem., 1988, 53, 6136.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4523–4532 | 4531
©

View Article Online
18 (a) C. Bertarelli, A. Bianco, V. Boffa, M. Mirenda, M. C. Gallazzi
and G. Zerbi, Adv. Funct. Mater., 2004, 14, 1129; (b) Y. Nakayama,
K. Hayashi and M. Irie, Bull. Chem. Soc. Jpn., 1991, 64, 789; (c) Y.
Nakayama, K. Hayashi and M. Irie, Bull. Chem. Soc. Jpn., 1991, 64,
202; (d) Y. Nakayama, K. Hayashi and M. Irie, J. Org. Chem., 1990,
55, 2592; (e) K. Uchida, Y. Nakayama and M. Irie, Bull. Chem. Soc.
Jpn., 1990, 63, 1311.
19 (a) D. H. Waldeck, Chem. Rev., 1991, 91, 415; (b) J. Saltiel, and Y. P. Sun,
Photochromism: Molecules and Systems, H. Durr, H. Bouas-Laurent,
(Eds.), Amsterdam, 1990, p. 64.
20 We interpret this as being due to excitation of CDCl3. Detailed
experiments concerning this outcome will be reported in due course.
S. B. Duckett, B. E. Moulton, and I. J. S. Fairlamb, unpublished results.
21 We attribute the line-broadening in the 1H NMR spectra to the presence
of dissolved iodine/radical species. On consumption of I2, the proton
signals sharpen.
Zimmerman, J. Phys. Chem. A, 1998, 102, 5616, and references cited
therein.
23 Compound 5 was prepared by three-component coupling of 1a,
iodobenzene and phenylboronic acid, in the presence of PdCl2(MeCN)2
as the precatalyst and NaHCO3 as base, according to the methodology
described: C. Zhou and R. C. Larock, J. Org. Chem., 2005, 70, 3765.
Also see the experimental section.
24 (a) A. D. Becke, J. Chem. Phys, 1993, 98, 5648; (b) B. Miehlich,
A. Savin, H. Stoll and H. Preuss, Chem. Phys. Lett., 1989, 157,
200; (c) C. Lee, W. Yang and G. Parr, Phys. Rev., 1988, B37,
785.
25 (a) K. Fukui, J. Phys. Chem., 1970, 74, 4161; K. Fukui, Acc. Chem.
Res., 1981, 14, 363.
26 P. C. Hariharan and J. A. Pople, Theor. Chim. Acta, 1973, 28, 213.
27 M. J. Frisch, et al., Gaussian 03, revision B05; Gaussian, Inc.,
Pittsburgh, PA, 2003.
22 (a) H. E. Zimmerman and V. R. Sandel, J. Am. Chem. Soc., 1963, 85,
28 C. Godard, P. L. Callaghan, J. L. Cunningham, S. B. Duckett, J. A. B.
Lohman and R. N. Perutz, Chem. Commun., 2002, 2836.
915; (b) H. E. Zimmerman, J. Am. Chem. Soc., 1995, 117, 8988; (c) H. E.
4532 | Org. Biomol. Chem., 2008, 6, 4523–4532
This journal is
The Royal Society of Chemistry 2008
©