Divergent reactivity of phenol- and anisole-tethered donor-acceptor α-diazoketones

Article abstract of DOI:10.1016/j.tet.2018.02.003

The first study of the divergent reactivity of phenol/anisole-tethered donor-acceptor α-diazoketones is described. Four distinct product classes were shown to be accessible from closely related α-diazoketone precursors, with the reaction outcome dependent

Full text of DOI:10.1016/j.tet.2018.02.003

Accepted Manuscript
Divergent reactivity of phenol- and anisole-tethered donor-acceptor α-diazoketones
Aimee K. Clarke, William P. Unsworth, Richard J.K. Taylor
PII:
S0040-4020(18)30128-5
10.1016/j.tet.2018.02.003
TET 29274
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 January 2018
Revised Date: 25 January 2018
Accepted Date: 1 February 2018
Please cite this article as: Clarke AK, Unsworth WP, Taylor RJK, Divergent reactivity of phenol- and
anisole-tethered donor-acceptor α-diazoketones, Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.003.
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Divergent reactivity of phenol- and anisole-
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tethered donor-acceptor α-diazoketones
Aimee K. Clarke, William P. Unsworth* and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK

1
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Tetrahedron
journal homepage: www.elsevier.com
Divergent reactivity of phenol- and anisole-tethered donor-acceptor α-diazoketones
Aimee K. Clarke, William P. Unsworth* and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first study of the divergent reactivity of phenol/anisole-tethered donor-acceptor α-
diazoketones is described. Four distinct product classes were shown to be accessible from
closely related α-diazoketone precursors, with the reaction outcome dependent on the nature of
the oxygen substituent on the phenol/anisole ring and the catalyst used to decompose the diazo
group. Anisole and TBS-protected derivatives selectively produce three products types
(cyclopropanes, tetralones and 1,2-dicarbonyls) while phenols selectively produce spirocyclic
dienones.
Available online
Keywords:
α-Diazocarbonyl compounds
Anisole
2009 Elsevier Ltd. All rights reserved
.
Buchner reaction
Phenol
Divergent reactivity
1. Introduction
α-Diazocarbonyl compounds are a versatile compound class
able to undergo a variety of synthetic transformations to generate
multiple products.1,2 Their diverse reactivity is well-known in the
literature and is a consequence of the many reactive intermediates
they can form, including carbenes, carbenoids, ylides and
diazonium cations. An excellent review by Maguire, McKervey
and co-workers details the importance of α-diazocarbonyl
compounds in modern organic synthesis, and demonstrates their
utility in
a
range of C-H insertion, cyclopropanation,
cycloaddition and ylide-forming reactions.1d
The versatile reactivity of α-diazocarbonyl compounds means
that they are well-suited for use in diversity-oriented synthesis,3
especially for research focused on the synthesis of multiple
product classes from the same starting material.4,5 Such processes
are particularly useful if the chemoselectivity can be controlled,
for example, by variation of the reaction conditions or reagents.
In our groups,5a,6 we are interested in developing divergent
reaction systems in which the outcome is controlled by the choice
of catalyst. Such ‘catalyst selective synthesis’7,8 has the power to
significantly streamline the synthesis of diverse compounds,
whilst also advancing our knowledge of the catalysis that
underpins the divergent reactivity. An instructive example of the
power of this approach was published by our groups in 2016, in
which we demonstrated that by careful choice of catalyst and
reaction conditions we could selectively generate six distinct
products from single indolyl α-diazoketone precursors of the
form 1 (Scheme 1A).5a To the best of our knowledge, this
represents the highest number of distinct products selectively
accessible from a single precursor by varying the catalyst and
reaction conditions reported date.
Scheme 1. Catalyst selective synthesis using α-diazoketones.
In this manuscript, we describe efforts to extend this catalyst
selective synthesis approach to phenol-/anisole-tethered α-

2
Tetrahedron
ACCEPTED MANUSCRIPT
diazoketones of the form 3 (i.e. ‘donor-acceptor’ diazoketones,9
Scheme 1B). There were no reports concerning the reactions of
diazo compounds of this type prior to this study,10 although we
drew inspiration from earlier studies detailing the reactivity of
related classes of phenol-tethered α-diazoketones. For example,
one of the first published intramolecular cyclisation reactions of
such a compound was reported by Mander et al. in 1974, in
which either Brønsted or Lewis acids were used to promote the
displacement of nitrogen from simple α-diazoketones of the form
8, leading to the formation of bridged tricyclic systems (e.g. 8 →
9, Scheme 2A).11 Iwata and co-workers later reported that similar
transformations could be promoted with copper(I) chloride to
generate spirocycles (e.g. 10 → 11, Scheme 2B);12 indeed,
Mander et al. had previously shown that spirocycles of this type
could be prepared using BF3·OEt2 to promote the reaction, albeit
with competing dienone-phenol rearrangement products being
formed in some cases.13 Apart from these works, surprisingly
little is known about the reactions of phenol-tethered α-
diazoketones, although Harada, Nemoto and co-workers recently
published a powerful strategy for the conversion of structurally
related α-diazoacetamides 12 into spirocyclic dienones 13 in high
yield and enantiomeric excess using chiral silver(I) salts (Scheme
2C).14 Encouragingly for us, divergent reactivity was observed
during initial catalyst screening in this study, with ring-annulated
and C–H insertion products also observed to some degree when
other catalysts were used.
Scheme 3. Use of related anisole-tethered α-diazocarbonyl
compounds in the literature.
Our previous work in this area (Scheme 1A) focused on
systems in which the diazo group is flanked on either side by
both a ketone and an aromatic ring (see 1, Scheme 1); controlling
the reactivity of such ‘donor-acceptor’ diazo systems9 is often
easier than in less stabilised diazo systems, and it was decided to
retain this feature in the current study (e.g. 3) in the hope that it
would allow us to impart similar chemoselectivity to that
achieved in our earlier work.5a Our interest in these systems was
further piqued by the fact that, to the best of our knowledge, there
have been no reports concerning the reactions of any
phenol/anisole-tethered α-diazoketones of this type (3) prior to
this study.10 Thus, herein, we describe our initial catalyst-
screening, reaction optimisation and provide mechanistic
proposals for a new, catalyst-driven divergent reaction series, that
enables cyclopropane, tetralone, 1,2-dicarbonyl and spirocyclic
products (4–7) to be selectively prepared from structurally related
α-diazoketone precursors of the form 3.
2. Results and discussion
2.1. Anisole-tethered α-diazoketones
We initiated our study by treating anisole-tethered α-
diazoketone 3a18 with a range of metal-based catalysts. The
expectation was that by forming different metal carbenoid
species, different reactive pathways would be accessed, resulting
in the preparation of multiple products. Selected screening results
are shown in Table 1, with details of the full screen included in
the Supporting Information. All catalysts were tested at 10 mol%
loading in CH2Cl2 (0.1 M) at RT unless stated, with the product
ratios determined by integration of their unpurified 1H NMR
spectra. As expected, many of the conditions produced mixtures
of products, although three major identifiable products were
observed in most cases: these were subsequently isolated and the
structures assigned as cyclopropane 4a, tetralone 5a and 1,2-
dicarbonyl 6a. Other minor products were also observable by 1H
NMR spectroscopy in some cases, but these could not be
obtained cleanly, hence the subsequent discussion is focused on
the ratio of the three major products 4a–6a. Cyclopropane 4a,
which was formed using the widest array of catalysts (via the
Buchner reaction), was the major product produced using Rh(II),
Cu(I) and Pd(II) catalysts (Table 1, entries 1–3), with Ag2O
producing this product with the highest purity of the catalysts
screened (entry 4). Conversely, more Lewis acidic catalysts
Cu(OTf)2 and AgOTf furnished tetralone 5a as the major product
Scheme 2. Use of related phenol-tethered α-diazocarbonyl
compounds in the literature.
Compared to phenol-tethered systems, more is known about
the reactivity of α-diazoketones tethered to anisoles, particularly
in the well-established Buchner reaction (e.g. Scheme 3A).15
Various mechanistic and kinetic studies have been performed,
most notably by McKervey and Maguire,16 with much of this
work focused on the reactions of H-/Me-substituted α-
diazoketones. More recently, related reactions on α-diazoketones
substituted with electron-withdrawing substituents have also
emerged17 (‘acceptor-acceptor’ diazo compounds), for example,
the anisole annulation method developed by Doyle and co-
workers, depicted in Scheme 3B.17a Notably, the reaction
outcomes in these studies typically differ to those observed in the
analogous phenol systems, in which spirocyclic products usually
dominate.
with good chemoselectivity (entries
5 and 6), whereas
Pd(PhCN)2Cl2 unexpectedly formed 1,2-dicarbonyl 6a as the
major component (entry 7).

3
Table 1. Catalyst screening on diazoketone 3aa.
cyclopropane 4a and tetralone 5a required little additional
ACCEPTED MANUSCRIPT
optimisation; changes to the reaction solvents and catalyst
loadings were briefly examined, and optimal conditions were
uncovered that enabled each product to be isolated in 83% and
79% yield respectively, using either 2 mol% Ag2O or 10 mol%
AgOTf, both in CH2Cl2 at room temperature (Scheme 4). We
were also able to perform a subsequent Diels–Alder reaction on
cyclopropane product 4a with dimethyl acetylenedicarboxylate
21 to generate compound 22a in good yield. This adds support to
the notion that compound 4a is norcaradiene-like in character.
Entry
Catalyst
Rh2(OAc)4
CuCl
3a : 4a : 5a : 6ab
15 : 65 : 0 : 20
5 : 85 : 0 : 10
0 : 80 : 0 : 20
0 : 95 : 0 : 5
1c
2
3
4
5
6
7
Pd(OAc)2
Ag2O
Cu(OTf)2
AgOTf
10 : 0 : 90 : 0
0 : 0 : 100 : 0
0 : 0 : 15 : 85d
Pd(PhCN)2Cl2
a Reactions were performed with 0.1 mmol of diazoketone 3a
and 10 mol% catalyst in CH2Cl2 (0.1 M) under argon at RT for
b
16 h unless stated otherwise. Product ratio was calculated using
the 1H NMR spectrum of the unpurified reaction mixture,
c
d
rounded to nearest 5%. 5 mol% catalyst used. Other minor
impurities (unidentified) were observed in this case.
Scheme 4. Formation of cyclopropane 4a and tetralone 5a.
In our initial catalyst screen, the most effective catalyst for the
preparation of 1,2-dicarbonyl 6a was Ph(PhCN)2Cl2, but after
further optimisation, we were unable to get full and clean
conversion into this product, with unwanted side products
(especially tetralone 5a) contaminating the desired product in all
cases. Of course, this reaction is a formal oxidation process, but
with no obvious oxidant present in the reaction, we reasoned that
adventitious impurities (in particular oxygen and water), may be
required for this transformation. However, changes to the solvent
and reagent quantities failed to deliver an improved procedure;
the addition of 1 equivalent of water, performing the reaction
open to air and purging the reaction solvent with oxygen failed to
improve the yield of this oxidation process. Pleasingly however,
we found that we could access this third product more reliably
using conditions originally reported by Toste et al; thus, 1,2-
diketone 6a was isolated in 90% yield following treatment with a
mixed Ag(I)/Au(I) catalyst system in the presence of diphenyl
sulfoxide (Scheme 5)22
Thus, these initial screening reactions uncovered three
complementary metal-catalysed processes to access three distinct
products. It is likely that products 4a and 5a are mechanistically
related; Scheme 3 shows a proposed mechanistic pathway
through which cyclopropane 4a could be converted into tetralone
5a. Presumably, following metal-mediated diazo decomposition,
Buchner cyclopropanation of the electron-rich anisole ring takes
place to form cyclopropane 4a which is in dynamic equilibrium
with cyclohepatriene 4a' arising from reversible electrocyclic
ring opening.19 Under certain conditions (e.g. Table 1, entries 1–
4) the cyclopropane/cyclohepatriene equilibrating mixture 4a/4a'
is isolable, but under more acidic conditions (for example, in the
presence of comparatively Lewis acidic catalysts such as
Cu(OTf)2 or AgOTf, see Table 1, entries 5 and 6) we propose that
Lewis acid-mediated20 ring expansion and tautomerisation (4a →
20 → 5a) results in its conversion into tetralone 5a.16b,21 In
support of this, it was observed that a purified sample of
cyclopropane 4a can be converted into tetralone 5a smoothly
upon treatment under our standard Ag(I)-mediated conditions
(c.f. Table 1, entry 6).
Scheme 5. Synthesis of 1,2-dicarbonyl 6a.
2.2. Phenol-tethered α-diazoketones
Given that para-anisole derivatives have been successfully
used23 in dearomatising spirocyclisation24 reactions to make
spirocyclic dienones via other electrophilic activation modes, we
were somewhat surprised that none of the catalysts tested on
anisole 3a delivered spirocycle 7. However, based on precedent
for the formation of spirocyclic dienones from related phenol
derivatives,11-13, 25 we were optimistic that shifting focus to the
analogous phenol-tethered α-diazoketone 3b would facilitate
access to this medicinally important compound class.26 Thus, the
Scheme 3. Buchner cyclisation and rearrangement.
Attention next turned to further optimising each of the three
individual processes. Pleasingly, the selective formation of

4
Tetrahedron
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same metal catalysts previously used on anisole system 3a,
formation of its phenol analogue 4b, but instead promoted
were tested on the new phenol substrate 3b, with full screening
results included in the Supporting Information. As we hoped,
many of the catalysts screened delivered spirocycle 7 as the
major product, along with 1,2-dicarbonyl 6a and other
unidentified minor impurities in some cases. The most effective
catalyst at promoting spirocyclisation was Cu(OTf)2; thus, the
treatment of α-diazoketone 3b with 5 mol% Cu(OTf)2 for 3 h at
RT in CH2Cl2 afforded spirocycle 7, which was isolated in 70%
yield (Scheme 6). The selective formation of this forth structural
class nicely complements the anisole studies outlined above
(Scheme 3–5).
desilylation and rearrangement to form spirocycle 7 in 67% yield,
presumably via the mechanism shown in Scheme 8. Thus, it
appears that cyclopropane 4b is unstable with respect to collapse
to spirocycle 7, which certainly helps to explain why we were
unable to isolate any products other than 7 from the phenol-
tethered α-diazoketone starting material 3b. Compound 4c is a
good Diels–Alder substrate, reacting with dimethyl
acetylenedicarboxylate 21 to form 22c in high yield, and
subsequent TBS-cleavage with TBAF afforded its ketone
derivative 22b in 85% yield.
The desilylation of 6c was more challenging; a variety of
deprotection conditions were tested on this substrate (TBAF at
−78 °C and at RT, TFA, TiCl4) but decomposition of starting
material 6c into a mixture of uncharacterisable products was
commonly observed. The best conditions we uncovered involved
reacting 6c with BF3·Et2O in CH2Cl2 at RT; deprotected diketone
6b was successfully formed using this method, although several
impurities were still obtained during this reaction, hence the
isolated yield (21%) is relatively low.
Scheme 6. Synthesis of spirocyclic dienone 7.
2.3. Silyl-protected α-diazoketones
As shown above, each of products 4a–6a can be selectively
obtained from anisole-tethered α-diazoketone 3a, while phenol-
tethered α-diazoketone 3b delivers spirocycle 7 in good yield, but
there is no crossover between the two series, meaning that the
phenol analogues of anisole products 4a–6a, (i.e. 4b–6b) were
inaccessible at this stage. To address this, it was decided to
examine a third α-diazoketone starting material (3c) in which the
tethered phenol is protected with a t-butyldimethylsilyl (TBS)
group. The expectation here was that this compound 3c would
react similarly to its anisole analogue 3a (to form TBS-protected
products 4c–6c), and that subsequent desilylation would enable
phenol derivatives 4b–6b to be isolated. Thus, TBS-protected α-
diazoketone 3c was reacted under the optimised conditions for
the preparation of 4a–6a (Scheme 7). First, the Ag2O-catalysed
conditions delivered the expected Buchner cyclopropane product
4c (as before, in dynamic equilibrium with its cyclohepatriene
form) in good yield. Next, the AgOTf conditions also worked
well, but proceeded with concomitant desilylation, affording
phenol-tetralone 5b directly in 86% yield, with none of its TBS-
protected analogue 5c observable. Finally, the oxidative
conditions proceeded as expected, to deliver 1,2-diketone 6c in
61% yield, with the TBS group still in place.
Scheme 8. Desilylation of 4c and 6c.
3. Conclusion
In conclusion, the first study of the divergent reactivity of
phenol/anisole-tethered donor-acceptor α-diazoketones has been
performed. In total, four distinct products classes have been
shown to be accessible, with the reaction outcome dependent on
the nature of the aromatic oxygen substituent and the catalyst
used to activate the diazo group. Anisole and TBS derivatives 3a
and 3c were both able to selectively produce three products types
(cyclopropanes, tetralones and 1,2-dicarbonyls 4–6) while phenol
derivative 3b produced only spirocycle 7, with this difference
believed to be a consequence of the instability of the phenol
Buchner cyclisation product 4b. These results are likely to be
useful from a synthetic standpoint, especially in diversity-
oriented synthesis. Furthermore, the insight gleaned from
studying a class of phenol/anisole-tethered α-diazoketones that
has previously not been examined is expected to be of value to
those interested in the study of diazo compounds and metal
carbenoids, complementing the important studies of related
systems summarised in the introduction.11-17
Scheme 7. Divergent reactivity of α-diazoketone 3c.
At this point, all that remained was to test whether desilylation of
products 4c and 6c could be achieved. Interestingly, treating
cyclopropane 4c with TBAF in THF at –78 °C, did not lead to the

5
4. Experimental
4.3.2. 4-(4-Methoxyphenyl)-1-phenylbutan-2-one
ACCEPTED MANUSCRIPT
To
a
solution of N-methoxy-3-(4-methoxyphenyl)-N-
4.1. General aspects
methylpropanamide (2.00 g, 8.96 mmol) in THF (90 mL) at 0 °C
under argon was added benzylmagnesium chloride (13.4 mL,
26.9 mmol, 2.0 M in THF) dropwise using a syringe pump. The
resulting solution was warmed to RT and stirred for 1.5 h. The
reaction was then cooled to 0 °C, quenched with sat. aq. NH4Cl
(20 mL), diluted with water (20 mL) and extracted with EtOAc
(3 x 30 mL). The organics were combined, washed with brine (20
mL), dried over MgSO4 and concentrated in vacuo. The crude
material was purified by column chromatography (9:1
hexane:EtOAc, then 8:2 hexane:EtOAc) to afford the title
compound as a clear and colourless oil (1.76 g, 77%); Rf 0.70
(7:3 hexane:EtOAc); νmax (thin film)/cm-1 2908, 1712, 1512,
1245, 1178, 1033, 830, 735, 699; δH (400 MHz, CDCl3) 2.72–
2.78 (2H, m), 2.79–2.86 (2H, m), 3.67 (2H, s), 3.79 (3H, s), 6.81
(2H, d, J = 8.0 Hz), 7.06 (2H, d, J = 8.0 Hz), 7.18 (2H, d, J = 7.0
Hz), 7.25–7.36 (3H, m); δC (100 MHz, CDCl3) 28.9, 43.7, 50.4,
55.2, 113.8, 127.0, 128.7, 129.2, 129.4, 132.9, 134.1, 157.9,
207.6; HRMS (ESI+): Found: 277.1189; C17H18NaO2 (MNa+)
Requires 277.1199.
Except where stated, all reagents were purchased from
commercial sources and used without further purification and all
experimental procedures were carried out under an atmosphere of
argon unless stated otherwise. Anhydrous CH2Cl2, toluene,
MeCN and DMF were obtained from an Innovative Technology
Inc. PureSolv® solvent purification system. Anhydrous THF was
obtained by distillation over sodium benzophenone ketyl
1
immediately before use. H NMR and 13C NMR spectra were
recorded on a JEOL ECX400 or JEOL ECS400 spectrometer,
operating at 400 MHz and 100 MHz, respectively. All spectral
data was acquired at 295 K. Chemical shifts (δ) are quoted in
parts per million (ppm). The residual solvent peaks, δH 7.27 and
δC 77.0 for CDCl3 and δH 3.31 and δc 49.1 for CD3OD were used
as a reference. Coupling constants (J) are reported in Hertz (Hz)
to the nearest 0.5 Hz. The multiplicity abbreviations used are: s
singlet, d doublet, t triplet, q quartet, m multiplet. Signal
assignment was achieved by analysis of DEPT, COSY, HMBC
and HSQC experiments where required. Infrared (IR) spectra
were recorded on a PerkinElmer UATR 2 Spectrometer as a thin
film dispersed from either CH2Cl2 or CDCl3. Mass spectra (high-
resolution) were obtained by the University of York Mass
Spectrometry Service, using Electrospray Ionisation (ESI) or
Liquid Injection Field Desorption Ionisation (LIFDI) on a Bruker
Daltonics, Micro-tof spectrometer. Melting points were
determined using Gallenkamp apparatus and are uncorrected.
Thin layer chromatography was carried out on Merck silica gel
60F254 pre-coated aluminium foil sheets and were visualised
using UV light (254 nm) and stained with basic aqueous
potassium permanganate. Flash column chromatography was
carried out using slurry packed Fluka silica gel (SiO2), 35–70 ꢀm,
60 Å, under a slight positive pressure, eluting with the specified
solvent system.
4.3.3. 1-Diazo-4-(4-methoxyphenyl)-1-phenylbutan-2-one (3a)
To a solution of 4-(4-methoxyphenyl)-1-phenylbutan-2-one
(977 mg, 3.84 mmol) and p-ABSA (1.11 g, 4.61 mmol) in MeCN
(11.5 mL) at RT under argon was added DBU (0.8 mL, 5.38
mmol) dropwise. The resulting solution was stirred for 50 min
before being concentrated in vacuo. The crude material was
purified by column chromatography (9:1 hexane:EtOAc then 7:3
hexane:EtOAc with 3% Et3N as a basic additive) to afford the
title compound 3a as a yellow solid (797 mg, 74%); mp 79–81
°C; Rf 0.73 (7:3 hexane:EtOAc); νmax (thin film)/cm-1 3009, 2951,
2836, 2074, 1631, 1611, 1511, 1497, 1362, 1246, 1176, 1034,
821, 753; δH (400 MHz, CDCl3) 2.87 (2H, t, J = 7.5 Hz), 2.99
(2H, t, J = 7.5 Hz), 3.97 (3H, s), 6.84 (2H, d, J = 8.5 Hz), 7.13
(2H, d, J = 8.5 Hz), 7.27 (1H, t, J = 7.5 Hz), 7.41 (2H, dd, J =
8.0, 7.5 Hz), 7.47 (2H, d, J = 8.0 Hz); δC (100 MHz, CDCl3) 29.8,
41.1, 55.2, 72.3, 113.9, 125.4, 126.1, 127.0, 129.0, 129.4, 132.7,
158.1, 192.0; HRMS (LIFDI+): Found: 280.1211; C17H16N2O2
(M+) Requires 280.1212.
4.2. General procedure A: Preparation of Weinreb amides
To a stirred solution of acid (1.00 mmol), MeNH(OMe)·HCl
(107 mg, 1.10 mmol) and DIPEA (0.52 mL, 3.00 mmol) in
CH2Cl2 (2.5 mL) was added T3P 50% in EtOAc (955 mg, 1.50
mmol). The solution was stirred at RT until completion was
observed by TLC. The reaction mixture was poured into water
(20 mL) and acidified using 10% aq. HCl (5 mL). The organics
were collected and the aqueous extracted with EtOAc (3 × 30
mL). The organics were combined, washed with aq. 2 M NaOH
(20 mL), brine (20 mL), dried over MgSO4 and concentrated in
vacuo to afford the Weinreb amide product.
4.3.4. 5-Methoxy-3a-phenyl-3a,3b-dihydro-1H-
cyclopenta[1,3]cyclopropa[1,2]benzen-3(2H)-one (4a)
A flame-dried round-bottomed flask was charged with 1-
diazo-4-(4-methoxyphenyl)-1-phenylbutan-2-one 3a (100 mg,
0.357 mmol) and Ag2O (1.7 mg, 7.13 µmol) and purged with
argon for 10 min. Anhydrous CH2Cl2 (3.6 mL) was degassed
with argon for 20 min before adding to the diazo/catalyst
mixture. The reaction mixture was then stirred at RT for 22.5 h
before being concentrated in vacuo to afford the crude product.
The crude material was purified by column chromatography (9:1
hexane:EtOAc) to afford the title compound 4a as a pale yellow
oil (74.5 mg, 83%); Rf 0.33 (9:1 hexane:EtOAc); νmax (thin
film)/cm-1 3028, 2934, 2829, 1745, 1715, 1647, 1489, 1446,
1416, 1219, 1167, 1109, 1020, 816, 756; δH (400 MHz, CDCl3)
2.33–2.45 (1H, m), 2.55–2.67 (1H, m), 2.72–2.82 (1H, m), 2.83–
2.95 (1H, m), 3.41 (3H, s), 5.07 (1H, br d, J = 8.5 Hz), 5.60 (1H,
d, J = 8.0 Hz), 5.87 (1H, d, J = 8.5 Hz), 6.38 (1H, d, J = 8.0 Hz),
7.14–7.24 (5H, m); δC (100 MHz, CDCl3) 27.4, 34.8, 54.6, 109.1,
115.5, 123.3, 126.9, 127.7, 128.5, 136.6, 157.2, 215.7; HRMS
(ESI+): Found: 275.1040; C17H16NaO2 (MNa+) Requires
275.1043, Found: 253.1222; C17H17O2 (MH+) Requires 253.1223.
Note: 1 13C NMR signal was not observed, presumably due to
peak broadening arising from the Buchner rearrangement.
4.3. Experimental procedures
4.3.1. N-Methoxy-3-(4-methoxyphenyl)-N-methylpropanamide
Synthesised using general procedure
A
with 3-(4-
hydroxyphenyl)propanoic acid (7.00 g, 38.8 mmol), T3P 50% in
EtOAc (37.0 g, 58.3 mmol), DIPEA (20.3 mL, 116 mmol) and
MeNH(OMe)·HCl (4.20 g, 42.7 mmol) in CH2Cl2 (100 mL) at
RT for 1 h. Afforded the title compound without further
purification as a yellow oil (8.70 g, 100%); Rf 0.46 (1:1
hexane:EtOAc); δH (400 MHz, CDCl3) 2.71 (2H, t, J = 7.5 Hz),
2.91 (2H, t, J = 7.5 Hz), 3.18 (3H, s), 3.61 (3H, s), 6.84 (2H, d, J
= 8.0), 7.15 (2H, d, J = 8.0 Hz); δC (100 MHz, CDCl3) 29.8, 32.1,
34.0, 55.2, 61.2, 113.8, 129.3, 133.4, 157.9, 173.7; HRMS
(ESI+): Found: 246.1097; C12H17NNaO3 (MNa+) Requires
246.1101, Found: 224.1277; C12H18NO3 (MH+) Requires
224.1281. Spectroscopic data matched those previously reported
in the literature.27
4.3.5. (3bR,4R,7R,7aR)-Dimethyl 8-methoxy-3-oxo-3a-phenyl-
2,3,3a,3b,4,7-hexahydro-1H-4,7-

6
Tetrahedron
ACCEPTED MANUSCRIPT
ethenocyclopenta[1,3]cyclopropa[1,2]benzene-5,6-
Synthesised using general procedure
A
with 3-(4-
dicarboxylate (22a)
hydroxyphenyl)propanoic acid (7.00 g, 42.1 mmol), T3P 50% in
EtOAc (40.2 g, 63.2 mmol), DIPEA (22.0 mL, 126 mmol) and
MeNH(OMe)·HCl (4.50 g, 46.3 mmol) in CH2Cl2 (105 mL) at
RT for 1 h. Afforded the title compound without further
purification as a yellow oil (7.61 g, 86%); Rf 0.21 (1:1
hexane:EtOAc); νmax (thin film)/cm-1 3263, 2938, 1632, 1614,
1593, 1515, 1446, 1388, 1266, 1228, 1172, 987; δH (400 MHz,
CDCl3) 2.72 (2H, t, J = 7.5 Hz), 2.90 (2H, t, J = 7.5 Hz), 3.19
(3H, s), 3.61 (3H, s), 5.85 (1H, br s), 6.77 (2H, d, J = 8.0), 7.08
(2H, d, J = 8.0 Hz); δC (100 MHz, CDCl3) 29.8, 32.2, 34.0, 61.2,
115.3, 129.5, 133.0, 154.3, 173.9; HRMS (ESI+): Found:
232.09591; C11H15NNaO3 (MNa+) Requires 232.0944, Found:
210.1127; C11H16NO3 (MH+) Requires 210.1125.
A round-bottomed flask was charged with cyclopropane 4a
(65 mg, 0.258 mmol) in toluene (0.5 mL) under argon. dimethyl
acetylenedicarboxylate 21 (63 µL, 0.515 mmol) was added and
the reaction mixture was stirred at 80 °C for 24 h. The reaction
mixture was then cooled to RT and concentrated in vacuo to
afford the crude product. The crude material was purified by
column chromatography (7:3 hexane:EtOAc) to afford the title
compound 22a as a clear and colourless oil (83.4 mg, 82%); Rf
0.21 (7:3 hexane:EtOAc); νmax (thin film)/cm-1 2952, 1713, 1653,
1626, 1435, 1265, 1211, 1111, 1058, 1007, 915, 728; δH (400
MHz, CDCl3) 1.83 (1H, d, J = 4.0 Hz), 2.17–2.31 (2H, m), 2.36–
2.49 (5H, m), 3.80 (3H, s), 3.85 (3H, s), 4.09–4.13 (2H, m), 4.33
(1H, dd, J = 7.0, 3.0 Hz), 6.89–6.93 (1H, m), 7.12 (1H, d, J = 7.5
Hz), 7.15–7.23 (2H, m), 7.29–7.34 (1H, m); δC (100 MHz,
CDCl3) 27.1, 33.6, 35.4, 44.0, 44.7, 52.3, 52.4, 52.8, 54.6, 60.2,
99.1, 126.5, 127.3, 128.1, 130.1, 130.5, 133.7, 144.0, 152.9,
160.6, 165.0, 167.2, 211.8; HRMS (ESI+): Found: 417.1316;
C23H22NaO6 (MNa+) Requires 417.1309, Found: 395.1485;
C23H23O6 (MH+) Requires 395.1489.
4.3.9. 4-(4-Hydroxyphenyl)-1-phenylbutan-2-one
To
a
solution of 3-(4-hydroxyphenyl)-N-methoxy-N-
methylpropanamide (1.53 g, 7.31 mmol) in THF (70 mL) at 0 °C
under argon was added benzylmagnesium chloride (14.6 mL,
29.2 mmol, 2.0 M in THF) dropwise using a syringe pump. The
resulting solution was warmed to RT and stirred for 2 h. The
reaction was then cooled to 0 °C, quenched with sat. aq. NH4Cl
(20 mL), diluted with water (20 mL) and extracted with EtOAc
(3 x 30 mL). The organics were combined, washed with brine (20
mL), dried over MgSO4 and concentrated in vacuo. The crude
material was purified by column chromatography (9:1
hexane:EtOAc then 3:2 hexane:EtOAc) to afford the title
compound as a white solid (1.51 g, 86%); mp 112–114 °C; Rf
0.46 (6:4 hexane:EtOAc); νmax (thin film)/cm-1 3387, 3027, 2929,
1707, 1614, 1515, 1451, 1362, 1221, 833, 741, 699; δH (400
MHz, CD3OD) 2.68–2.81 (4H, m), 3.68 (2H, s), 6.66 (2H, d, J =
8.0 Hz), 6.93 (2H, d, J = 8.0 Hz), 7.11–7.17 (2H, m), 7.19–7.33
(3H, m); δC (100 MHz, CD3OD) 30.2, 44.9, 51.0, 116.3, 128.0,
129.7, 130.4, 130.7, 133.2, 136.0, 156.8, 210.7; HRMS (ESI+):
Found: 263.1034; C16H16NaO2 (MNa+) Requires 263.1043.
4.3.6. 7-Methoxy-1-phenyl-3,4-dihydronaphthalen-2(1H)-one
(5a)
A flame-dried round-bottomed flask was charged with 1-
diazo-4-(4-methoxyphenyl)-1-phenylbutan-2-one 3a (100 mg,
0.357 mmol) and AgOTf (9.2 mg, 35.7 µmol) and purged with
argon for 10 min. Anhydrous CH2Cl2 (3.6 mL) was degassed
with argon for 20 min before adding to the diazo/catalyst
mixture. The reaction mixture was then stirred at RT for 16 h
before being concentrated in vacuo to afford the crude product.
The crude material was purified by column chromatography (9:1
hexane:EtOAc) to afford the title compound 5a as a yellow oil
(71.1 mg, 79%); Rf 0.38 (9:1 hexane:EtOAc); νmax (thin film)/cm-
1 2940, 2844, 1714, 1611, 1502, 1450, 1260, 1156, 1037, 729; δH
(400 MHz, CDCl3) 2.52–2.61 (1H, m), 2.72 (1H, ddd, J = 17.0,
6.5, 6.0 Hz), 2.93–3.11 (2H, m), 3.75 (3H, s), 4.72 (1H, s), 6.56
(1H, d, J = 2.5 Hz), 6.84 (1H, dd, J = 8.0, 2.5 Hz), 7.12 (2H, d, J
= 7.5 Hz), 7.21 (1H, d, J = 8.0 Hz), 7.24–7.34 (3H, m); δC (100
MHz, CDCl3) 27.2, 37.2, 55.2, 59.9, 113.0, 114.6, 127.2, 128.56,
128.64, 128.8, 129.0, 137.3, 137.6, 158.7, 209.6; HRMS (ESI+):
Found: 275.1044; C17H16NaO2 (MNa+) Requires 275.1043,
Found: 253.1232; C17H17O2 (MH+) Requires 253.1223.
4.3.10. 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-phenylbutan-
2-one
To a solution of 4-(4-hydroxyphenyl)-1-phenylbutan-2-one
(1.39 g, 5.77 mmol) in anyhrous DMF (11.5 mL) was added
imidazole (590 mg, 8.66 mmol) at 0 °C. TBSCl (1.30 g, 8.66
mmol) was then added at 0 °C and then the reaction was warmed
to RT and stirred for 2 h. The reaction mixture was then diluted
with Et2O (20 mL) and the organic layer was washed with water
(3 x 30 mL). The organic layer was then washed with brine (20
mL), dried over MgSO4 and concentrated in vacuo. The crude
material was purified by column chromatography (9:1
hexane:EtOAc) afforded the title compound as a white solid
(1.53 g, 75%); mp 64–66 °C; Rf 0.51 (9:1 hexane:EtOAc); νmax
(thin film)/cm-1 2955, 2931, 2859, 1708, 1510, 1255, 910, 839,
779, 732; δH (400 MHz, CDCl3) 0.19 (6H, s), 0.99 (9H, s), 2.71–
2.77 (2H, m), 2.78–2.84 (2H, m), 3.66 (2H, s), 6.74 (2H, d, J =
8.0 Hz), 6.99 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 7.5 Hz), 7.24–
7.36 (3H, m); δC (100 MHz, CDCl3) −4.5, 18.2, 25.7, 29.0, 43.7,
50.4, 120.0, 127.0, 128.7, 129.2, 129.4, 133.5, 134.1, 153.9,
207.7; HRMS (ESI+): Found: 377.1905; C22H30NaO2Si (MNa+)
Requires 377.1907, Found: 355.2084; C22H31O2Si (MH+)
Requires 355.2088.
4.3.7. 4-(4-Methoxyphenyl)-1-phenylbutane-1,2-dione (6a)
To a solution of 1-diazo-4-(4-methoxyphenyl)-1-phenylbutan-
2-one 3a (30.0 mg, 0.107 mmol) in CH2Cl2 (0.5 mL) was added
diphenyl sulfoxide (86.6 mg, 0.428 mmol). This solution was
then added to a premixed solution of Ph3PAuCl (2.65 mg, 5.35
µmol) and AgSbF6 (1.84 mg, 5.35 µmol) in CH2Cl2 (0.5 mL)
cooled to 0 °C, the vial containing diazo solution was also rinsed
with CH2Cl2 (0.2 mL). The reaction mixture was stirred at 0 °C
for 2 h. The crude mixture was concentrated in vacuo to afford
the crude product. The crude material was purified by column
chromatography (9:1 hexane:EtOAc) to afford the title compound
6a as a yellow oil (25.9 mg, 90%); Rf 0.32 (9:1 hexane:EtOAc);
νmax (thin film)/cm-1 2934, 2836, 1711, 1670, 1596, 1449, 1245,
1177, 1033, 825, 689; δH (400 MHz, CDCl3) 3.00 (2H, t, J = 7.5
Hz), 3.21 (2H, t, J = 7.5 Hz), 3.79 (3H, s), 6.83 (2H, d, J = 8.5
Hz), 7.15 (2 H, d, J = 8.5 Hz), 7.48 (2 H, dd, J = 7.5, 7.5 Hz),
7.64 (1 H, t, J = 7.5 Hz), 7.91 (2 H, d, J = 7.5 Hz); δC (100 MHz,
CDCl3) 28.0, 40.4, 55.2, 113.9, 128.7, 129.4, 130.2, 131.8, 132.1,
134.6, 158.1, 192.1, 202.4; HRMS (ESI+): Found: 291.0990;
C17H16NaO3 (MNa+) Requires 291.0992.
4.3.11. 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-diazo-1-
phenylbutan-2-one (3c)
To a solution of 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-
phenylbutan-2-one (150 mg, 0.423 mmol) and p-ABSA (122 mg,
0.508 mmol) in MeCN (1.5 mL) at RT under argon was added
DBU (88.5 µL, 0.592 mmol) dropwise. The resulting solution
was stirred for 1 h before being concentrated in vacuo. The crude
material was purified by column chromatography (9:1
4.3.8. 3-(4-Hydroxyphenyl)-N-methoxy-N-methylpropanamide

7
hexane:EtOAc with 3% Et3N as a basic additive) to afford the
A flame-dried round-bottomed flask was charged with 4-(4-
((tert-butyldimethylsilyl)oxy)phenyl)-1-diazo-1-phenylbutan-2-
ACCEPTED MANUSCRIPT
title compound 3c as an orange oil (109 mg, 68%); Rf 0.49 (9:1
hexane:EtOAc); νmax (thin film)/cm-1 2955, 2929, 2857, 2067,
1648, 1509, 1497, 1252, 1204, 912, 838, 780, 1176, 1034, 821,
753; δH (400 MHz, CDCl3) 0.19 (6H, s), 0.98 (9H, s), 2.86 (2H, t,
J = 7.5 Hz), 2.97 (2H, t, J = 7.5 Hz), 6.76 (2H, d, J = 8.0 Hz),
7.06 (2H, d, J = 8.0 Hz), 7.24–7.29 (1H, m), 7.41 (2H, dd, J =
8.0, 7.5 Hz), 7.46 (2H, d, J = 8.0 Hz); δC (100 MHz, CDCl3)
−4.5, 18.2, 25.7, 30.1, 41.0, 72.4, 120.1, 124.1, 126.1, 127.1,
129.0, 129.3, 133.2, 154.1, 192.1; HRMS (ESI+): Found:
403.1816; C22H28N2NaO2Si (MNa+) Requires 403.1812.
one 3c (150 mg, 0.394 mmol) and Ag2O (4.57 mg, 19.7 µmol)
and purged with argon for 10 min. Anhydrous CH2Cl2 (3.9 mL)
was degassed with argon for 20 min before adding to the
diazo/catalyst mixture. The reaction mixture was then stirred at
RT for 16 h before being concentrated in vacuo to afford the
crude product. The crude material was purified by column
chromatography (10:1 hexane:EtOAc) to afford the title
compound 4c as a yellow oil (110 mg, 79%); Rf 0.42 (9:1
hexane:EtOAc); νmax (thin film)/cm-1 2955, 2929, 2857, 1747,
1622, 1407, 1252, 1202, 1183, 1110, 900, 873, 837, 781, 749; δH
(400 MHz, CDCl3) −0.36 (3H, s), −0.27 (3H, s), 0.77 (9H, s),
2.38 (1H, ddd, J = 18.0, 9.0, 6.5 Hz), 2.64 (1H, ddd, J = 18.0,
11.0, 7.0 Hz), 2.80–3.03 (2H, m), 5.41 (1H, d, J = 9.5 Hz), 5.76
(1H, d, J = 7.5 Hz), 5.98 (1H, d, J = 9.5 Hz), 6.41 (1H, d, J = 7.5
Hz), 7.11–7.21 (3H, m), 7.21–7.26 (2H, m); δC (100 MHz,
CDCl3) −5.4, −5.1, 17.8, 25.4, 27.3, 35.3, 56.9, 114.0, 116.1,
122.4, 123.8, 127.1, 127.74, 127.79, 137.4, 153.2, 216.0; HRMS
(ESI+): Found: 353.1939; C22H29O2Si (MH+) Requires 353.1931.
Note: 1 13C NMR signal was not observed, presumably due to
peak broadening arising from the Buchner rearrangement.
4.3.12. 1-Diazo-4-(4-hydroxyphenyl)-1-phenylbutan-2-one (3b)
To a solution of 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-
diazo-1-phenylbutan-2-one 3c (785 mg, 2.06 mmol) in THF (4
mL) at 0 °C was added TBAF (3.09 mL, 3.09 mmol, 1 M
solution in THF). The resulting solution was warmed to RT and
stirred for 30 min. The reaction mixture was then diluted with
Et2O (10 mL) and washed with water (10 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo to afford the
title compound 3b without further purification as a yellow solid
(509 mg, 93%); mp 77–79 °C; Rf 0.63 (6:4 hexane:EtOAc); νmax
(thin film)/cm-1 3361, 2077, 1612, 1515, 1497, 1448, 1370, 1205,
830, 756; δH (400 MHz, CDCl3) 2.86 (2H, t, J = 7.5 Hz), 2.97
(2H, t, J = 7.5 Hz), 4.70 (1H, br s), 6.76 (2H, d, J = 8.5 Hz), 7.08
(2H, d, J = 8.5 Hz), 7.24–7.29 (1H, m), 7.41 (2H, dd, J = 8.0, 7.5
Hz), 7.47 (2H, d, J = 7.5 Hz); δC (100 MHz, CDCl3) 30.0, 41.1,
72.6, 115.4, 125.4, 126.2, 127.2, 129.0, 129.5, 132.5, 154.2,
192.4; HRMS (ESI+): Found: 289.0951; C16H14N2NaO2 (MNa+)
Requires 289.0947.
4.3.15. 7-Hydroxy-1-phenyl-3,4-dihydronaphthalen-2(1H)-one
(5b)
A flame-dried round-bottomed flask was charged with 4-(4-
((tert-butyldimethylsilyl)oxy)phenyl)-1-diazo-1-phenylbutan-2-
one 3c (150 mg, 0.394 mmol) and AgOTf (10.1 mg, 39.4 µmol)
and purged with argon for 10 min. Anhydrous CH2Cl2 (3.9 mL)
was degassed with argon for 20 min before adding to the
diazo/catalyst mixture. The reaction mixture was then stirred at
RT for 16 h before being concentrated in vacuo to afford the
crude product. The crude material was purified by column
chromatography (7:3 hexane:EtOAc) to afford the title compound
5b as an orange oil (80.9 mg, 86%); Rf 0.38 (7:3 hexane:EtOAc);
νmax (thin film)/cm-1 3372, 3027, 1704, 1612, 1587, 1493, 1450,
1342, 1297, 1232, 1153, 821; δH (400 MHz, CDCl3) 2.57 (1H,
ddd, J = 17.0, 6.5, 6.5 Hz), 2.70 (1H, ddd, J = 17.0, 6.5, 6.5 Hz),
2.91–3.09 (2H, m), 4.66 (1H, s), 5.63 (1H, br s), 6.46 (1H, d, J =
2.5 Hz), 6.76 (1H, dd, J = 8.0, 2.5 Hz), 7.10 (2H, d, J = 7.0 Hz),
7.14 (1H, d, J = 8.0 Hz), 7.25–7.33 (3H, m); δC (100 MHz,
CDCl3) 27.3, 37.3, 59.7, 114.5, 116.0, 127.3, 128.69, 128.71,
128.8, 129.1, 137.2, 137.7, 154.9, 210.5; HRMS (ESI+): Found:
261.0885; C16H14NaO2 (MNa+) Requires 261.0886.
4.3.13. 1-Phenylspiro[4.5]deca-6,9-diene-2,8-dione (7)
Method 1: A flame-dried round-bottomed flask was charged
with 1-diazo-4-(4-hydroxyphenyl)-1-phenylbutan-2-one 3b (38
mg, 0.143 mmol) and Cu(OTf)2 (2.6 mg, 7.14 µmol) and purged
with argon for 10 min. Anhydrous CH2Cl2 (1.4 mL) was
degassed with argon for 20 min before adding to the
diazo/catalyst mixture. The reaction mixture was then stirred at
RT for 3 h before being concentrated in vacuo to afford the crude
product. The crude material was purified by column
chromatography (1:1 hexane:EtOAc) to afford the title compound
7 as a yellow solid (23.4 mg, 70%); mp 135–137 °C; Rf 0.21 (6:4
hexane:EtOAc); νmax (thin film)/cm-1 3035, 1746, 1663, 1622,
1499, 1135, 868, 700; δH (400 MHz, CDCl3) 2.17 (1H, ddd, J =
13.5, 8.5, 2.5 Hz), 2.32–2.42 (1H, m), 2.64–2.84 (2H, m), 3.75
(1H, s), 6.14 (1H, dd, J = 10.0, 2.0 Hz), 6.32 (1H, dd, J = 10.0,
2.0 Hz), 6.86 (1H, dd, J = 10.0, 3.0 Hz), 6.93–6.97 (2H, m), 7.00
(1H, dd, J = 10.0, 3.0 Hz), 7.21–7.29 (3H, m); δC (100 MHz,
CDCl3) 31.4, 35.3, 51.4, 65.5, 127.9, 128.3, 129.4, 130.1, 130.5,
132.5, 147.5, 152.4, 185.3, 213.1; HRMS (ESI+): Found:
261.0875; C16H14NaO2 (MNa+) Requires 261.0886, Found:
239.1057; C16H15O2 (MH+) Requires 239.1067.
4.3.16. 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-
phenylbutane-1,2-dione (6c)
A heterogeneous solution of Ph3PAuCl (32.5 mg, 65.7 µmol)
and AgSbF6 (22.5 mg, 65.7 µmol) in CH2Cl2 (6 mL) was stirred
for 5 min under air and cooled to 0 °C. A solution of 4-(4-((tert-
butyldimethylsilyl)oxy)phenyl)-1-diazo-1-phenylbutan-2-one 3c
(500 mg, 1.31 mmol) and diphenyl sulfoxide (1.06 g, 5.24 mol)
in CH2Cl2 (6 mL) was then added to the catalyst mixture at 0 °C
and the reaction mixture was stirred under air for 1.5 h. The
reaction mixture was then concentrated in vacuo to afford the
crude product. The crude material was purified by column
chromatography (20:1 hexane:EtOAc) to afford the title
compound 6c as a yellow oil (294 mg, 61%); Rf 0.70 (9:1
hexane:EtOAc); νmax (thin film)/cm-1 2955, 2930, 2858, 1713,
1672, 1509, 1253, 912, 838, 781; δH (400 MHz, CDCl3) 0.18
(6H, s), 0.98 (9H, s), 2.98 (2H, t, J = 7.5 Hz), 3.21 (2H, t, J = 7.5
Hz), 6.76 (2H, d, J = 8.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 7.48 (2H,
dd, J = 7.5, 7.5 Hz), 7.64 (1H, t, J = 7.5 Hz), 7.91 (2H, d, J = 7.5
Hz); δC (100 MHz, CDCl3) −4.5, 18.2, 25.7, 28.1, 40.4, 120.1,
128.8, 129.3, 130.2, 131.8, 132.7, 134.6, 154.1, 192.1, 202.5;
HRMS (ESI+): Found: 391.1705; C22H28NaO3Si (MNa+) Requires
391.1700.
Method 2: To a solution of 5-((tert-butyldimethylsilyl)oxy)-
3a-phenyl-3a,3b-dihydro-1H-
cyclopenta[1,3]cyclopropa[1,2]benzen-3(2H)-one 4c (36.8 mg,
0.104 mmol) in THF (0.6 mL) at −78 °C was added TBAF (0.16
mL, 0.156 mmol, 1 M solution in THF) dropwise to afford an
orange solution. The resulting solution was stirred at −78 °C for 3
h. The reaction mixture was then quenched with water (10 mL)
and extracted with EtOAc (3 x 10 mL). The organics were
combined, dried over MgSO4 and concentrated in vacuo to afford
the crude product. The crude material was purified by column
chromatography (7:3 hexane:EtOAc, then 1:1 hexane:EtOAc) to
afford the title compound 7 as a yellow solid (16.6 mg, 67%).
4.3.14. 5-((tert-Butyldimethylsilyl)oxy)-3a-phenyl-3a,3b-dihydro-
1H-cyclopenta[1,3]cyclopropa[1,2]benzen-3(2H)-one (4c)

8
Tetrahedron
ACCEPTED MANUSCRIPT
hexane:EtOAc); νmax (thin film)/cm-1 3416, 3027, 2932, 1712,
4.3.17. (3bR,4S,7R,7aR)-Dimethyl 9-((tert-
butyldimethylsilyl)oxy)-3-oxo-3a-phenyl-2,3,3a,3b,4,7-
hexahydro-1H-4,7-
ethenocyclopenta[1,3]cyclopropa[1,2]benzene-5,6-dicarboxylate
(22c)
1669, 1596, 1515, 1449, 1254; δH (400 MHz, CDCl3) 2.98 (2H, t,
J = 7.5 Hz), 3.20 (2H, t, J = 7.5 Hz), 4.90 (1H, br s), 6.76 (2H, d,
J = 8.0 Hz), 7.10 (2H, d, J = 8.0 Hz), 7.48 (2H, dd, J = 8.0, 7.5
Hz), 7.64 (1H, t, J = 7.5 Hz), 7.91 (2H, d, J = 7.5 Hz); δC (100
MHz, CDCl3) 28.0, 40.4, 115.3, 128.8, 129.6, 130.2, 131.8,
132.3, 134.6, 154.0, 192.1, 202.5; HRMS (ESI+): Found:
277.0837; C16H14NaO3 (MNa+) Requires 277.0835.
A round-bottomed flask was charged with cyclopropane 4c
(191 mg, 0.541 mmol) in toluene (1.1 mL) under argon and
dimethyl acetylenedicarboxylate 21 (0.13 mL, 1.08 mmol) was
added and the reaction mixture stirred at 80 °C for 30 h. The
reaction mixture was then cooled to RT and concentrated in
vacuo to afford the crude product. The crude material was
purified by column chromatography (20:1 hexane:EtOAc, then
1:1 hexane:EtOAc) to afford the title compound 22c as a clear
and colourless oil (220 mg, 82%); Rf 0.58 (6:4 hexane:EtOAc);
νmax (thin film)/cm-1 2953, 2858, 1714, 1651, 1625, 1435, 1342,
1303, 1256, 1225, 1204, 1110, 1061, 913, 864, 839, 785; δH (400
MHz, CDCl3) −0.32 (3H, s), −0.19 (3H, s), 0.75 (9H, s), 1.80
(1H, d, J = 4.0 Hz), 2.13–2.33 (2H, m), 2.34–2.49 (2H, m), 3.81
(3H, s), 3.83 (3H, s), 3.91–3.95 (1H, m), 4.07 (1H, d, J = 6.5 Hz),
4.49 (1H, dd, J = 6.5, 3.0 Hz), 6.82 (1H, d, J = 7.5 Hz), 7.11–
7.22 (3H, m), 7.24–7.29 (1H, m); δC (100 MHz, CDCl3) −5.4,
−4.7, 17.9, 25.4, 27.2, 34.0, 35.4, 44.7, 47.0, 52.3, 52.4, 52.9,
60.4, 106.9, 126.5, 127.5, 128.2, 130.0, 130.6, 133.8, 146.1,
151.0, 156.7, 165.7, 166.8, 212.2; HRMS (ESI+): Found:
517.2017; C28H34NaO6Si (MNa+) Requires 517.2017, Found:
495.2195; C28H35O6Si (MH+) Requires 495.2197.
5. Acknowledgements
The authors would like to thank the University of York (A.K.C.,
W.P.U.) and the Leverhulme Trust (for an Early Career
Fellowship, ECF-2015-013, W.P.U.) for financial support. Dr
Michael J. James is thanked for useful advice.
6. Dedication
In recognition of the many contributions of Sir Derek Barton,
not least his memorable lectures on ‘The Invention of Chemical
Reactions’.
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