Regioselective synthesis of 1- and 4-tetralones from heteroaryl-3-cyclobutanols

Article abstract of DOI:10.1016/j.tet.2020.131636

Herein we describe the first transition-metal-free ring expansion of four-membered rings to 1-tetralones from 3-substituted heteroaromatic compounds, and the first example of an oxetanol ring expansion to an oxa-tetralone. We also experimentally investiga

Full text of DOI:10.1016/j.tet.2020.131636

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of 1- and 4-tetralones from heteroaryl-3-
cyclobutanols
Philipp Natho, Annie B. Rouse, Jake L. Greenfield, Lewis A.T. Allen, Andrew J.P. White,
Zeyu Yang, Philip J. Parsons*
Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, W12 0BZ, London, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe the first transition-metal-free ring expansion of four-membered rings to 1-tetralones
from 3-substituted heteroaromatic compounds, and the first example of an oxetanol ring expansion to an
oxa-tetralone. We also experimentally investigate the mechanism of the silver-mediated ring expansion
and elucidate the active oxidant in these systems using electrochemical techniques.
© 2020 Elsevier Ltd. All rights reserved.
Received 20 July 2020
Received in revised form
18 September 2020
Accepted 21 September 2020
Available online xxx
Keywords:
Cyclobutanols
Ring expansion
Heteroaromatics
Divergent synthesis
Cyclic voltammetry
1. Introduction
significant attention in medicinal chemistry [18e22]. Of particular
note are the synthetic heteroaromatic 1-tetralones 1 and 2, which
The cyclobutanol moiety has emerged as a valuable building
block for the introduction of skeletal diversity [1,2]. In the last
decade, a large number of distinctive protocols for the ring-opening
were shown to exhibit different biological activity, despite solely
varying in the heteroatom [19,22]. They exhibit in vitro cytotoxicity
against human non-small lung cancer (IC50 0.0703 mM) and mild
to
g
-functionalised materials and ring expansions to five-
in vitro antibacterial activity against gram-positive bacteria
respectively. The WHO essential drug ondansetron is the regioiso-
meric 4-tetralone, which is structurally related to 1 and acts as a
serotonin 5-HT3 receptor antagonist to prevent post-surgery
nausea or vomiting. These compounds demonstrate that (1) many
biologically active heteroaromatic fused 1-tetralones contain one or
more substituents on the cyclohexanone ring, (2) a change in het-
eroatom significantly impacts and changes the molecular mecha-
nism of action and biological target (cf. compounds 1 and 2), and (3)
a change in the regiochemical orientation of the tetralone moiety
also leads to a variation in the therapeutic action of the product (cf.
compound 1 and ondansetron).
membered rings was developed using transition-metal-free or
photo-/electrochemical techniques [3e9]. Protocols leading from
cyclobutanols to annulated six-membered rings however remain
limited, despite their clear utility [10e14].
Heterocycles annulated to six-membered ring ketones are a
common motif in pharmaceutically important molecules (Fig. 1).
For example, indole-based epi-20-dasycarpidone exhibits strong
in vitro inhibition against multi-drug resistant K1 strains of the
human malaria parasite Plasmodium falciparum (IC50 4.5
mg/mL)
[15]. Murrayafoline A, a carbazole, has been investigated as an
apoptosis inducer [16]. Benzofuran-based propolisbenzofuran B, on
the other hand, was found to show mild cytotoxicity toward murine
colon 26-L5 carcinoma, as well as human HT-1080 fibrosarcoma
cells (ED50 13.7 mg/mL and 43.2 mg/mL respectively) [17]. Also, non-
natural compounds with the same core structure have received
The development of ring expansion protocols for the direct
annulation of cyclobutanols onto aromatic rings started with
Uemura’s report of a palladium-mediated ring opening reaction of
cyclobutanols to aryl/vinyl-substituted ketones; for substrates
where
b-hydride elimination was blocked, 1-tetralone products
were isolated in up to 92% yield (Scheme 1, a) [13]. Over a decade
later, Murakami reported a rhodium-catalysed cyclobutanol ring
expansion to 1-tetralones in up to 96% yield, which hinged on the
* Corresponding author.
E-mail address: p.parsons@imperial.ac.uk (P.J. Parsons).
https://doi.org/10.1016/j.tet.2020.131636
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Natho, A.B. Rouse, J.L. Greenfield et al., Regioselective synthesis of 1- and 4-tetralones from heteroaryl-3-
cyclobutanols, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131636

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
Scheme 2. Divergent cyclobutanol ring expansions to heteroaromatic-fused 1-& 4-
tetralones from a common starting material (✓ ¼ Advantage).
synthesis of heteroaromatic-fused substituted 1- & 4-tetralones
from the same starting material (Scheme 2). We herein present
our studies on a general N-bromosuccinimide (NBS) mediated
cyclobutanol ring expansion to heteroaromatic-fused 1-tetralones,
which allows for the instalment of the required substituents on the
cyclohexanone ring and the variation of the heteroatom in the ar-
omatic system. Further, we draw a comparison to the silver(I)-
mediated ring expansion of the same starting materials to obtain
the regioisomeric 4-tetralones, and we justify the inferior perfor-
mance of this process in comparison to the NBS-mediated meth-
odology through cyclic voltammetry analysis.
Fig. 1. Natural and synthetic biologically active 1- & 4-tetralone derivatives.
2. Results and discussion
Our investigations began with the preparation of benzofuran-
substituted cyclobutanol 3a as a model substrate for the proposed
transformation. Lithium-halogen exchange of commercially avail-
able 3-bromobenzofuran in diethyl ether followed by addition of
cyclobutanone provided the desired 3-substituted cyclobutanol.
When cyclobutanol 3a was treated with NBS in acetonitrile, 1-
tetralone 4a was formed in 38% yield with full conversion of the
starting material achieved within 10 min (Scheme 3). The isolated
yield compares favourably with the 40% yield obtained in a silver-
mediated cyclobutanol ring expansion developed by Zhu et al.
[10] The advantages of this NBS-mediated approach to 1-tetralones
include the omission of transition metals, a significant reduction in
reaction duration (from 9 h to 10 min), and simplicity of operation
as evacuation/inert-fill cycles can be avoided.
Additionally, heteroaryl-substituted cyclobutanols 3b-i were
treated with NBS in acetonitrile at room temperature, forming 1-
tetralones 4b-i (Scheme 4). Benzothiophene and indole equiva-
lents 3b & 3c showed complete conversion in less than 15 min,
although the isolated yields were lower than for the benzofuran
model 3a. This observation was attributed to the more facile sta-
bilisation of the intermediate carbocation in the 3-position of the
benzofuran ring by conjugative relay. Spectroscopic analysis of the
crude materials revealed the remaining mass balance consisted of
inseparable brominated by-products, and a spirocyclic brominated
semi-pinacol product, suggesting the potential intermediacy of this
compound in the reaction mechanism. Our focus then shifted to
four-membered rings containing an aryl substituent or annulated
alicyclic ring, as the expansion products are more difficult to pre-
Scheme 1. Previous cyclobutanol ring expansions to 1-tetralones and their associated
shortcomings (7 ¼ Disadvantage).
presence of an ortho-aryl bromine bond, and an appropriate 3,3-
disubstitution pattern on the four-membered ring to block b-hy-
dride elimination pathways (Scheme 1, b) [14]. In 2015, Zhu isolated
several 1-tetralone products selectively from aryl-substituted
cyclobutanols by employing silver catalysis; this report featured
only two successful substrates containing heterocyclic rings, which
were isolated in 40e63% yield after long reaction durations of
7e9 h (Scheme 1, c) [10]. Similarly, Gong described a synthesis of 1-
tetralones from cyclobutanols using excess ceric ammonium ni-
trate, featuring thiophene and benzothiophene substrates (Scheme
1, d) [11]. The last two reports and a serendipitous finding reported
by Peng and co-workers [12] (Scheme 1, e), however, mainly
explored substrates derived from unsubstituted cyclobutanone,
which lead to products of only limited biological utility (cf. Fig. 1).
We recently developed a transition-metal-free cyclobutanol
ring expansion to the regioisomeric 4-tetralones [23,24]. In line
with our group’s interest in ring expansion protocols, and the
development of diversity-oriented syntheses of pharmacophores
[25], we sought to develop a protocol which enables the divergent
pare by
a conventional synthetic approach [26], and their
Scheme 3. Initial results for the ring expansion to 1-tetralone 4a.
2

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
Scheme 6. Silver-mediated expansion to 4-tetralones.
silver-mediated expansion [10] of the 3-substituted benzofuran 3a
would provide the regioisomeric 4-tetralone, facilitating the
preparation of both tetralone isomers from a common intermedi-
ate. To this end, cyclobutanol 3a was treated with silver nitrate and
potassium persulfate; after 19 h, the 4-tetralone 10a was isolated in
only 13% yield, despite complete conversion of the starting material
(Scheme 6). This is a significant reduction in both the rate of re-
action and isolated yield relative to the established NBS-mediated
expansion from the isomeric heteroaryl-2-cyclobutanols, where
the 4-tetralone 10a was produced in 63% yield in under 3 h [23,24].
To investigate the scope of the silver-mediated transformation
to 4-tetralones, heteroaryl-substituted cyclobutanols 3b-3i were
also treated with silver nitrate and potassium persulfate (Scheme
7). This substrate scope contrasts with previously developed
transition-metal-catalysed methodologies that focused predomi-
nantly on aryl-substituted cyclobutanols. Similar to benzofuran 3a,
benzothiophene 3b and indole 3c formed 4-tetralones 10b and 10c
in significantly lower yield than the previously published NBS-
mediated rearrangement of the isomeric heteroaryl-2-
cyclobutanols to 4-tetralones (11% vs. 49% and 13% vs. 52%
respectively), after a significantly longer reaction duration (40 h vs.
4 h and 132 h vs. 10 min respectively) [23,24]. Additional substrates
3e e 3i were also successfully converted to the expected 4-
tetralones in up to 41% yield, with a similar extended reaction
duration. The regiochemistry of product 10g was confirmed by X-
ray crystallography (See Supporting Information). Notably, the
Scheme 4. Substrate scope for the NBS-mediated ring expansion to 1-tetralones.
preparation has been neglected by previously reported ring
expansion protocols. Expansion of phenyl-substituted four-
membered rings gratifyingly nearly doubled the isolated yield for
the 1-tetralones 4d and 4g. Satisfactory ring expansion yields were
also obtained when the four-membered ring was fused to five- and
six-membered rings. The cyclobutanone starting materials for
these substrates were readily prepared in a single synthetic step
[27]. Annulated examples 3e, 3f, 3h and 3i all expanded within
10 min and isolated yields of up to 41% were obtained. The for-
annulated examples (3e, 3f, 3h, and 3i) formed the
b,g-fused
products (10e, 10f, 10h, 10i) regioselectively. Unexpectedly, no
conversion was observed for alcohol 3d after three days, and the
starting material was isolated exclusively. Overall, 1- and 4-
tetralones fused to heteroaromatic rings were more reliably
formed using an NBS-mediated ring expansion, as higher yields can
mation of b,g-fused products (4e, 4f, 4h, 4i) was observed with
complete regiocontrol as the most substituted carbon migrates in
the initial semi-pinacol-like step.
To account for these observations, a radical-polar crossover
mechanism was proposed (Scheme 5). Radical bromination of 1
forms a highly stabilised benzylic tertiary radical 5, which is sub-
sequently oxidised to the cation 6. Alternatively, an electrophilic
bromination of the 2-position can be invoked to obtain tertiary
carbocation 6. In line with our previous report, we propose that this
cationic intermediate is stabilised by acetonitrile as the Ritter
adduct 7 [24]. Rearrangement of this intermediate leads to the
spirocyclic ketone 8, which may be observed spectroscopically. Loss
of bromide initiates further migration of the carbonyl group,
leading to the desired 1-tetralone 4.
As the regiochemical orientation of the ketone can significantly
alter the exhibited bioactivity (cf. Fig. 1), we hypothesised that a
Scheme 5. Suggested mechanism for the NBS-mediated ring expansion.
Scheme 7. Substrate scope for the silver-mediated ring expansion to 4-tetralones.
3

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
Scheme 8. Structural diversity within two steps from a common starting material.
Reaction conditions: a) PhMe3NBr3, THF, 0 ꢀC; then Li2CO3, LiBr, DMF, 150 ꢀC; b) NaBH4,
MeOH, rt; c) Lawesson’s reagent, toluene, 110 ꢀC.
Scheme 9. Ring expansion of heteroatom-containing four-membered rings to six-
membered rings. Reaction conditions: a) AgNO3 (20 mol%), K2S2O8 (3 equiv.),
CH2Cl2:H2O (1:1), rt.
be obtained in significantly shorter reaction durations. Neverthe-
less, access to both regioisomers from a common starting material
can facilitate the design of synthetic routes to diverse compound
libraries of material and biological interest.
Diversification of the obtained tetralone products was also
investigated (Scheme 8). The tetralones 4b & 10b were readily
investigate these observations experimentally, cyclic voltammetry
studies were performed on a series of cyclobutanol starting mate-
rials to elucidate their oxidation potential. The lowest energy
oxidation wave was irreversible, indicating significant structural
and electronic rearrangement upon oxidation (See Supporting In-
formation). As no reduction feature was observed in the return
sweep of this first oxidation process, the anodic peak potential is
used as an indication of the oxidation potential of each of the
substrates (Fig. 2). The yield of the ring-rearranged product at
complete conversion was found to inversely correlate with the
measured anodic peak potential. This observation suggests that the
oxidised to yield fully aromatised phenols 11 & 14 by an a-bromi-
nation/elimination procedure [28]. Furthermore, the ketone can be
reduced to form alcohols 12 & 15 through treatment with sodium
borohydride in methanol in up to 88% yield. Treatment of ketones
4b & 10b with Lawesson’s reagent provided thioketones 13 & 16.
Similarly derived thioketones have been used for the synthesis of
molecular motors using a Barton-Kellogg reaction[29,30,31].
Recently, a few examples of oxetanol ring expansion to five-
membered rings using
a photochemical or transition-metal-
catalysed semi-pinacol rearrangement have been noted in the
literature [32e38]. However, the expansion of an aromatic-
substituted oxetanol to the corresponding six-membered ring is
still unknown. To investigate this potential transformation to oxa-
tetralones, thiophene-substituted oxetanols 17a
& 17b were
formed from commercially available materials. Gratifyingly, treat-
ment of 17a & 17b with silver nitrate and persulfate produced the
oxa-tetralones 18a & 18b in 21% and 16% yield respectively (Scheme
9). The structure of 18a was confirmed by X-ray crystallography
(See Supporting Information). This constitutes the first report of an
oxetanol ring expansion to an oxa-tetralone.
Benzofuran-substituted oxetanol 17c however was less suc-
cessful, and no conversion to the oxa-tetralone 18c was observed.
Furthermore, when the heteroaromatic-substituted azetidinol 17d
was treated under the same reaction conditions, a-amino ketone
18d was obtained in 16% yield through an oxidative deconstruction
mechanism, which we have since optimised [39]. To our surprise,
NBS-mediated oxidative ring expansion did not occur for these
substrates (17a-17d), and instead the 3-brominated products were
observed. One potential reason is, that the enthalpic benefit
through release of ring-strain is reduced upon inclusion of a het-
eroatom, so that rearrangement is not initiated [40,41].
The yields obtained for the silver-catalysed ring expansion onto
heteroaromatic rings are significantly lower than those achieved
for the previously studied aryl systems [10]. We were intrigued by
the low yield of this process, as well as the cessation of the reaction
(3d and 17c), upon small changes in the starting material. To
Fig. 2. Plot of the anodic peak potential for substrates 3 and 17c and the isolated yield
of the ring-expanded product. The peak potential was obtained from cyclic voltam-
mograms using a three-electrode setup, see ESI. Measurements were performed in a
0.1 M TBAPF6/MeCN electrolyte (TBA ¼ nBu4Nþ) at a scan speed of 200 mV sꢁ1. In each
experiment, a ferrocene/ferrocenium redox couple (Fc/Fcþ) was measured as an in-
ternal standard and the resulting anodic peak potentials of the substrates were then
referenced to the SHE using a potential value of 0.63 V [42,43].
4

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
yield of the desired product formation may be limited by the
oxidation potential of the oxidising agent (Fig. 2).
received. Nuclear magnetic resonance spectra (NMR) were recor-
ded on a Bruker AV-400 (400 MHz for 1H NMR and 101 MHz for 13
C
The slow conversion of successful substrates and the cessation
for compounds with an oxidation potential >2.08 V (3d & 17c)
suggests the involvement of an oxidising agent with a standard
electrode potential close to 2.0 V (vs SHE). The redox couple pre-
viously suggested by Zhu and co-workers for this reaction is the
Ag2þ/Agþ couple [10]; the oxidation potential of this redox couple is
2.0 V (vs SHE), which is in agreement with the synthetic and
analytical observations made within this article [44]. It is known
that upon the reaction between silver nitrate and a persulfate salt,
silver (I,III) oxide is formed [45]. The qualitative observation of
formation of dark brown particles in the reaction mixture further
confirms this suggestion. The Ag2þ ion, which can undergo reduc-
tion with the necessary reduction potential, is effectively formed
from this intermediate only under strongly acidic conditions. The
slow formation of Ag2þ under neutral conditions has previously
been reported [46e48]. This will limit the conversion of cyclo-
butanols with oxidation potentials close to that of the active redox
couple, and offers an explanation for the cessation of reactivity of
substrates 3d and 17c.
NMR) and referenced to the non-deuterated residual solvent peaks
of chloroform. Chemical shifts are reported in parts per million
(ppm) and reported to two decimal places for proton shifts, and one
decimal place for carbon shifts. Multiplicity of spectral peaks is
assigned as follows: singlet (s), doublet (d), triplet (t), quartet (q),
pentet (p) or multiplet (m), and combinations thereof. Coupling
constants (J) are reported to the nearest 0.1 Hz. Infrared spectra
were recorded using an Agilent Cary 630 Fourier Transform
Infrared Spectrometer. Samples were loaded neat. Mass spectra
were recorded using Micromass AutoSpec Premier or Waters LCT
Premier instruments and ionised by means of electrospray ionisa-
tion (ES) or electron ionisation (EI). Melting points were measured
using a Stanford Research Systems OptiMelt system and are
uncorrected.
4.2. General procedure A for the synthesis of cyclobutanol starting
materials
To a solution of the 3-halogenated heteroaromatic compound
(3-bromobenzofuran [49], 3-bromobenzothiophene [50] or 3-
iodotosylindole [51]) (1 equiv.) in diethyl ether (0.25 M) cooled
to ꢁ78 ꢀC, was added n-butyllithium solution (2.3 M in hexane, 1.1
equiv.) at a rate to maintain the internal temperature below ꢁ70 ꢀC.
The resulting reaction mixture was allowed to stir for 1 h at the
same temperature, before a solution of the respective cyclo-
butanone (1.2 equiv.) in diethyl ether (0.5 M) was added as drops.
The reaction mixture was allowed to stir for 1 h at ꢁ78 ꢀC and then
allowed to warm to room temperature at which it was stirred until
completion of the reaction (followed by TLC). Upon completion, the
reaction was diluted with ethyl acetate and quenched by the slow
addition of saturated aqueous ammonium chloride solution. The
aqueous phase was extracted with ethyl acetate (3x), and the
combined organic layers were washed with saturated sodium
chloride solution. The organic phase was dried over magnesium
sulfate, filtered and concentrated under reduced pressure to yield
the crude material, which was purified by flash column
chromatography.
3. Conclusion
In conclusion, ring expansion reactions of cyclobutanols
substituted at the 3-position of a range of heteroaromatic rings
were studied. It was shown that 1-tetralones could be formed un-
der NBS-mediation, whereas 4-tetralones were obtained using
silver catalysis from a common intermediate. We have further
established that biologically relevant heteroaromatic-fused 1-
tetralones with substitution on the cyclohexanone ring can be
more efficiently obtained through the work disclosed herein
compared to previously established methodologies which are
limited by the oxidation potential of the oxidant. This work also
includes the first examples of the expansion of oxetanols to oxa-
tetralones. Using electrochemical techniques, we have been able
to elucidate the nature of the oxidation step. This work opens up
new methodology for the construction of biologically important
molecules, including ondansetron and epi-20-dasycarpidone.
NB: The 2-substituted heteroaromatic cyclobutanols were ob-
tained when THF was used as the reaction solvent, due to migration
of the anion [52].
4. Experimental
4.1. General information
4.3. General procedure B for the NBS-mediated cyclobutanol ring
rearrangement
Chemical symbols have their usual meaning and SI units and
their respective standard symbols are used. Evaporation of solvent
was achieved using a Büchi B-481 rotary evaporator under reduced
pressure (0e1000 mbar) with a bath temperature of 30 ꢀC. Reaction
solvents are anhydrous and purified through a Grubbs’ tower sol-
vent purification system. Dry acetonitrile (99.9%, extra dry over
molecular sieves) was acquired from Acros Organics™ and used
without further purification. Reagents were obtained from com-
mercial suppliers and used as received without further purification,
unless otherwise stated. Reactions were performed in oven-dried
glassware (dried at 130 ꢀC for 12 h). n-Butyllithium was titrated
against diphenylacetic acid before use. N-Bromosuccinimide was
recrystallised from deionised water, dried under high vacuum and
stored under nitrogen at 4 ꢀC. Thin layer chromatography (TLC) was
conducted on aluminium backed silica plates precoated with
fluorescent indicator (60 F254 Merck), and visualized using a
Mineralight lamp Multiband UV 254/365 nm and stained with
vanillin solution. Flash column chromatography was performed
To a solution of cyclobutanol starting material (1 equiv.) in
acetonitrile (0.1 M) at room temperature was added N-bromo-
succinimide (1.15 equiv.). The resulting reaction mixture was stirred
at room temperature until completion was indicated by TLC. Upon
completion, the reaction mixture was diluted with ethyl acetate,
and quenched by addition into saturated aqueous sodium thiosul-
fate solution. The aqueous layer was separated and extracted with
ethyl acetate (3x). The combined organic layers were washed with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, filtered and concentrated to yield the crude material, which
was purified through flash column chromatography.
4.4. General procedure C for the silver nitrate-mediated
cyclobutanol ring rearrangement
A reaction tube was filled with the cyclobutanol starting mate-
rial (0.3 mmol,1 equiv.), silver nitrate (10 mg, 0.06 mmol, 0.2 equiv.)
and potassium persulfate (243 mg, 0.9 mmol, 3 equiv.). The reaction
tube was evacuated and backfilled with nitrogen three times,
using silica gel (40e63 mm, VWR Chemicals) using head pressure
achieved by the use of head bellows. All solvents used for chro-
matography were acquired from commercial suppliers and used as
5

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
before degassed dichloromethane (0.5 mL) and degassed deionised
water (0.5 mL) were added simultaneously. The reaction tube was
sealed, and the reaction mixture stirred at room temperature. Upon
completion, the reaction mixture was diluted with dichloro-
methane (10 mL) and water (10 mL). The aqueous layer was sepa-
rated and extracted with dichloromethane (3x15 mL). The
combined organic layers were washed with saturated aqueous
sodium chloride solution (20 mL), dried over magnesium sulfate,
filtered and concentrated to yield the crude material, which was
purified using flash column chromatography.
column chromatography (2% EtOAc/pentane). Yellow solid; 518 mg,
2.27 mmol, 31%. 1H NMR (400 MHz, CDCl3): dH 7.73 (1H, m), 7.59
(1H, s), 7.49 (1H, dt, J ¼ 8.3, 0.9 Hz), 7.31 (1H, ddd, J ¼ 8.3, 7.2,
1.5 Hz), 7.25 (1H, m), 3.09 (1H, m), 2.74 (1H, ddd, J ¼ 13.0, 8.7,
3.0 Hz), 2.62 (1H, m), 2.21 (1H, m), 2.00 (1H, dq, J ¼ 18.5, 6.4 Hz),
1.90 (1H, m), 1.84 (1H, s), 1.68e1.47 (4H, m). 13C NMR (101 MHz,
CDCl3): dC 156.2, 140.4, 127.7, 125.9, 124.5, 122.5, 121.2, 111.6, 68.7,
49.3, 40.0, 32.7, 31.4, 26.3, 26.0. IR (neat, v cmꢁ1): 3553, 3411, 2947,
2851, 1452, 1096. HRMS (MS ESþ) m/z calculated for C15H15
O
(M ꢁ OH)þ 211.1123, found 211.1126. Melting point: 68.2e77.0 ꢀC.
4.5. Characterisation of compounds
4.5.6. 7-(Benzofuran-3-yl)bicyclo[4.2.0]octan-7-ol; (3f)
Prepared following general procedure A. Purified by flash col-
umn chromatography (5% EtOAc/pentane). Yellow solid; 430 mg,
1.77 mmol, 51%. 1H NMR (400 MHz, CDCl3): dH 7.71 (1H, ddd, J ¼ 7.7,
1.4, 0.7 Hz), 7.61 (1H, s), 7.49 (1H, dt, J ¼ 8.2, 0.9 Hz), 7.31 (1H, ddd,
J ¼ 8.3, 7.2, 1.4 Hz), 7.25 (1H, m), 2.66 (1H, m), 2.41 (2H, dd, J ¼ 9.2,
1.8 Hz), 2.11 (1H, m), 1.99 (1H, s), 1.89 (2H, m), 1.76 (1H, m),
1.63e1.41 (4H, m), 1.15 (1H, m). 13C NMR (101 MHz, CDCl3): dC 156.0,
140.9, 126.4, 125.7, 124.5, 122.5, 121.3, 111.6, 70.0, 42.8, 37.2, 25.8,
24.7, 22.7, 21.8. IR (neat, v cmꢁ1): 3546, 3383, 2918, 2846, 1577,
1450, 1224. HRMS (MS ESþ) m/z calculated for C16H17O (M ꢁ OH)þ
225.1279, found 228.1282. Melting point: 45.5e53.9 ꢀC.
4.5.1. 1-(Benzofuran-3-yl)cyclobutan-1-ol; (3a)
Prepared following general procedure A. Purified by flash col-
umn chromatography (10% EtOAc/pentane). White solid; 138 mg,
0.73 mmol, 47%. 1H NMR (400 MHz, CDCl3): dH 7.74 (1H, ddd, J ¼ 7.7,
1.5, 0.7 Hz), 7.60 (1H, s), 7.49 (1H, dt, J ¼ 8.2, 0.9 Hz), 7.32 (1H, ddd,
J ¼ 8.3, 7.2, 1.4 Hz), 7.26 (1H, m), 2.57 (2H, m), 2.46 (2H, m), 2.15 (1H,
s), 1.94 (1H, dtt, J ¼ 11.2, 9.6, 3.9 Hz), 1.70 (1H, dp, J ¼ 11.2, 8.7 Hz).
13C NMR (101 MHz, CDCl3): dC 156.1, 140.8, 126.0, 125.2, 124.6,122.6,
121.2, 111.6, 72.1, 36.5, 13.1. IR (neat, v cmꢁ1): 3282, 2987, 2950,
1448, 1124, 1093. HRMS (FTMS þ p) m/z calculated for C11H11
O
(M ꢁ OH)þ 171.0804, found 171.0799. Melting point: 93.8e98.9 ꢀC.
4.5.7. 1-(Benzo[b]thiophen-3-yl)-3-phenylcyclobutan-1-ol; (3g)
Prepared following general procedure A. Purified by flash col-
umn chromatography (10%e20% Et2O/pentane). Off-white solid;
370 mg,1.32 mmol, 44%. 1H NMR (400 MHz, CDCl3): dH 8.08 (1H, m),
7.92 (1H, m), 7.49 (1H, s), 7.46e7.21 (7H, m), 3.23e3.01 (3H, m), 2.66
(2H, ddt, J ¼ 9.4, 8.2,1.7 Hz), 2.46 (1H, s). 13C NMR (101 MHz, CDCl3):
dC 144.4, 141.4, 139.3, 137.3, 128.5, 126.7, 126.2, 124.6, 124.2, 124.1,
123.1, 122.5, 70.4, 43.9, 31.2. IR (neat, v cmꢁ1): 3547, 3349, 3023,
3056, 3023, 2973, 2933, 1601, 1494, 1456, 1427, 1237. HRMS (MS
ESþ) m/z calculated for C18H15S (M ꢁ OH)þ 263.0894, found
263.0897. Melting point: 74.6e82.8 ꢀC.
4.5.2. 1-(Benzo[b]thiophen-3-yl)cyclobutan-1-ol; (3b)
Prepared following general procedure A. Purified by flash col-
umn chromatography (20% Et2O/pentane). White solid; 397 mg,
1.94 mmol, 82%. 1H NMR (400 MHz, CDCl3): dH 8.01 (1H, m), 7.87
(1H, m), 7.45e7.29 (3H, m), 2.68 (2H, m), 2.51 (2H, m), 2.18 (1H, br.
s), 1.98 (1H, dtt, J ¼ 11.2, 9.5, 4.1 Hz),1.67 (1H, dp, J ¼ 11.1, 8.6 Hz). 13
C
NMR (101 MHz, CDCl3): dC 141.3, 140.0, 137.2, 124.4, 124.0, 123.9,
122.9, 122.0, 74.7, 36.3, 13.5. IR (neat, v cmꢁ1): 3255, 2970, 2938,
2864, 1456, 1427, 1247, 1118. HRMS (FTMS þ p) m/z calculated for
C
12H12OS (M)þ 204.0603, found 204.0608. Melting point:
94.6e100.4 ꢀC.
4.5.8. 6-(Benzo[b]thiophen-3-yl)bicyclo[3.2.0]heptan-6-ol; (3h)
Prepared following general procedure A. Purified by flash col-
umn chromatography (10% EtOAc/pentane). Off-white solid;
465 mg,1.90 mmol, 63%. 1H NMR (400 MHz, CDCl3): dH 7.97 (1H, m),
7.87 (1H, m), 7.43e7.33 (3H, m), 3.19 (1H, tt, J ¼ 8.7, 7.0, 2.9 Hz), 2.89
(1H, ddd, J ¼ 13.2, 8.8, 3.1 Hz), 2.54 (1H, m), 2.29 (1H, dd, J ¼ 13.4,
6.9 Hz), 2.10e1.82 (4H, m), 1.75e1.46 (3H, m). 13C NMR (101 MHz,
CDCl3): dC 142.2, 141.5, 137.2, 124.4, 124.2, 123.9, 123.0, 121.5, 70.9,
49.0, 39.6, 32.8, 31.6, 26.5, 26.0. IR (neat, v cmꢁ1): 3314, 2944, 2845,
1425, 1107. HRMS (MS ESþ) m/z calculated for C15H15S (M ꢁ OH)þ
227.0889, found 227.0890. Melting point: 77.2e83.0 ꢀC.
4.5.3. 1-(1-Tosyl-1H-indol-3-yl)cyclobutan-1-ol; (3c)
Prepared following general procedure A. Purified by flash col-
umn chromatography (40% Et2O/pentane). Off-white solid; 2.21 g,
6.47 mmol, 65%. 1H NMR (400 MHz, CDCl3): dH 7.98 (1H, dt, J ¼ 8.3,
0.9 Hz), 7.78 (2H, m), 7.70 (1H, dt, J ¼ 7.8, 1.0 Hz), 7.53 (1H, s), 7.32
(1H, ddd, J ¼ 8.4, 7.2, 1.3 Hz), 7.23 (3H, m), 2.56 (2H, dddd, J ¼ 12.5,
8.6, 3.9, 2.7 Hz), 2.43 (2H, m), 2.35 (3H, s), 2.09 (1H, s), 1.93 (1H, dtt,
J ¼ 11.2, 9.6, 3.9 Hz), 1.66 (1H, m). 13C NMR (101 MHz, CDCl3): dC
145.0, 136.0, 135.3, 129.9, 128.8, 126.9, 126.7, 124.9, 123.1, 122.2,
121.4, 113.7, 72.8, 36.5, 21.6, 13.2. IR (neat, v cmꢁ1): 3535, 2983,
2925, 2853, 1595, 1446, 1364, 1170, 1128. HRMS (MS ESþ) m/z
calculated for C19H18NO2S (M ꢁ OH)þ 324.1058, found 324.1053.
Melting point: 122.8e136.7 ꢀC.
4.5.9. 7-(Benzo[b]thiophen-3-yl)bicyclo[4.2.0]octan-7-ol; (3i)
Prepared following general procedure A. Purified by flash col-
umn chromatography (10% Et2O/pentane). Off-white solid; 120 mg,
0.46 mmol, 20%. 1H NMR (400 MHz, CDCl3): dH 7.96 (1H, m), 7.86
(1H, m), 7.40 (1H, s), 7.40e7.31 (2H, m), 2.75 (1H, qd, J ¼ 8.9, 4.4 Hz),
2.56 (1H, ddd, J ¼ 11.1, 7.9, 4.5 Hz), 2.45 (1H, t, J ¼ 11.0 Hz), 2.03 (2H,
m), 2.00e1.89 (2H, m), 1.77 (1H, dtt, J ¼ 12.8, 3.1 Hz), 1.62e1.57 (2H,
m), 1.50e1.41 (2H, m), 1.14 (1H, m). 13C NMR (101 MHz, CDCl3): dC
141.3, 140.4, 137.6, 124.4, 124.0, 123.9, 122.9, 121.9, 72.5, 42.8, 37.1,
25.8, 24.8, 22.8, 22.0, 21.8. IR (neat, v cmꢁ1) 3537, 3425, 3264, 2922,
2847, 1456, 1428, 1229, 1061. HRMS (MS ESþ) m/z calculated for
4.5.4. 1-(Benzofuran-3-yl)-3-phenylcyclobutan-1-ol; (3d)
Prepared following general procedure A. Purified by flash col-
umn chromatography (20% Et2O/pentane). White solid; 480 mg,
1.82 mmol, 20%. 1H NMR (400 MHz, CDCl3): dH 7.79 (1H, ddd, J ¼ 7.7,
1.5, 0.7 Hz), 7.72 (1H, s), 7.53 (1H, dt, J ¼ 8.2, 0.9 Hz), 7.31 (6H, m),
7.23 (1H, m), 3.14 (1H, m), 3.04 (2H, m), 2.63 (2H, m), 2.23 (1H, s).
13C NMR (101 MHz, CDCl3): dC 156.2, 144.3, 141.1, 128.4, 126.7, 126.2,
126.0, 124.8, 122.8, 121.2, 111.8, 67.9, 43.9, 31.0. IR (neat, v cmꢁ1):
3338, 3056, 3025, 2973, 2961, 2933, 1451, 1424, 1373, 1234, 1229.
HRMS (MS ESþ) m/z calculated for C18H15O (M ꢁ OH)þ 247.1123,
found 247.1122. Melting point: 93.4e96.5 ꢀC.
C
16H17S (M ꢁ OH)þ 241.1040, found 241.1045.
4.5.10. 3-(Benzo[b]thiophen-3-yl)oxetan-3-ol; (17a)
Prepared following general procedure A. Purified by flash col-
umn chromatography (30% Et2O/pentane). Yellow solid; 290 mg,
1.41 mmol, 30%. 1H NMR (400 MHz, CDCl3): dH 7.94e7.85 (2H, m),
4.5.5. 6-(Benzofuran-3-yl)bicyclo[3.2.0]heptan-6-ol; (3e)
Prepared following general procedure A. Purified by flash
6

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
7.45 (1H, s), 7.43e7.38 (2H, m), 5.11 (2H, dd, J ¼ 6.8, 0.8 Hz), 5.01
(2H, dd, J ¼ 6.9, 0.8 Hz), 2.80 (1H, s). 13C NMR (101 MHz, CDCl3): dC
141.2, 136.6, 136.4, 124.8, 124.6, 123.4, 123.2, 122.7, 83.8, 74.2. IR
(neat, v cmꢁ1) 3843, 2947, 2872, 1457, 1428. HRMS (MS ESþ) m/z
calculated for C11H9OS (M ꢁ OH)þ 189.0374, found 189.0368.
Melting point: 80.2e84.1 ꢀC.
1588, 1394, 1079. HRMS (MS ESþ) m/z calculated for C12H11O2 (M)þ
187.0759, found 187.0762. The data obtained are in agreement with
those previously reported [10].
4.5.14. 2,3-Dihydrodibenzo[b,d]thiophen-4(1H)-one; (4b)
Prepared following general procedure B from alcohol 3b (3.99 g,
19.3 mmol). Purified by flash column chromatography (20% Et2O/
pentane). White solid; 820 mg, 4.05 mmol, 21%. 1H NMR (400 MHz,
CDCl3): dH 7.88 (1H, dt, J ¼ 8.1, 1.0 Hz), 7.82 (1H, dt, J ¼ 7.8, 1.0 Hz),
7.49 (1H, ddd, J ¼ 8.2, 7.1, 1.4 Hz), 7.43 (1H, ddd, J ¼ 8.2, 7.1, 1.2 Hz),
3.07 (2H, t, J ¼ 6.1 Hz), 2.74 (2H, dd, J ¼ 7.3, 5.8 Hz), 2.32 (2H, p,
J ¼ 6.3 Hz). 13C NMR (101 MHz, CDCl3): dC 193.7, 147.9, 142.5, 138.3,
4.5.11. 3-(Benzo[b]thiophen-2-yl)oxetan-3-ol; (17b)
To a solution of benzothiophene (500 mg, 3.73 mmol) in THF
(15 mL) cooled to ꢁ78 ꢀC was added n-butyllithium solution (1.9 M
in hexane, 2.2 mL, 4.1 mmol) as drops. The reaction mixture was
allowed to stir at ꢁ78 ꢀC for 2 h before a solution of 3-oxetanone
(0.24 mL, 4.1 mmol) in THF (3 mL) was added as drops. The
resulting solution was allowed to warm to room temperature and
stirred for a further 1.5 h. Upon completion, the reaction was
diluted with ethyl acetate and quenched by the slow addition of
saturated aqueous ammonium chloride solution. The aqueous
phase was extracted with ethyl acetate (3x), and the combined
organic layers were washed with saturated sodium chloride solu-
tion. The organic phase was dried over magnesium sulfate, filtered
and concentrated under reduced pressure to yield the title com-
pound (693 mg, 3.36 mmol, 90%) as an off-white solid which was
used without further purification. 1H NMR (400 MHz, CDCl3): dH
7.83 (1H, ddd, J ¼ 7.4, 1.7, 0.7 Hz), 7.76 (1H, m), 7.40 (1H, d,
J ¼ 0.7 Hz), 7.40e7.31 (2H, m), 4.96 (4H, m), 3.01 (1H, s). 13C NMR
(101 MHz, CDCl3): dC 147.0, 139.6, 139.5, 124.7, 123.8, 122.5, 120.2,
85.3, 74.8. IR (neat, v cmꢁ1) 3232, 2940, 2871,1419,1456,1433, 1237,
1140. HRMS (FTMS þ p) m/z calculated for C11H9OS (M ꢁ OH)þ
189.0369, found 189.0364. Melting point: 104.8e112.9 ꢀC.
136.2, 128.1, 124.8, 123.9, 123.5, 38.6, 24.1, 24.0. IR (neat, v cmꢁ1
)
3057, 2947, 2887, 1662, 1523, 1380, 1282. HRMS (MS ESþ) m/z
calculated for C12H11OS (M)þ 203.0525, found 203.0523. Melting
point: 106.7e111.3 ꢀC. The data obtained are in agreement with
those previously reported [12].
4.5.15. 9-Tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one; (4c)
Prepared following general procedure
B from alcohol 3c
(153 mg, 0.45 mmol). Purified by flash column chromatography
(40% Et2O/pentane). Pale brown solid; 23 mg, 0.068 mmol, 15%. 1H
NMR (400 MHz, CDCl3): dH 8.37 (1H, dt, J ¼ 8.7, 0.9 Hz), 8.04 (2H, m),
7.63 (1H, dt, J ¼ 7.9, 1.0 Hz), 7.55 (1H, ddd, J ¼ 8.6, 7.2, 1.3 Hz), 7.34
(1H, ddd, J ¼ 8.0, 7.1, 0.9 Hz), 7.31 (2H, m), 2.95 (2H, t, J ¼ 6.1 Hz),
2.61 (2H, m), 2.40 (3H, s), 2.19 (2H, m). 13C NMR (101 MHz, CDCl3):
dC 187.7, 144.4, 139.7, 137.7, 137.3, 132.3, 129.3, 129.2, 127.7, 127.1,
123.6,121.3,116.0, 39.5, 23.5, 21.8, 21.7. IR (neat, v cmꢁ1) 3052, 2924,
2866, 1675, 1596, 1551, 1366. HRMS (MS ESþ) m/z calculated for
C
19H18NO3S (M)þ 340.1007, found 340.0999. The data obtained are
4.5.12. 3-(Benzofuran-2-yl)oxetan-3-ol; (17c)
in agreement with those previously reported [53].
To a solution of benzofuran (1.60 mL,14.5 mmol) in diethyl ether
(30 mL) cooled to ꢁ78 ꢀC was added n-butyllithium solution (2.3 M
in hexane, 6.3 mL, 14.5 mmol) as drops. The reaction mixture was
allowed to stir at ꢁ78 ꢀC for 1 h, before it was warmed to room
temperature and stirred for further 3 h. The reaction mixture was
then cooled to ꢁ78 ꢀC before a solution of 3-oxetanone (0.64 mL,
11 mmol) in THF (3 mL) was added as drops. The resulting solution
was allowed to warm to room temperature and stirred for a further
1.5 h. Upon completion, the reaction was diluted with ethyl acetate
and quenched by the slow addition of saturated aqueous ammo-
nium chloride solution. The aqueous phase was extracted with
ethyl acetate (3x), and the combined organic layers were washed
with saturated sodium chloride solution. The organic phase was
dried over magnesium sulfate, filtered and concentrated under
reduced pressure to yield the crude material, which was purified
through flash column chromatography (50% Et2O/pentane) to yield
the title compound (1.66 g, 8.73 mmol, 79%) as an off-white solid.
1H NMR (400 MHz, CDCl3): dH 7.58 (1H, ddd, J ¼ 7.6,1.5, 0.7 Hz), 7.50
(1H, dq, J ¼ 8.2, 0.9 Hz), 7.32 (1H, m), 7.26 (1H, m), 6.78 (1H, d,
J ¼ 1.0 Hz), 5.05 (2H, dd, J ¼ 6.9, 0.9 Hz), 4.89 (2H, m), 3.04 (1H, s).
13C NMR (101 MHz, CDCl3): dC 156.6, 155.0, 127.9, 124.8, 123.2, 121.3,
111.4, 102.9, 82.8, 72.6. IR (neat, v cmꢁ1) 3279, 3127, 2954, 2878,
1451, 1407, 1253, 1174. HRMS (FTMS þ p) m/z calculated for C11H9O2
(M ꢁ OH)þ 173.0597, found 173.0601.
4.5.16. 2-Phenyl-2,3-dihydrodibenzo[b,d]furan-4(1H)-one; (4d)
Prepared following general procedure B from alcohol 3d (78 mg,
0.30 mmol). Purified by flash column chromatography (10% EtOAc/
pentane). White solid; 51 mg, 0.19 mmol, 65%. 1H NMR (400 MHz,
CDCl3): dH 7.62 (2H, ddt, J ¼ 15.3, 8.4, 1.0 Hz), 7.52 (1H, ddd, J ¼ 8.4,
7.1, 1.3 Hz), 7.42e7.29 (6H, m), 3.68 (1H, ddt, J ¼ 12.2, 11.0, 4.7 Hz),
3.33 (1H, ddd, J ¼ 16.9, 4.7, 1.1 Hz), 3.16 (1H, dd, J ¼ 16.9, 11.0 Hz),
2.98 (2H, m). 13C NMR (101 MHz, CDCl3): dC 187.1, 156.3, 147.6, 142.7,
133.9, 129.3, 128.9, 127.3, 126.8, 126.2, 123.8, 121.8, 113.0, 45.5, 42.8,
29.4. IR (neat, v cmꢁ1) 3060, 3028, 2954, 2941, 2906, 1669, 1396,
1306, 1128, 1109, 1072. HRMS (MS ESþ) m/z calculated for C18H15O2
(M)þ 263.1072, found 263.1073.
4.5.17. 1,2,3,3a,4,10c-hexahydro-5H-indeno[5,4-b]benzofuran-5-
one; (4e)
Prepared following general procedure B from alcohol 3e (67 mg,
0.3 mmol). Purified by flash column chromatography (10% EtOAc/
pentane). Yellow solid; 25 mg, 0.11 mmol, 37%. 1H NMR (400 MHz,
CDCl3): dH 7.70 (1H, dt, J ¼ 7.9, 1.0 Hz), 7.57 (1H, dt, J ¼ 8.4, 0.9 Hz),
7.49 (1H, ddd, J ¼ 8.4, 7.1, 1.3 Hz), 7.32 (1H, ddd, J ¼ 8.0, 7.1, 1.0 Hz),
3.54 (1H, dt, J ¼ 8.0, 6.0 Hz), 2.85 (1H, m), 2.81e2.68 (2H, m), 2.28
(1H, dtd, J ¼ 13.0, 8.3, 6.8 Hz), 2.10 (1H, ddt, J ¼ 12.7, 8.5, 6.0 Hz),1.96
(1H, dtd, J ¼ 12.8, 8.0, 6.2 Hz), 1.77 (2H, ddt, J ¼ 15.0, 8.4, 6.5 Hz),
1.55 (1H, m). 13C NMR (101 MHz, CDCl3): dC 187.9, 156.3, 146.4,
136.0, 128.9, 126.4, 123.5, 122.2, 113.0, 41.3, 40.3, 37.0, 31.3, 30.4,
24.6. IR (neat, v cmꢁ1) 2943, 2868, 1670, 1586, 1577, 1444, 1394,
1113, 1079. HRMS (MS ESþ) m/z calculated for C15H15O2 (M)þ
227.1072, found 227.1065. Melting point: 42.4e46.6 ꢀC.
4.5.13. 2,3-Dihydrodibenzo[b,d]furan-4(1H)-one; (4a)
Prepared following general procedure B from alcohol 3a (93 mg,
0.5 mmol). Purified by flash column chromatography (15% EtOAc/
pentane). White solid; 35 mg, 0.19 mmol, 38%. 1H NMR (400 MHz,
CDCl3): dH 7.64 (1H, dt, J ¼ 7.8, 1.0 Hz), 7.55 (1H, dt, J ¼ 8.4, 1.0 Hz),
7.48 (1H, ddd, J ¼ 8.4, 7.1, 1.3 Hz), 7.31 (1H, ddd, J ¼ 8.0, 7.1, 1.1 Hz),
2.99 (2H, t, J ¼ 6.0 Hz), 2.69 (2H, m), 2.28 (2H, m). 13C NMR
(101 MHz, CDCl3): dC 188.4, 155.8, 147.7, 134.7, 129.1, 126.4, 123.6,
121.8,112.8, 38.6, 24.1, 21.4. IR (neat, v cmꢁ1) 3056, 2947, 2884,1661,
4.5.18. 1,3,4,4a,5,11c-Hexahydronaphtho[2,1-b]benzofuran-6(2H)-
one; (4f)
Prepared following general procedure B from alcohol 3f (71 mg,
0.30 mmol). Purified by flash column chromatography (5% EtOAc/
7

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
pentane). Faint yellow solid; 29 mg, 0.12 mmol, 41%. 1H NMR
(400 MHz, CDCl3): dH 7.70 (1H, dt, J ¼ 7.9, 1.0 Hz), 7.57 (1H, dt,
J ¼ 8.5, 0.9 Hz), 7.48 (1H, ddd, J ¼ 8.4, 7.2, 1.3 Hz), 7.31 (1H, ddd,
J ¼ 8.1, 7.1, 1.0 Hz), 3.22 (1H, dt, J ¼ 10.7, 4.4 Hz), 2.92 (1H, dd,
J ¼ 16.9, 12.2 Hz), 2.64 (1H, dp, J ¼ 13.0, 4.3 Hz), 2.48 (1H, dd,
J ¼ 16.9, 4.2 Hz), 2.03 (1H, dq, J ¼ 12.1, 3.8 Hz), 1.80e1.65 (4H, m),
1.62 (1H, m), 1.50 (2H, m). 13C NMR (101 MHz, CDCl3): dC 188.8,
156.2, 147.1, 138.6, 128.9, 125.9, 123.6, 121.9, 113.0, 40.5, 35.9, 34.6,
29.9, 28.4, 24.9, 21.4. IR (neat, v cmꢁ1) 3058, 2923, 2851, 1673, 1588,
1576, 1444, 1395, 1309, 1142, 1070. HRMS (MS ESþ) m/z calculated
4.5.23. 3,4-Dihydrodibenzo[b,d]thiophen-1(2H)-one; (10b)
Prepared following general procedure from alcohol 3b
C
(100 mg, 0.45 mmol). Purified by flash column chromatography
(12% EtOAc/pentane). Brown solid; 11 mg, 0.05 mmol, 11%. 1H NMR
(400 MHz, CDCl3): dH 8.67 (1H, dt, J ¼ 8.1, 1.0 Hz), 7.77 (1H, dt,
J ¼ 8.0, 1.0 Hz), 7.45 (1H, ddd, J ¼ 8.2, 7.2, 1.2 Hz), 7.36 (1H, ddd,
J ¼ 8.3, 7.1, 1.3 Hz), 3.15 (2H, t, J ¼ 6.1 Hz), 2.67 (2H, m), 2.29 (2H, tt,
J ¼ 7.5, 5.8 Hz). 13C NMR (101 MHz, CDCl3): dC 193.6, 160.1, 137.3,
136.5, 130.0, 125.8, 125.1, 125.0, 121.7, 38.8, 26.6, 24.3. The data
obtained are in agreement with those previously reported [23].
for
C
16H17O2 (M)þ 241.1229, found 241.1240. Melting point:
96.1e100.4 ꢀC.
4.5.24. 9-Tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one; (10c)
Prepared following general procedure
C from alcohol 3c
4.5.19. 2-Phenyl-2,3-dihydrodibenzo[b,d]thiophen-4(1H)-one; (4g)
(100 mg, 0.30 mmol). Purified by flash column chromatography
(15% EtOAc/pentane). Colourless oil; 13 mg, 0.038 mmol, 13%. 1H
NMR (400 MHz, CDCl3): dH 8.24 (1H, m), 8.16 (1H, m), 7.76 (2H, m),
7.34 (2H, m), 7.27 (2H, m), 3.33 (2H, t, J ¼ 6.2 Hz), 2.56 (2H, m), 2.37
(3H, s), 2.22 (2H, dq, J ¼ 7.8, 6.3 Hz). 13C NMR (101 MHz, CDCl3): dC
195.0, 150.9, 145.8, 136.0, 135.6, 130.3, 126.6, 125.8, 125.3, 124.9,
121.9, 118.0, 113.9, 37.9, 24.5, 23.2, 21.7. The data obtained are in
agreement with those previously reported [23].
Prepared following general procedure
B from alcohol 3g
(105 mg, 0.37 mmol). Purified by flash column chromatography (5%
EtOAc/pentane). White solid; 43 mg, 0.15 mmol, 41%. 1H NMR
(400 MHz, CDCl3): dH 7.91 (1H, dt, J ¼ 8.2, 0.9 Hz), 7.80 (1H, dt,
J ¼ 7.9, 1.0 Hz), 7.51 (1H, ddd, J ¼ 8.2, 7.1, 1.3 Hz), 7.46e7.28 (6H, m),
3.67 (1H, m), 3.47 (1H, m), 3.14 (1H, dd, J ¼ 16.9, 11.3 Hz), 3.01 (2H,
m). 13C NMR (101 MHz, CDCl3): dC 192.7, 146.8, 142.9, 142.8, 138.0,
136.1, 128.9, 128.2, 127.3, 126.9, 124.9, 123.8, 123.6, 45.4, 42.5, 32.2.
IR (neat, v cmꢁ1) 3056, 3027, 2919, 2891, 2949, 1661, 1523, 1381,
1288. HRMS (MS ESþ) m/z calculated for C18H15OS (M)þ 279.0844,
found 279.0836. Melting point: 91.1e108.4 ꢀC.
4.5.25. 1,2,3,3a,4,10b-hexahydro-5H-indeno[4,5-b]benzofuran-5-
one; (10e)
Prepared following general procedure C from alcohol 3e (69 mg,
0.30 mmol). Purified by flash column chromatography (5% EtOAc/
pentane). Yellow oil; 20 mg, 0.088 mmol, 29%. 1H NMR (400 MHz,
CDCl3): dH 8.06 (1H, m), 7.47 (1H, m), 7.32 (2H, m), 3.48 (1H, td,
J ¼ 7.0, 5.7 Hz), 2.81 (2H, m), 2.64 (1H, dd, J ¼ 16.7, 5.1 Hz), 2.20 (2H,
m), 1.95 (1H, m), 1.74 (2H, m), 1.53 (1H, m). 13C NMR (101 MHz,
CDCl3): dC 194.4, 172.1, 154.9, 124.9, 124.4, 123.8, 121.9, 115.4, 111.1,
41.0, 39.4, 38.3, 30.6, 30.0, 24.3. The data obtained are in agreement
with those previously reported [23].
4.5.20. 1,2,3,3a,4,10c-hexahydro-5H-benzo[b]indeno[4,5-d]
thiophen-5-one; (4h)
Prepared following general procedure
B from alcohol 3h
(121 mg, 0.50 mmol). Purified by flash column chromatography
(10% Et2O/pentane). Pink solid; 37 mg, 0.15 mmol, 31%. 1H NMR
(400 MHz, CDCl3): dH 7.86 (2H, ddt, J ¼ 13.6, 7.8, 0.9 Hz), 7.45 (2H,
m), 3.52 (1H, td, J ¼ 8.5, 6.5 Hz), 2.96 (1H, dtd, J ¼ 13.5, 6.6, 3.9 Hz),
2.69 (1H, d, J ¼ 1.4 Hz), 2.67 (1H, d, J ¼ 4.2 Hz), 2.41 (1H, dddd,
J ¼ 12.1, 9.7, 7.1, 2.5 Hz), 2.07e1.78 (4H, m), 1.63 (1H, m). 13C NMR
(101 MHz, CDCl3): dC 193.5, 149.8, 143.0, 138.6, 134.7, 127.8, 124.7,
124.3, 123.6, 41.2, 40.8, 39.2, 31.1, 31.0, 24.6. IR (neat, v cmꢁ1) 2943,
2869, 1659, 1523, 1384, 1329, 1287, 1240. HRMS (FTMS þ p) m/z
calculated for C15H15OS (M þ H)þ 243.0838, found 243.0832.
Melting point: 79.4e89.0 ꢀC.
4.5.26. 1,3,4,4a,5,11b-Hexahydronaphtho[1,2-b]benzofuran-6(2H)-
one; (10f)
Prepared following general procedure C from alcohol 3f (71 mg,
0.30 mmol). Purified by flash column chromatography (10% Et2O/
pentane). Colourless film; 12 mg, 0.050 mmol, 17%. 1H NMR
(400 MHz, CDCl3): dH 8.06 (1H, m), 7.48 (1H, m), 7.32 (2H, m), 3.28
(1H, dt, J ¼ 7.5, 4.7 Hz), 2.69 (1H, dd, J ¼ 17.4, 9.2 Hz), 2.56 (2H, dt,
J ¼ 11.4, 4.3 Hz), 2.09 (1H, br. s), 1.92 (1H, ddt, J ¼ 13.4, 8.8, 4.8 Hz),
1.72e1.39 (6H, m). 13C NMR (101 MHz, CDCl3): dC 194.9, 173.4, 154.8,
124.8, 124.4, 123.9, 121.8, 115.4, 111.2, 35.9, 35.5, 28.8, 26.9, 23.6,
22.9. The data obtained are in agreement with those previously
reported [24].
4.5.21. 1,3,4,4a,5,11c-Hexahydrobenzo[b]naphtho[1,2-d]thiophen-
6(2H)-one; (4i)
Prepared following general procedure B from alcohol 3i (80 mg,
0.33 mmol). Purified by flash column chromatography (10% Et2O/
pentane). Light pink film; 20 mg, 0.083 mmol, 25%. 1H NMR
(400 MHz, CDCl3): dH 7.86 (2H, ddt, J ¼ 16.5, 7.8, 0.9 Hz), 7.45 (2H,
dddd, J ¼ 21.7, 8.1, 7.1,1.3 Hz), 3.25 (1H, dt, J ¼ 12.0, 4.4 Hz), 3.02 (1H,
dd, J ¼ 17.0, 14.3 Hz), 2.69 (1H, dt, J ¼ 14.4, 3.8 Hz), 2.46 (1H, dd,
J ¼ 17.0, 4.2 Hz), 2.03 (1H, m), 1.82 (3H, m), 1.68 (1H, m), 1.52 (3H,
m). 13C NMR (101 MHz, CDCl3): dC 194.4, 152.8, 143.0, 137.6, 135.6,
127.9, 124.7, 123.9, 123.7, 39.1, 36.8, 35.3, 30.6, 28.1, 25.8, 20.4. IR
(neat, v cmꢁ1) 3056, 2922, 2851, 1654, 1521, 1448, 1380, 1290, 1280.
HRMS (FTMS þ p) m/z calculated for C16H17OS (M þ H)þ 257.0995,
found 257.0998.
4.5.27. 3-Phenyl-3,4-dihydrodibenzo[b,d]thiophen-1(2H)-one;
(10g)
Prepared following general procedure C from 3g (81 mg,
0.30 mmol). Purified by flash column chromatography (10% Et2O/
pentane). Crystals suitable for X-ray diffraction analysis were ob-
tained through slow evaporation from CDCl3. White solid; 13 mg,
0.047 mmol, 16%. 1H NMR (400 MHz, CDCl3): dH 8.70 (1H, d,
J ¼ 8.0 Hz), 7.79 (1H, d, J ¼ 8.0 Hz), 7.48 (1H, t, J ¼ 7.6 Hz), 7.42e7.28
(6H, m), 3.67 (1H, dtd, J ¼ 12.3, 8.1, 4.5 Hz), 3.43 (1H, dd, J ¼ 17.1,
4.6 Hz), 3.32 (1H, dd, J ¼ 17.1, 11.2 Hz), 2.94 (2H, m). 13C NMR
(101 MHz, CDCl3): dC 192.6, 159.1, 142.5, 137.6, 136.3, 129.8, 128.9,
127.3, 126.8, 126.0, 125.3, 125.0, 121.8, 45.8, 42.5, 34.1. The data
obtained are in agreement with those previously reported [23].
4.5.22. 3,4-Dihydrodibenzo[b,d]furan-1(2H)-one; (10a)
Prepared following general procedure C from alcohol 3a (61 mg,
0.30 mmol). Purified by flash column chromatography (15% EtOAc/
pentane). White solid; 8 mg, 0.04 mmol, 13%. 1H NMR (400 MHz,
CDCl3): dH 8.05 (1H, m), 7.47 (1H, m), 7.32 (2H, m), 3.04 (2H, t,
J ¼ 6.3 Hz), 2.61 (2H, m), 2.28 (2H, m). 13C NMR (101 MHz, CDCl3): dC
194.8, 170.8, 154.5, 125.0, 124.5, 123.7, 121.8, 116.5, 111.1, 37.9, 23.8,
22.5. The data obtained are in agreement with those previously
reported [23].
4.5.28. 1,2,3,3a,4,10b-hexahydro-5H-benzo[b]indeno[5,4-d]
thiophen-5-one; (10h)
Prepared following general procedure C from alcohol 3h (74 mg,
0.30 mmol). Purified by flash column chromatography (5% EtOAc/
8

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
pentane). White solid; 30 mg, 0.12 mmol, 41%. 1H NMR (400 MHz,
CDCl3): dH 8.66 (1H, ddd, J ¼ 8.1, 1.3, 0.7 Hz), 7.78 (1H, dt, J ¼ 8.0,
0.9 Hz), 7.44 (1H, ddd, J ¼ 8.2, 7.2, 1.2, Hz), 7.35 (1H, ddd, J ¼ 8.4, 7.2,
1.3 Hz), 3.58 (1H, dt, J ¼ 7.5, 5.8 Hz), 2.82 (2H, m), 2.66 (1H, dd,
J ¼ 16.4, 6.6 Hz), 2.24 (1H, ddt, J ¼ 13.0, 8.7, 7.6 Hz), 2.07 (1H, m),
1.97 (1H, m), 1.78 (2H, m), 1.55 (1H, m). 13C NMR (101 MHz, CDCl3):
dC 193.3, 163.7, 137.7, 136.5, 129.0, 125.7, 125.0, 121.8, 41.4, 41.2, 40.2,
34.5, 30.1, 23.9. The data obtained are in agreement with those
previously reported [23].
131.2, 124.3, 124.0, 122.3, 121.4, 63.6, 31.9, 25.9, 19.0. IR (neat, v
cmꢁ1) 3305, 2935, 2902, 2878, 2861, 2831, 1465, 1434, 1272, 1257,
1072. HRMS (FTMS þ p) m/z calculated for C12H11S (M ꢁ OH)þ
187.0576, found 187.0577. Melting point: 97.5e102.4 ꢀC.
4.5.33. 1,2,3,4-Tetrahydrodibenzo[b,d]thiophen-4-ol; (15)
To a suspension of ketone (50 mg, 0.25 mmol) in methanol
(1 mL) at room temperature was added sodium borohydride
(12 mg, 0.31 mmol, 1.25 equiv.). The resulting solution was allowed
to stir for 20 min, before it was cooled to 0 ꢀC and quenched by the
addition of deionised water (1 mL) and stirred for 10 further mi-
nutes. The methanol was removed under reduced pressure and the
aqueous layer extracted with ethyl acetate (3 x 10 mL). The com-
bined organic layers were washed with saturated aqueous sodium
chloride solution (10 mL), dried over magnesium sulfate, filtered
and concentrated to obtain the crude product, which was purified
through flash column chromatography (30% Et2O/pentane). White
solid; 43 mg, 0.21 mmol, 84%. 1H NMR (400 MHz, CDCl3): dH 7.82
(1H, m), 7.62 (1H, m), 7.35 (2H, m), 4.98 (1H, q, J ¼ 5.5 Hz), 2.81 (1H,
4.5.29. 1,3,4,4a,5,11b-Hexahydrobenzo[b]naphtho[2,1-d]thiophen-
6(2H)-one; (10i)
Prepared following general procedure C from alcohol 3i (77 mg,
0.30 mmol). Purified by flash column chromatography (5% EtOAc/
pentane). Colourless oil; 23 mg, 0.090 mmol, 30%. 1H NMR
(400 MHz, CDCl3): dH 8.68 (1H, dt, J ¼ 8.2, 0.9 Hz), 7.79 (1H, dt,
J ¼ 8.0, 0.9 Hz), 7.45 (1H, ddd, J ¼ 8.2, 7.1, 1.2 Hz), 7.36 (1H, m), 3.40
(1H, dt, J ¼ 7.1, 4.8 Hz), 2.73 (1H, dd, J ¼ 16.7, 7.9 Hz), 2.63 (1H, dd,
J ¼ 16.8, 4.5 Hz), 2.54 (1H, m), 2.15e1.87 (2H, m), 1.74e1.39 (6H, m).
13C NMR (101 MHz, CDCl3): dC 193.8, 164.8, 137.5, 136.8, 129.1, 125.7,
125.0, 124.9, 121.8, 42.8, 38.2, 36.6, 31.0, 28.6, 23.4, 23.0. The data
obtained are in agreement with those previously reported [24].
m), 2.72 (1H, m), 2.20 (1H, m), 2.08 (1H, m), 2.03e1.83 (3H, m). 13
C
NMR (101 MHz, CDCl3): dC 139.4, 139.0, 132.0, 124.6, 124.1, 122.7,
121.5, 66.1, 33.5, 23.7, 19.2. IR (neat, v cmꢁ1) 3351, 2945, 2916, 2877,
2851, 1435, 1292, 1169, 1045. HRMS (FTMS þ p) m/z calculated for
4.5.30. 1H-Benzo[4,5]thieno[2,3-c]pyran-4(3H)-one; (18a)
C
11H11S (M ꢁ OH)þ 187.0576, found 187.0580. Melting point:
Prepared following general procedure C from alcohol 17a
(62 mg, 0.30 mmol). Purified by flash column chromatography (10%
EtOAc/pentane). Red solid; 13 mg, 0.063 mmol, 21%. 1H NMR
(400 MHz, CDCl3): dH 8.59 (1H, dt, J ¼ 8.1, 1.0 Hz), 7.84 (1H, dt,
J ¼ 8.0, 1.0 Hz), 7.50 (1H, ddd, J ¼ 8.2, 7.2, 1.1 Hz), 7.42 (1H, ddd,
90.6e100.6 ꢀC.
4.5.34. Dibenzo[b,d]thiophen-1-ol; (11)
To a solution of ketone (100 mg, 0.5 mmol) in THF (3 mL) cooled
to 0 ꢀC, was added trimethylphenylammonium tribromide (207 mg,
0.55 mmol) and the solution stirred at 0 ꢀC for 1 h, before it was
allowed to warm to room temperature and stirred for further 4.5 h.
At that point, the reaction mixture was diluted with ethyl acetate
(10 mL) and deionised water (10 mL). The aqueous layer was
separated and extracted with ethyl acetate (3x15 mL). The com-
bined organic layers were washed with saturated aqueous sodium
chloride solution (15 mL), dried over magnesium sulfate, filtered
and concentrated to yield the crude material as a dark grey solid.
This was immediately dissolved in DMF (4 mL) and to the solution
was added lithium carbonate (164 mg, 2.22 mmol, 4.5 equiv.) and
lithium bromide (193 mg, 2.22 mmol, 4.5 equiv.). The reaction
mixture was heated to 150 ꢀC and stirred at the same temperature
for 4 h, before it was allowed to cool down to room temperature
and quenched by the addition into deionised water (20 mL). The
aqueous layer was extracted with ethyl acetate (3 x 20 mL), and the
combined organic layers were subsequently washed with deion-
ised water (2x20 mL) and saturated aqueous sodium chloride so-
lution (20 mL), dried over magnesium sulfate, filtered and
concentrated to yield the crude material, which was purified
through flash column chromatography (10% Et2O/pentane). White
solid; 57 mg, 0.28 mmol, 57%. 1H NMR (400 MHz, CDCl3): dH 8.66
(1H, m), 7.84 (1H, m), 7.52e7.41 (3H, m), 7.29 (1H, t, J ¼ 7.9 Hz), 6.77
(1H, dd, J ¼ 7.8, 0.8 Hz), 5.48 (1H, d, J ¼ 1.3 Hz). 13C NMR (101 MHz,
CDCl3): dC 153.0, 141.4, 138.6, 135.0, 127.1, 125.9, 125.8, 124.5, 123.7,
122.1, 115.3, 110.5. IR (neat, v cmꢁ1) 3283, 3055, 1565, 1423, 1229.
HRMS (FTMS-p) m/z calculated for C12H7OS (M ꢁ H)- 199.0212,
found 199.0218. Melting point: 136.4e141.8 ꢀC.
J ¼ 8.3, 7.2,1.3 Hz), 5.11 (2H, d, J ¼ 0.8 Hz), 4.36 (2H, d, J ¼ 0.9 Hz). 13
C
NMR (101 MHz, CDCl3): dC 189.0, 156.6, 137.4, 135.4, 128.2, 126.3,
125.8, 125.0, 122.1, 72.6, 65.3. IR (neat, v cmꢁ1) 3062, 2967, 2840,
1671, 1466, 1392, 1198, 1088. HRMS (FTMS þ p) m/z calculated for
C
11H9O2S (M þ H)þ 205.0318, found 205.0318. Melting point:
113.6e116.4 ꢀC.
4.5.31. 1H-Benzo[4,5]thieno[3,2-c]pyran-4(3H)-one; (18b)
Prepared following general procedure C from alcohol 17b
(63 mg, 0.30 mmol). Purified by flash column chromatography (10%
EtOAc/pentane). Light-red solid; 10 mg, 0.049 mmol, 16%. 1H NMR
(400 MHz, CDCl3): dH 7.94 (1H, dt, J ¼ 8.2, 0.9 Hz), 7.73 (1H, ddd,
J ¼ 8.0, 1.3, 0.8 Hz), 7.54 (1H, ddd, J ¼ 8.2, 7.1, 1.3 Hz), 7.46 (1H, ddd,
J ¼ 8.1, 7.1, 1.1 Hz), 5.13 (2H, d, J ¼ 1.0 Hz), 4.43 (2H, m). 13C NMR
(101 MHz, CDCl3): dC 189.3, 146.3, 143.0, 135.4, 132.7, 128.6, 125.3,
123.8, 123.6, 72.8, 64.6. IR (neat, v cmꢁ1) 3053, 2848, 2818, 1670,
1525, 1343, 1327, 1293. HRMS (FTMS þ p) m/z calculated for
C
11H9O2S (M þ H)þ 205.0318, found 205.0319.
4.5.32. 1,2,3,4-Tetrahydrodibenzo[b,d]thiophen-1-ol; (12)
To a suspension of ketone (50 mg, 0.25 mmol) in methanol
(1 mL) at room temperature was added sodium borohydride
(12 mg, 0.31 mmol, 1.25 equiv.). The resulting solution was allowed
to stir for 20 min, before it was cooled to 0 ꢀC and quenched by the
addition of deionised water (1 mL) and stirred for 10 further mi-
nutes. The methanol was removed under reduced pressure and the
aqueous layer extracted with ethyl acetate (3 x 10 mL). The com-
bined organic layers were washed with saturated aqueous sodium
chloride solution (10 mL), dried over magnesium sulfate, filtered
and concentrated to obtain the crude product, which was purified
through flash column chromatography (25% Et2O/pentane). White
solid; 44 mg, 0.22 mmol, 88%. 1H NMR (400 MHz, CDCl3): dH 7.86
(1H, dt, J ¼ 8.0, 0.9 Hz), 7.77 (1H, dt, J ¼ 7.9, 0.9 Hz), 7.37 (1H, ddd,
J ¼ 8.0, 7.1, 1.2 Hz), 7.29 (1H, ddd, J ¼ 8.3, 7.2, 1.3 Hz), 5.07 (1H, dt,
J ¼ 6.8, 3.8 Hz), 2.93 (1H, m), 2.80 (1H, m), 2.17-1-87 (4H, m), 1.78
(1H, d, J ¼ 6.2 Hz). 13C NMR (101 MHz, CDCl3): dC 141.4, 138.7, 138.6,
4.5.35. Dibenzo[b,d]thiophen-4-ol; (14)
To a solution of ketone (100 mg, 0.5 mmol) in THF (3 mL) cooled
to 0 ꢀC, was added trimethylphenylammonium tribromide (207 mg,
0.55 mmol) and the solution stirred at 0 ꢀC for 1 h, before it was
allowed to warm to room temperature and stirred for further 4.5 h.
At that point, the reaction mixture was diluted with ethyl acetate
(10 mL) and deionised water (10 mL). The aqueous layer was
separated and extracted with ethyl acetate (3x15 mL). The
9

P. Natho, A.B. Rouse, J.L. Greenfield et al.
Tetrahedron xxx (xxxx) xxx
combined organic layers were washed with saturated aqueous
sodium chloride solution (15 mL), dried over magnesium sulfate,
filtered and concentrated to yield the crude material as a dark grey
solid. This was immediately dissolved in DMF (4 mL) and to the
solution was added lithium carbonate (164 mg, 2.22 mmol, 4.5
equiv.) and lithium bromide (193 mg, 2.22 mmol, 4.5 equiv.). The
reaction mixture was heated to 150 ꢀC and stirred at the same
temperature for 4 h, before it was allowed to cool down to room
temperature and quenched by the addition into deionised water
(20 mL). The aqueous layer was extracted with ethyl acetate (3 x
20 mL), and the combined organic layers were subsequently
washed with deionised water (2x20 mL) and saturated aqueous
sodium chloride solution (20 mL), dried over magnesium sulfate,
filtered and concentrated to yield the crude material, which was
purified through flash column chromatography (10% EtOAc/
pentane). Grey solid; 50 mg, 0.25 mmol, 50%. 1H NMR (400 MHz,
CDCl3): dH 8.14 (1H, m), 7.89 (1H, m), 7.79 (1H, dd, J ¼ 7.9, 0.9 Hz),
7.47 (2H, m), 7.35 (1H, t, J ¼ 7.8 Hz), 6.89 (1H, dd, J ¼ 7.8, 0.9 Hz),
5.24 (1H, s). 13C NMR (101 MHz, CDCl3): dC 150.4, 139.6, 138.0, 135.9,
years of age and he was a creative and highly productive scientist
before and during his 24 years as Professor of Organic Chemistry at
the University of Bath. He was kind and gracious and he will be
sorely missed by all those fortunate enough to have worked with
him. We condole with his family and we know that his memory will
live on.
The authors gratefully acknowledge an EPSRC Imperial College
President’s scholarship (to P.N.) and an Imperial College UROP
bursary (to A.B.R.). Additional funding from Dr Isabel Bader and her
late husband Dr Alfred Bader (to P.J.P.), and Oxana Bennett (to P.J.P)
is gratefully recognised. The authors thank Pete Haycock and Dr
Lisa Haigh for NMR and mass spectrometric analysis, respectively.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131636.
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J. Waser, J. Org. Chem. 83 (2018) 12334e12356.
3231, 3060, 1567, 1442, 1249, 1047. HRMS (FTMS þ p) m/z calculated
for C12H9OS (M þ H)þ 201.0369, found 201.0368. The data obtained
are in agreement with those previously reported [54].
4.5.36. 3,4-Dihydrodibenzo[b,d]thiophene-1(2H)-thione; (13)
To a solution of ketone (47 mg, 0.23 mmol, 1 equiv.) in toluene
(8 mL) was added Lawesson’s reagent (202 mg, 0.5 mmol, 2 equiv.)
and the solution heated to reflux for 4 h. The reaction mixture was
allowed to cool to room temperature and concentrated to yield the
crude material, which was purified by flash column chromatog-
raphy (10% Et2O/pentane). Purple oil; 42 mg, 0.19 mmol, 84%. 1H
NMR (400 MHz, CDCl3): dH 9.32 (1H, d, J ¼ 8.3 Hz), 7.77 (1H, d,
J ¼ 7.9 Hz), 7.49 (1H, t, J ¼ 7.7 Hz), 7.39 (1H, t, J ¼ 7.7 Hz), 3.28e3.15
(4H, m), 2.25 (2H, p, J ¼ 5.7 Hz). 13C NMR (101 MHz, CDCl3): dC
229.3, 156.9, 137.4, 137.4, 126.5, 126.4, 125.6, 125.0, 121.8, 50.8, 27.9,
25.1. IR (neat, v cmꢁ1) 3056, 2931, 2861,1482,1454,1420,1361,1339.
HRMS (FTMS þ p) m/z calculated for C12H11S2 (M þ H)þ 219.0297,
found 219.0298.
4.5.37. 2,3-Dihydrodibenzo[b,d]thiophene-4(1H)-thione; (16)
To a solution of ketone (47 mg, 0.23 mmol, 1 equiv.) in toluene
(8 mL) was added Lawesson’s reagent (202 mg, 0.5 mmol, 2 equiv.)
and the solution heated to reflux for 4 h. The reaction mixture was
allowed to cool to room temperature and concentrated to yield the
crude material, which was purified by flash column chromatog-
raphy (5% Et2O/pentane). Green solid; 32 mg, 0.15 mmol, 59%. 1
H
NMR (400 MHz, CDCl3): dH 7.81 (2H, td, J ¼ 7.7, 1.0 Hz), 7.49 (1H,
ddd, J ¼ 8.1, 7.1, 1.3 Hz), 7.39 (1H, ddd, J ¼ 8.2, 7.1, 1.1 Hz), 3.19 (2H,
m), 3.02 (2H, t, J ¼ 6.2 Hz), 2.29 (2H, p, J ¼ 6.3 Hz). 13C NMR
(101 MHz, CDCl3): dC 227.9, 147.6, 144.4, 140.3, 139.1, 128.5, 125.1,
125.0, 123.1, 47.5, 24.9, 24.6. IR (neat, v cmꢁ1) 3055, 2924, 2861,
1653, 1499, 1423, 1333, 1293, 1150. HRMS (FTMS þ p) m/z calculated
for C12H11S2 (M þ H)þ 219.0297, found 219.0297.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
This paper is a contribution to the memory of a very dear friend
who was a true scholar in his field of synthetic chemistry. Jon
Williams was appointed to the chair of organic chemistry at 31
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