Multi-bond forming and iodo-selective base-promoted homolytic aromatic substitution

Article abstract of DOI:10.1039/c5ra03460d

Base-promoted homolytic aromatic substitution (BHAS) has been applied as a means to effect multi-bond forming reactions. Using the dioxepine framework to illustrate the concept, BHAS was used to rapidly access regio-defined polycycles in merely 2 or 3 ste

Full text of DOI:10.1039/c5ra03460d

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Multi-Bond Forming and Iodo-Selective Base-Promoted Homolytic Aromatic
Substitution
Kye-Simeon Masters*
Chemistry, Physics and Mechanical Engineering School (CPME), Queensland University of
Technology (QUT), Brisbane, Queensland, Australia
kye.masters@qut.edu.au
Base-promoted homolytic aromatic substitution (BHAS) has been applied as a means to effect
multi-bond forming reactions. Using the dioxepine framework to illustrate the concept, BHAS was
used to rapidly access regio-defined polycycles in merely 2 or 3 steps from iodophenol. Both liquid
and solid arenes of an electronically-diverse nature were used as the coupling partner/solvent. DMSO
additive was found to promote this multi-BHAS reaction. A pathway consistent with observations is
suggested, this hypothesis was exploited to further develop an iodo-selective BHAS reaction.
Introduction
1
Since Ullmann’s copper-mediated biaryl synthesis, this most crucial of carbon-carbon
bonds has been the subject of extensive synthetic advances. As a result, most methods which
have been developed for the construction of multiple biaryl bonds in a single operation have
hitherto relied on transition metal-catalysis. Arguably the most promising metal-free

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2
3
alternative to established transition metal-mediated methods of cross-catalysis and C−H
4
functionalization
is the recently-discovered Base-promoted Homolytic Aromatic
5
Substitution (BHAS). BHAS features the use of a tert-butoxide base alongside a sub-
6
stoichiometric amount of diamine (or other) initiator to generate aryl radical species and is
a
6b
a hot topic in the contemporary iteration of a ‘radical renaissance’.
7
Multi-bond forming reactions provide expedient, selective and often high-yielding access
to desirable targets and synthetic intermediates with minimal expenditure of chemical
resources. Early BHAS work has demonstrated its potential to generate multiple C–C bond
5b,c,8,9
formations via twofold substitutions
10
and showcased interesting cyclizations. Initial
multi-BHAS examples have been restricted to substitution of two halide functional handles
upon a single arene core with benzene as coupling partner (Scheme 1); further advances
appear not to have been made on this aspect of BHAS methodology to date. In this work, a
multi-bond forming methodology has been developed to effect both an intramolecular BHAS
to a tethered arene and an intermolecular BHAS with the arene solvent/reactant. Uniquely for
multi-bond forming BHAS reactions: i) the two reactive halo-functionalities of the multi-bond
forming reaction are located on separate arenes; ii) the H–arene is not limited to benzene; and
iii) conditions have been found for effective control of iodo-(over bromo-)arene selectivity.
Mechanistic reasoning suggests that this reaction may comprise elements of each ‘domino’
7d
and ‘multi-bond forming transformation of independent’ reactions.

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SCHEME 1. Existing and new classes of BHAS transformation
Break-through publication on transition metal-free, alkali-metal tert-butoxide-promoted
5
C–H substitution have been contributed by Itami and co-workers and the groups of Hayashi
a
5
b
5c
5d
and Shirakawa, Lei and Kwong, and Shi. The literature has since seen a rapidly-
9
increasing interest in BHAS, which has demonstrated that it may be promoted photolytically
1
or with a variety of additives to effect cyclization, arene-arene coupling, and Heck-like
1
10
12
1
3
6a
substitution. Studer and Curran described the mechanism of this homolytic aromatic
substitution as a radical chain-reaction, where the electron is passed from reactant to
1
reactant –i.e. the ‘electron is a catalyst’. The source of the initial electron (the initiation
4
6c
1
5
step) in this reaction is the subject of some debate -several suggestions have been made.
1
6
Inspired by both the ‘lactone method’ and the innovative early BHAS cyclization work
1
0a
of Charette and co-workers,
the ‘acetal method’ is a strategy for the synthesis of
2
,2ʹ-(ortho,ortho-)biphenols via dibenzo[1,3]dioxepines utilizing BHAS for the key ring-
1
7
closing reaction.
Expanding on this initial work, non-symmetrical aryl-substituted

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dibenzo[1,3]dioxepines were chosen as targets to explore BHAS in the context of multi-bond
forming reactions.
Results
Synthesis of non-symmetrical and symmetrical di(haloaryloxy)methylene ethers by the
1
7b
previously-reported method saw conversion of 4-iodophenol to the mixed O,S–methylene
diether, 2 (Scheme 2), which was substituted in a two-stage one-pot reaction with sulfuryl
chloride and then 2-bromophenol, delivering bromoaryl-iodoarene 4 in 84% yield (over 2
steps). This sequence with 2-iodophenol led to 2,4ˊ-diiodoaryloxy ether 6 (79% over 2 steps).
2-Iodophenol was also converted to 2,3ˊ-diiodoaryloxy methane 10 (by way of 8, 87%, two
steps) and to bis-(2-iodoaryloxy)methane 7 (93%, one step).
SCHEME 2. Dihaloarene Substrates for Multi-bond Forming BHAS
Conditions: (a) NaH, then ClCH , DMF, r.t; (b/i) SO Cl
2
SCH
3
2
2 2 2
, CH Cl , r.t., (ii) Halophenol, NaH,
2 2
DMF, r.t., then mixture from (b/i) in DMF; (c) NaH, CH I , DMF, r.t.
The cascade reaction was explored utilizing 2-bromophenoxy-4ʹ-iodophenoxymethane, 4,
1
8
with the conditions optimised by Charette and previously successful for the simple
cyclization to dioxepines: Potassium tert-butoxide (6.0 equiv., i.e. 3.0 equivalents per
halogen moiety), 1,10-phenanthroline (80 %) at 140 °C with benzene and pyridine as
substrate and solvent, respectively (ratio = 1:7, entry 1, Table 1). These initial conditions

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proved to be unsatisfactory, as only traces of desired product 11 were observed. Using
benzene as both solvent/reactant delivered the multi-BHAS compound in 23% yield, albeit as
part of a complex mixture of at least four identifiable products (11–14). These (by)products
17b
19
result from coupling -and 7-ortho-cyclization (11), -and de-halogenation (12), -then 6-
1
0a
20
17b
ipso-cyclization then C→O transposition and elimination of formaldehyde (to 13),
-
19
and aryl alkoxylation by nucleophilic or radical aromatic substitution (14). Change of the
substrate to diiodide 6 gave an improved ratio between the products (entry 3), but the yield of
11 remained low (21%).
TABLE 1. Optimization of the Multi-Bond Forming BHAS
Entry,
Substrate
Solvent
Conc.
(M)
DMSO
(equiv.)
Time
(h)
11
(%)
12
(%)
13
(%)
14
(%)
1
2
3
4
, 4
, 4
, 6
, 6
Pyr./PhH (7:1)
0.25
0.25
-
120
240
120
240
240
ND
23
24
5
ND
12
ND
50
C
6
6
H
H
6
6
6
6
-
C
0.125
0.125
0.125
-
21
12
19
ND
11
30
C H
6
5.0
5.0
59
14
ND
ND
5, 6*
C
6
H
ND
ND
Conditions: 1,10-Phen. (80 mol%), KOtBu (6.0 equiv.), Ar-H (20-40 equiv.), DMSO (5.0 equiv.),
microwave irradiation (MWI), 140 °C. All yields are isolated. *1,10-phenanthroline was excluded.
ND = none detected.
Rossi and co-workers have discovered that DMSO improves BHAS yields under
9
photoactivation at room temperature -happily, when a small amount of DMSO was included
as an additive with the conditions above(5.0 equiv., entry 4), the outcome of this thermally-
promoted reaction was also greatly improved in terms of yield and selectivity. DMSO

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additive increased the isolated yield of cascade product 11 from 59%, and prevented
generation of alkoxy-substituted byproduct 14. A control experiment with DMSO in the
absence of 1,10-phenanthroline showed that DMSO alone is not capable of promoting the
reaction (entry 5).
With satisfactory conditions determined, the cascade BHAS was then applied to
cyclization/coupling with several electronically-diverse arene partners. Complementing the
usual use of liquid arenes (benzene and 1,4-difluorobenzene,) some of these were solids at
room temperature (1,4-dimethoxybenzene, pyrazine, naphthalene, Scheme 3). Physical
separation of the base and initiator in distinct layers of the reaction vessel prior to heating
ensured that the reaction did not commence until the arene was liquefied (see Figure 1,
supporting information). Diiodides 6 and 7 produced 2- and 4-aryl-substituted dioxepines
15–18 and 19─24a/b in moderate to good yields (50–71%, Scheme 3), and meta-iodo
substrate 10 gave a mixture of each of the two possible products (24a/b). Coupling of
symmetrical diiodide 7 with benzene to afford 20 was notably poor in yield
(38% -unsubstituted dioxepine was consistently isolated in 12–14% yield). These yields are
satisfactory when considered in light of the two discrete C─C bond forming events that must
take place. All 4 possible Ph-substituted isomers (11, 20, 24a and 24b) were isolated and
characterized.
Although multiple equivalents of arene are used in this method, the low cost of these
coupling partners makes their use nonetheless advantageous. In contrast with typical cross-
coupling substrates to form biaryls (aryl-zincs, -boronic acids, etc.), standard H-arenes not
2
requiring preactivation or in situ preparation, are cheap, non-toxic, do not require careful
1
preparation, and are readily to hand in most chemistry laboratories.

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SCHEME 3. Multi-bond Forming to Aryl-substituted Dibenzo[1,3]dioxepines
Conditions: 1,10-Phen. (80 mol%), KOtBu (6.0 equiv.), Ar-H (10-30 equiv.), DMSO (5.0 equiv.),
MWI, 140 °C, 4 h.
Discussion
A reaction pathway accounting for observations and isolated byproducts is proposed
below (Scheme 4). EPR studies have demonstrated the generation of radicals in BHAS

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2
2a,b
reactions.
and a recent report by Jutand and Lei has investigated the reaction with of
22c
cyclic voltametry. Single-electron-transfer (SET) is thought to initially result in a radical
anion located upon the haloarene –the observed non-reactivity of substrate 6 in the presence
2
of 1,4-dinitrobenzene an established radical anion scavenger, further supports the role of a
3
radical anion (see Scheme 3).
The multi-BHAS from diiodoaryl 6 exhibits a uniform arene-coupling outcome at the
(formerly iodo-bearing) C-(para) position, whereas there are a range of at least four possible
modes of reaction for the C-(ortho) position, as evidenced by the products isolated (their
distribution varies with reaction conditions, see Table 1). These results suggest that in
2
4
addition to the most straightforward ortho-σ-radical pathway to 11 via initially-cyclised 26,
there is some degree of independently-operating pathway where initial substitution is at the
apparently more reactive para-iodo-substituted position of 6 to form radical intermediate 25
then 28. This cyclohexadienyl radical undergoes rapid transfer of its (extremely acidic)
2
5,22a
proton
then either intramolecular ET (to 29 then 11) or intermolecular ET to another
iodoarenyl moiety on a different molecule (6 or 30), and continuation of the chain process.
Intermediate ortho-σ-type radical 29 can apparently follow one of four divergent pathways:
Pathway 1 involves 7-ortho cyclization to also result in 11, pathway 2 sees 6-ipso cyclization,
then C→O transposition and loss of ‘CH O’ to (relatively) stable phenoxyl radical then
2
phenol 13, and in pathway 3 the ortho-σ-radical abstracts hydrogen is quenched to anion with
another in situ-generated electron-donor, giving 12. Lastly, tert-butoxyl substituted 14 may
19a
be generated by either a radical or nucleophilic aromatic substitution
11m,19b
pathway, from
1
9c
2
9 or 30, respectively (or perhaps both). Having previously established that 2-bromo
substrate 4 gave more of t-butyl ether 14 than 2-iodo 6 (see Table 1), the latter pathway
appears likely. It is likely that the pathways from substrates 7 and 10 are similarly complex.

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SCHEME 4. Likely Mechanism for the Multi-BHAS to form 11–14.
The role of DMSO co-solvent in promoting formation of 11 and suppressing the side-
reactions to e.g. tert-butoxyl substituted arene 14 is not yet clear, but may be to enhance the
domino pathway over the ‘multiple independent reaction’ pathway. Visually, these reactions

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exhibited a more rapid formation of the dark coloration linked to initiation, and enhanced
radical-initiation is another strong possibility.
SCHEME 5. Possible Roles of DMSO in Promoting the BHAS Initiation
The addition of KOt-Bu to DMSO rapidly forms an equilibrium mixture with t-
2
6
2 3
BuOH/dimsyl potassium superbase (KCH SOCH , 34, Scheme 5). In the presence of 1,10-
phenanthroline, the potassium dimsyl salt may be chelating to form a potassium amide
superbase 38 analogous to 1,3-diaminopropane which makes KAPA (potassium 3-
2
7 a
aminopropy-1-amide, 36),
still more basic than potassium dimsyl by a factor of
5
6 27b
•
1
0 ─10 . Such a species may undergo an inner-sphere electron-tansfer to form Phen ¯ and

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•
tBuO in the as suggested by Lei and Jutand,
22c
or perhaps promote the formation of the
attractive super electron donor 39, proposed by Tuttle and Murphy, which requires
15a
deprotonations of 1,10-phenanthroline, 37. To present a further possibility, Wilden and co-
workers have recently described a dynamic equilibrium between ‘nearly-covalent’ KOt-Bu
(29), its charge-separated form (39a), and a charge separated form with a loosely-bound
electron (40a), which alone can provide for the initial SET to the haloarene at elevated
2
8
temperatures (160 °C). It may be the case that a shifting in the equilibrium position to favor
the latter of these species (39 and 40) is enhanced in the presence of cation-stabilising
DMSO. An alternative is that the dimsyl potassium superbase, which is a strong electrolyte
29
itself, also has a loosely-bound electron form which can be donated. Regardless, the effect
of DMSO addition is enhancement of the pathway to 11, outcompeting that to 14.
Given the postulated mechanism above, it was hoped that the reaction conditions could be
tuned so as to block reactivity of the 2-halo position upon the initially-used bromoaryl species
4
. Selectivity for the p-iodo functionality BHAS was convincingly induced by excluding the
DMSO additive, decreasing the reaction temperature to 100 °C, and shortening the duration
of the reaction to 60 minutes, conditions which maintained the 2ˊ-bromoaryl functionality
intact (43–46, 50–86% yield). Chemo-/regio-selective control is so far poorly controllable in
the BHAS reaction, but could allow for sequential BHAS/BHAS and BHAS/TM-catalysis
coupling sequences, e.g. in divergent synthesis. The scope of para-iodo-selective coupling
partners matched that of the multi-BHAS (Scheme 6).

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SCHEME 6. Iodoarene-Selective BHAS in the presence of a bromoarene moiety
O
O
O
O
O
O
O
I
O
O
O
Br
Br
Br
Br
Br
MeO
N
4
N
OMe
4
3, 58%
44, 68%
45, 50%
46a/b, 87%
1/2-Np = 3:2)
Conditions: 1,10-Phen. (40 mol%), KOtBu (3.0 equiv.), Ar-H (20-40 equiv.), MWI, 100 °C, 1 h.
(
Conclusion
The BHAS reaction should be considered a synthetic option when multi-bond forming reactions
are desired for rapid, modular generation of polycycles or other compounds with multiple biaryl
connections. A multi-BHAS approach can work well, eschewing the use of transition-metals. Iodo-
selective conditions were also established to allow attachment of only one arene to the scaffold,
leaving the bromoarene intact for a host of subsequent reaction methods. The multi-bond and stepwise
BHAS methods makes use of relatively cheap and environmentally benign substrates/reagents, and
thus holds promise for efficient transformations in chemical Industry, decreasing costs ‘on scale’ and
precluding trace amounts of toxic transition metals. Continuation of studies focusing on the further
scope of the multi-bond forming BHAS and role of DMSO is currently underway in the laboratory.
Experimental Section
General Experimental
Chemicals and solvents were used as commercially supplied without further purification, unless
otherwise noted. Potassium tert-butoxide (95%), 1,10-phenanthroline (99%), sodium hydride (60%
dispersion in mineral oil), dimethyl sulfoxide (Reagentplus ≥99.5% purity), chloromethyl
methylsulfide (95%), 1,4-dimethoxybenzene (99%), pyrazine (≥99%), naphthalene (99+%), sulfuryl
chloride (97%) and dimethylformamide (99.5%, anhydrous) were supplied by Aldrich. Benzene

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(
analytical reagent grade, obtained from Chemsupply Australia) was dried over anhydrous molecular
sieves prior to use. Optimal results for this methodology required the storage of potassium tert-
butoxide in a desiccator, and commercially-available 1,10-Phenanthroline was dried of water prior to
use by addition of dry toluene azeotroping out on the rotavap (repeat x 2). Microwave reactions were
+
performed in a Biotage Initiator with a maximum power of 400 W, reactions were in new vials with
securely-sealed (crimped) microwave tubes. Column chromatography was performed on Davisil
(
(
LC60A, 40-63um Grace). Preparative HPLC was performed on an Agilent HPLC with a C18 column
25 x 200 mm) using tetrahydrofuran and water (both HPLC grade, Merck). NMR data were recorded
1
13
on a Varian Infinity-Plus 400 spectrometer ( H at 400 MHz; C at 100 MHz), and resonances are
reported in terms of chemical shift (δ) in parts per million (ppm) referenced to the solvent peak;
coupling constants (J) are given in Hertz (Hz) and the number of protons per signal as nH. Splitting is
reported as br. = broad, s = singlet, d = doublet and m = multiplet.
General Procedures (1–4):
1) Multi-Bond BHAS Reactions with arenes (solids at room temperature)
To a 2-5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially 1,10-
phenanthroline (72 mg, 0.40 mmol), half the solid arene (10-20 mmol), the halo-substituted substrate
(
0.50 mmol), DMSO (195 mg, 2.5 mmol), the second half of the arene substrate (10─20 mmol) and
lastly potassium tert-butoxide (336 mg, 3.0 mmol) under a shower of argon. The reagents were
layered with portions of arene separating them, such that the phenanthroline and potassium tert-
butoxide did not come into contact until such time as the arene has melted (see Figure 1 in the
supporting Information). The vial was capped and the atmosphere cautiously removed by vacuum
through an inserted needle with stirring, then replaced with argon (repeat three times). The reaction
mixture was then heated to 140 °C via microwave irradiation for 240 minutes (reactions involving
pyrazine were brought to this temperature with 10 minutes ramp time to ensure that exotherms did not
occur). After this time, the blackish-coloured reaction mixture was allowed to cool to room
temperature, then layered onto a plug of silica gel, which was then flushed with ethyl acetate (150

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mL). The volatiles were removed by rotary evaporation under diaphragm pump vacuum (to 30 MBar),
then the crude was purified by column chromatography on silica gel with mixtures of hexane and co-
eluent (see specific compounds for details).
2) Multi-Bond BHAS Reactions with arenes (liquids at room temperature)
To a 2-5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially the 1,10-
phenanthroline (72 mg, 0.40 mmol) the dihalo-substituted substrate (0.50 mmol) and potassium tert-
butoxide (336 mg, 3.00 mmol) and anhydrous benzene (40 mmol) or 1,4-difluorobenzene (2.5 g, 22
mmol) added, followed by DMSO (195 mg, 2.50 mmol). The vial was capped and cooled 0 °C and
the atmosphere cautiously removed by vacuum through an inserted needle with stirring, then replaced
with argon (repeat three times). The reaction mixture was then heated to 140 °C via microwave
irradiation for 240 minutes (reactions involving pyrazine were brought to this temperature with 10
minutes ramp time to ensure that exotherms did not occur). After this time, the blackish-coloured
reaction mixture was allowed to cool to room temperature, then layered onto a plug of silica gel,
which was then flushed with ethyl acetate (150 mL). The volatiles were removed by rotary
evaporation under diaphragm pump vacuum (to 30 MBar), then the crude was purified by column
chromatography on silica gel with mixtures of hexane and co-eluent (see specific compounds for
details).
3) Iodo-Selective BHAS Reactions with arenes (solids at room temperature)
To a 2-5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially 1,10-
phenanthroline (36 mg, 0.20 mmol), half the solid arene (10–20 mmol), the halo-substituted substrate
(
(
0.50 mmol), the second half of the arene substrate (10─20 mmol) and lastly potassium tert-butoxide
168 mg, 1.5 mmol) under a shower of argon. The reagents were layered with portions of arene
separating them, such that the phenanthroline and potassium tert-butoxide did not come into contact
until such time as the arene has melted (see labelled photograph). The vial was capped and the
remainder of the procedure carried out as in general procedure 1, except that the reaction mixture
was only heated to 100 °C for 60 minutes.

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4) Iodo-Selective BHAS Reactions with arenes (liquids at room temperature)
To a 2-5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially the 1,10-
phenanthroline (36 mg, 0.20 mmol) the dihalo-substituted substrate (0.50 mmol) and potassium tert-
butoxide (168 mg, 2.00 mmol) and anhydrous benzene (30 mmol) or 1,4-difluorobenzene (2.5 g, 22
mmol) added, followed by DMSO (195 mg, 2.50 mmol). The vial was capped and cooled 0 °C and
the atmosphere cautiously removed by vacuum through an inserted needle with stirring, then replaced
with argon (repeat three times). The remainder of the procedure carried out as in general procedure
2, except that the reaction mixture was only heated to 100 °C for 60 minutes.
Preparation of Specific Compounds
Compound 2 / ((4-Iodophenoxy)methyl)(methyl)sulfane. To a dried 250 mL round-bottomed flask
fitted with a stirring bar and maintained under a positive pressure of argon were added 4-iodophenol
(
(
11.0 g, 50.0 mmol), DMF (50 mL) and the two stirred to -5 °C in a salt/ice bath. Sodium hydride
2.40 g, 60.0 mmol, 1.2 equiv., 60% dispersion in mineral oil) was added under argon and the reaction
mixture stirred until gas evolution had ceased (~10 minutes) and then allowed to warm up to room
temperature (~20 minutes), before recooling. To the opaque reaction mixture was added dropwise
chloromethyl methyl sulfide (5.0 mL, 60.0 mmol, 1.2 equiv.) and the reaction mixture stirred at room
temperature for 12-14 hours. After this time, the mixture was poured into H
2
2
O (300 mL) and extracted
O (200 mL × 2), brine
with CH Cl /hexanes (1:1, 150 mL, × 2). The organics were washed with H
2
2
(
50 mL) and dried over sodium sulfate. Filtration and removal of the volatiles by rotary evaporation
under diaphragm pump vacuum (to 30 MBar) followed, then the crude was purified by column
chromatography on silica gel with hexane/CH
2
Cl
2
(9:1). Isolated as a colourless semi-solid, 13.14 g,
1
6.9 mmol, 94% yield. MP: ca. room temperature; H NMR (400 MHz, CDCl
4
3
): δ = 7.58 (dt, J = 9.0,
1
3
2
.0 Hz, 2H), 6.73 (dd, J = 9.0, 2.3 Hz, 2H), 5.11 (s, 2H), 2.23 (s, 3H); C NMR (101 MHz, CDCl ): δ
3
=
156.8, 138.3, 118.3, 84.2, 72.4, 14.6; LRMS (+EI, GCMS): Found 280.0; HRMS (+EI):
•+
8 9
Calculated [C H IOS] : 279.9419; Found:279.9419

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Compound 4 / 1-Bromo-2-((4-iodophenoxy)methoxy)benzene. Stage 1: Prepared in a 2-stage
pseudo-1-pot reaction from Compound 2 and 2-bromophenol by a modification of the method of
17
Masters and Bräse (two stages, 89%). To a stirred solution of [(4-Iodophenoxy)methyl]
(
methyl)sulfane 2 (1.40 g, 5.00 mmol) in dry CH Cl (25 mL) under argon in a 100 mL round-
2
2
bottomed flask held at -5 °C in a salt/ice bath was added dropwise sulfuryl chloride (410 mL, 5.125
mmol, 1.025 equiv.). The ice bath was removed and the reaction mixture was stirred up to room
temperature over 60 minutes, becoming pale-yellow. After this time the volatiles were removed by
rotary evaporation under diaphragm pump vacuum (to 30 Mbar; this should be done with a rotary
evaporator in a fume-cupboard). The crude product is invariably obtained with complete conversion
1
and in quantitative yield, and can be checked if desired ( H-NMR, CDCl
3
). This crude material was
taken up in dry, non-hydrolyzed or amine-free DMF and added directly to the deprotonated phenols in
stage 2.
Stage2: To a stirred solution of 2-bromophenol (951 mg, 5.5 mmol, 1.1 equiv.) in dry, non-hydolyzed
or amine-free DMF (27.5 mL) under argon and at 0 °C was added sodium hydride (240 mg, 6.0 mmol,
1.2 equiv., 60% dispersion in mineral oil) and the mixture stirred for 30 minutes with warming to
room temperature. After re-cooling to 0 °C, the aryloxymethylenechloride from stage 1 was added
dropwise as a solution in DMF (5.0 mL, 2 mL washings). After stirring overnight, the reaction
2
mixture was heated at 50 °C for 4 hours, then poured into H O (70 mL) and extracted with
CH Cl /hexanes (1:1, 50 mL, × 2). The combined organics were washed with H O (50 mL x 2), then
2
2
2
brine (20 mL) and dried over sodium sulfate. Filtration and removal of the volatiles by rotary
evaporation under diaphragm pump vacuum (to 30 MBar) followed, then the crude was purified by
column chromatography on silica gel with hexane/CH Cl (9:1). Isolated as a colourless oil which
2
2
solidified overnight, recrystallization from MeOH/CH
2
Cl
2
yielded the compound as colourless
): δ = 7.63 - 7.57
1
needles, 1.80 g, 4.45 mmol, 89% yield. MP: 40-42°C; H NMR (400 MHz, CDCl
3
(
m, 2 H), 7.54 (dd, J = 1.6, 7.8 Hz, 1 H), 7.30 - 7.26 (m, 1 H), 7.23 - 7.16 (m, 1 H), 6.98 - 6.85 (m, 3
1
3
H), 5.74 (s, 2 H); C NMR (101 MHz, CDCl ): δ = 156.8, 153.2, 138.4, 133.6, 128.5, 124.0, 118.8,
3

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116.7, 113.1, 91.4, 85.3; LRMS (+EI, GCMS): Found 403.9; HRMS (+EI): Calculated
•
+
[
C H BrIO ] : 403.8903; Found: 403.8909.
13 10 2
Compound 6 / 1-Iodo-2-((4-iodophenoxy)methoxy)benzene. Prepared in a 2-stage pseudo-1-pot
reaction from compound 2 and 2-iodophenol (two steps, 84%) by a close modification of the
procedure to prepare compound 4. Starting from ((4-Iodophenoxy) methyl)(methyl)sulfane 2 (2.45 g,
8.75 mmol), compound 6 was delivered as colourless needles, 3.98 g, 7.35 mmol, 84% yield. MP:
1
5-86°C; H NMR (400MHz, CDCl
8
3
) δ = 7.76 (dd, J = 1.6, 7.8 Hz, 1 H), 7.66 - 7.53 (m, 2 H), 7.29
(
ddd, J = 1.6, 7.2, 8.4 Hz, 1 H), 7.13 (dd, J = 1.2, 8.2 Hz, 1 H), 6.96 - 6.88 (m, 2 H), 6.78 (dt, J = 1.4,
1
.5 Hz, 1 H), 5.72 (s, 2 H); C NMR (101MHz, CDCl
3
7
3
) δ = 156.7, 155.5, 139.6, 138.4, 129.5, 124.4,
118.8, 115.2, 91.2, 87.2, 85.3; LRMS (+EI, GCMS): Found 451.9; HRMS (+EI): Calculated
•+
13 10 2 2
[C H I O ] : 451.8765; Found: 451.8770.
Compound 7 / Bis(2-iodophenoxy)methane. To a stirred solution of 2-iodophenol (2.50 g, 12.3
mmol) in dimethylformamide under argon was added potassium carbonate (4.23 g, 30.6 mmol, 2.50
equiv.) then methyl iodide (0.77 mL, 1.75 g, 12.3 mmol. 2.0 eq.), and the resulting reaction mixture
heated to 40 °C with stirring for 12 h. After this time, the reaction mixture was partitioned between
H
2
O and diethyl ether (each 30 mL) and the aqueous phase extracted with diethyl ether twice more.
The combined organics were washed with H O (30 mL) once more, then with brine (5 mL) and dried
2
over sodium sulphate. The volatiles were removed by rotary evaporation under diaphragm pump
vacuum (to 30 MBar), then the crude was purified by column chromatography on silica gel with
hexane and CH
2
Cl
2
(8:1). Isolated as a colourless solid, recrystallization from MeOH/CH
2
Cl
2
yielded
) δ
1
the compound as colourless needles, 5.18 g, 93% yield. MP: 94-95°C; H NMR (400MHz, CDCl
3
=
7.79 (d, J = 7.8 Hz, 2 H), 7.39 - 7.32 (m, 2 H), 7.28 (s, 2 H), 6.81 (t, J = 7.6 Hz, 2 H), 5.82 (s, 2 H);
13
3
C NMR (101 MHz, CDCl ): δ = 155.7, 139.6, 129.7, 124.4, 115.5, 91.7, 87.1; LRMS (+EI, GCMS):
•
+
Found 451.9; HRMS (+EI): Calculated [C13
10 2 2
H I O ] : 451.8765; Found: 451.8768.
Compound 8 / ((2-Iodophenoxy)methyl)(methyl)sulfane. Prepared by modification of the
procedure to prepare compound 2. 2-iodophenol (5.50 g, 25.0 mmol.) was converted to compound 9,

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1
isolated as a colourless liquid, 6.52 g, 23.3 mmol, 93% yield. H NMR (400 MHz, CDCl
3
): δ = 7.77
(
dd, J = 7.8, 2.0 Hz, 1H), 7.26 - 7.34 (m, 1H), 6.88 (dd, J = 8.4, 1.4 Hz, 1H), 6.75 (td, J = 7.5, 1.4 Hz,
1
3
1
8
2
H), 5.20 (s, 2H), 2.28 (s, 3H); C NMR (101 MHz, CDCl
3
): δ = 155.5, 139.7, 129.2, 123.6, 114.3,
•+
7.8, 73.3, 14.; LRMS (+EI, GCMS): Found 280.1; HRMS (+EI): Calculated [C H IOS] :
8
9
79.94188; Found: 279.9422.
Compound 10 / 1-Iodo-2-((3-iodophenoxy)methoxy)benzene. Prepared in a 2-stage pseudo 1-pot
reaction from compound 8 and 3-iodophenol (two steps, 84%) by a close modification of the
procedure to prepare compound 4. Starting from ((4-Iodophenoxy) methyl)(methyl)sulfane 9 (2.67 g,
9.5 mmol), compound 10 was delivered as colourless needles, 4.27 g, 8.93 mmol, 94% yield. MP:
1
0 °C; H NMR (400MHz, CDCl
4
3
) δ = 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.39
(
d, J = 7.4 Hz, 1H), 7.31 (td, J = 8.6, 2.0 Hz, 1H), 7.10 - 7.17 (m, 2H), 7.03 (dd, J = 8.6, 7.4 Hz, 1H),
1
3
6
.80 (t, J = 7.6 Hz, 1H), 5.74 (s, 2H); C NMR (101MHz, CDCl
3
) δ = 157.3, 155.4, 139.7, 131.8,
130.9, 129.5, 125.8, 124.4, 115.8, 115.2, 94.2, 91.1, 87.2; LRMS (+EI, GCMS): Found 451.9;
•+
10 2 2
HRMS (+EI): Calculated [C13H I O ] : 451.8765; Found: 451.8770.
2 2
Compound 11 / 2-Phenyldibenzo[d,f][1,3]dioxepine. Chromatography was performed with CH Cl
in hexane fraction as eluent (gradient, 0 to 10%). Isolated as a colourless oil, 81.0 mg, 0.295 mmol, 59%
1
yield. H NMR (400MHz, CDCl
3
) δ = 7.85 (d, J = 2.0 Hz, 1 H), 7.73 (dd, J = 1.4, 7.6 Hz, 1 H), 7.63 -
7
7
1
9
2
.57 (m, 2 H), 7.51 (dd, J = 2.3, 8.2 Hz, 1 H), 7.45 (t, J = 7.4 Hz, 2 H), 7.38 - 7.29 (m, 2 H), 7.27 -
1
3
.19 (m, 2 H), 7.17 (dd, J = 1.2, 8.2 Hz, 1 H), 5.64 (s, 2 H); C NMR (101MHz, CDCl
3
) δ = 155.5,
54.6, 140.7, 137.7, 129.6, 129.2, 129.1, 128.9, 128.8, 127.7, 127.6, 127.3, 127.1, 124.7, 121.3, 121.0,
•+
14 2
9.3; LRMS (+EI, GCMS): Found 274.1; HRMS (+EI): Calculated [C19H O ] : 274.0988; Found:
74.0988.
Compound 12 / 4-(Phenoxymethoxy)-1,1'-biphenyl. Isolated from the test reaction to produce 2-
phenyldibenzo[d,f][1,3]dioxepine (Compound 11) after continuation of the column with CH Cl in
2
2
hexane fraction as eluent (gradient, 0 to 10%, eluted just prior to the dioxepine). Isolated as a
1
colourless oil, 16.7 mg, 0.060 mmol, 12% yield. H NMR (400 MHz, CDCl ) δ = 7.55 - 7.50 (m, 4 H),
3

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7.43 - 7.38 (m, 2 H), 7.33 - 7.28 (m, 3 H), 7.19 - 7.15 (m, 2 H), 7.12 (dd, J = 1.0, 8.8 Hz, 2 H), 7.03 (t,
1
3
J = 7.2 Hz, 1 H), 5.76 (s, 2 H); C NMR (101 MHz, CDCl
3
) δ = 156.9, 156.4, 140.6, 135.5, 129.6,
128.7, 128.2, 126.9, 126.8, 122.5, 116.7, 116.4, 91.1; LRMS (+EI, GCMS): Found 276.1; HRMS
•
+
(
16 2
+EI): Calculated [C19H O ] : 276.1150; Found: 276.1150.
Compound 13 / [1,1':3',1''-Terphenyl]-4'-ol. Isolated from the test reaction to produce 2-
phenyldibenzo[d,f][1,3]dioxepine (Compound 11) after continuation of the column with Et
2
O in
1
hexane fraction as eluent (10%). Isolated as a colourless solid, 13.0 mg, 0.054 mmol, 11% yield. H
NMR (400MHz, CDCl ) δ = 7.72 (d, J = 8.2 Hz, 2 H), 7.64 (d, J = 7.4 Hz, 2 H), 7.56 (d, J = 7.8 Hz, 2
H), 7.47 (t, J = 7.6 Hz, 2 H), 7.41 - 7.35 (m, 1 H), 7.32 - 7.22 (m, 2 H), 7.05 - 6.97 (m, 2 H), 5.25 (s, 1
3
1
3
H); C NMR (101MHz, CDCl
3
) δ = 152.5, 140.7, 140.5, 136.0, 130.2, 129.5, 129.2, 128.9, 127.9,
127.7, 127.5, 127.1, 120.9, 115.9; LRMS (+EI, GCMS): Found 246.1; HRMS (+EI): Calculated
•
+
[
C H O] : 246.1039; Found: 246.1045.
18 14
Compound 14 / 4-((2-(tert-Butoxy)phenoxy)methoxy)-1,1'-biphenyl. Isolated from the test reaction
to produce 2-phenyldibenzo[d,f][1,3]dioxepine (Compound 11) after continuation of the column with
Et
2
O in hexane fraction as eluent (gradient, 3 to 10%). Isolated as a milky gum, 51.8 mg, 0.149 mmol,
1
3
0% yield. H NMR (400MHz, CDCl ) δ = 7.49-7.65 (m, 4 H), 7.37-7.46 (m, 2 H), 7.27-7.36 (m, 1
3
H), 7.03-7.24 (m, 3 H), 6.87 (dq, J = 8.2, 1.0 Hz, 1 H), 6.80 (t, J = 2.2 Hz, 1 H), 6.70 (dq, J = 8.1, 0.9
1
3
Hz, 1 H), 5.74 (m, 2 H), 1.36 ppm (m, 9 H); C NMR (101MHz, CDCl
40.7, 135.5, 129.5, 129.2, 128.7, 128.2, 126.9, 126.8, 118.1, 116.7, 112.5, 111.3, 91.1, 78.7, 28.8;
HRMS (+EI, GCMS): Found 348.2 (11%), 333 (8%), 292.1 (100%), 183.1 (85%); HRMS (+EI):
3
) δ = 157.4, 156.6, 156.4,
1
•+
24 3
Calculated [C23H O ] : 348.1720; Found: 348.1727
Compound 15 / 2-(Dibenzo[d,f][1,3]dioxepin-2-yl)pyrazine. Prepared by general procedure 1.
Chromatography was performed with (CH
3
)
2
CO in hexane fraction (12.5%) as eluent. Isolated as a
1
colourless waxy solid, 93.4 mg, 0.338 mmol, 68% yield. H NMR (400MHz, CDCl
3
) δ = 9.06 (br. s.,
1
H), 8.63 (br. s., 1 H), 8.51 (br. s., 1 H), 8.39 (d, J = 2.0 Hz, 1 H), 7.92 (dd, J = 2.2, 8.4 Hz, 1 H),
.82 (dd, J = 1.2, 7.8 Hz, 1 H), 7.37 - 7.29 (m, 1 H), 7.29 - 7.23 (m, 2 H), 7.16 (dd, J = 1.4, 8.0 Hz, 1
7

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1
3
H), 5.64 (s, 2 H); C NMR (101MHz, CDCl
3
) δ = 156.7, 156.0, 144.1, 142.7, 141.8, 132.3, 129.2,
128.8, 128.8, 128.2, 127.9, 127.2, 124.7, 121.6, 120.9, 98.6; LRMS (+EI, GCMS): Found 276.1;
•
+
12 2 2
HRMS (+EI): Calculated [C17H N O ] : 276.0893; Found: 276.0899.
Compound 16 / 2-(2,5-Dimethoxyphenyl)dibenzo[d,f][1,3]dioxepine. Prepared by general
procedure 1. Chromatography was performed with (CH
3
)
2
CO in hexane fraction (12.5%)as eluent.
1
Isolated as a pale brown gum, 84.0 mg, 0.252 mmol, 50% yield. H NMR (400MHz, CDCl
3
) δ = 7.81
(
d, J = 2.0 Hz, 1 H), 7.69 (dd, J = 7.8, 1.2 Hz, 1 H), 7.46 (dd, J = 8.2, 2.3 Hz, 1 H), 7.27 - 7.32 (m, 1
H), 7.11 - 7.23 (m, 3 H), 6.90 - 6.95 (m, 2 H), 6.83 - 6.87 (m, 1 H), 5.63 (s, 2 H), 3.80 (s, 3 H), 3.76
1
ppm (s, 3 H); C NMR (101MHz, CDCl
3
3
) δ = 155.5, 154.3, 153.7, 150.7, 134.5, 130.9, 130.6, 130.6,
130.0, 129.9, 128.8, 128.8, 128.3, 124.4, 120.8, 120.4, 116.6, 113.0, 112.6, 99.0, 56.3, 55.8; LRMS
•
+
(
18 4
+EI, GCMS): Found 334.2; HRMS (+EI): Calculated [C21H O ] ; 334.1205; Found: 334.1206.
Compound 17a and Compound 17b. Prepared by general procedure 1. Chromatography was
performed with CH Cl in hexane fraction as eluent (gradient, 5 to 20%). The 1-napthyl regioisomer
17a) was isolated as a colourless gum, 54.0 mg, 0.15 mmol, 33% yield. Later fractions were
2
2
(
combined and subjected to chromatography with toluene in hexane fraction (gradient, 15-30%) to
deliver the 2-naphthyl isomer 17b, which was not able to be completely separated from a coupled but
not cyclized compound with a mass of 326.1 (as determined by GCMS). Isolated as a colourless gum,
44.8 mg, 0.14 mmol, 28% yield.
1
Compound 17a / 2-(Naphthalen-1-yl)dibenzo[d,f][1,3]dioxepine . H NMR (400MHz, CDCl ): δ =
3
7
.91 (d, J = 8.2 Hz, 1 H), 7.88 (d, J = 7.0 Hz, 1 H), 7.84 (d, J = 6.7 Hz, 2 H), 7.60 (d, J = 8.2 Hz, 1 H),
.49 - 7.52 (m, 2 H), 7.46 - 7.48 (m, 3 H), 7.42 - 7.45 (m, 2 H), 7.38 (d, J = 1.6 Hz, 1 H), 7.31 - 7.34
7
1
3
(
(
m, 1 H), 7.22 - 7.25 (m, 2 H), 6.90 (d, J = 7.4 Hz, 2 H), 5.56 - 5.63 ppm (m, 2 H); C NMR
101MHz, CDCl ): δ = 156.2, 154.5, 134.5, 133.8, 133.4, 132.1, 130.9, 129.1, 128.3, 128.0, 127.7,
27.4, 126.8, 126.6, 126.0, 125.8, 125.6, 125.4, 125.2, 122.6, 116.0, 115.5, 91.2 ppm; LRMS (+EI,
3
1
•+
GCMS): Found 324.1; HRMS (+EI): Calculated [C H O ] : 324.1145; Found: 324.1152.
16
23
2

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1
Compound 17b / 2-(Naphthalen-2-yl)dibenzo[d,f][1,3]dioxepine. H NMR (400MHz, CDCl
3
):  =
.91 - 7.98 (m, 2 H), 7.89 (d, J = 8.2 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.67 - 7.70 (m, 1 H), 7.49 -
.58 (m, 2 H), 7.48 (s, 1 H), 7.42 - 7.47 (m, 2 H), 7.30 - 7.34 (m, 1 H), 7.28 (d, J =8.2 Hz, 1 H), 7.17 -
7
7
7
1
1
1
3
.22 (m, 2 H), 5.71 (s, 2 H); C NMR (101MHz, CDCl
3
): δ = 155.6, 154.5, 139.5, 136.9, 133.8, 131.7,
30.5, 130.4, 129.0, 128.9, 128.7, 128.6, 128.3, 127.7, 127.0, 126.2, 125.9, 125.8, 125.4, 124.5, 121.0,
•+
16 2
20.8, 99.1; LRMS (+EI, GCMS): Found: 324.1; HRMS (+EI): Calculated [C23H O ] : 324.1145;
Found: 324.1152.
Compound 18 / 2-(2,5-Difluorophenyl)dibenzo[d,f][1,3]dioxepine. Prepared by general procedure
2
. Chromatography was performed with (CH
)
3 2
CO in hexane fraction (12.5%)as eluent. Isolated as a
1
colourless oil, 83.4 mg, 0.27 mmol, 54% yield. Caution: Product somewhat volatile from toluene. H
NMR (400MHz, CDCl ) δ = 7.83 (s, 1H), 7.71 (dd, J = 7.8, 1.6 Hz, 1H), 7.47 (dt, J = 8.5, 1.8 Hz, 1H),
3
7
7
1
.30 - 7.36 (m, 1H), 7.20 - 7.26 (m, 2H), 7.15 - 7.20 (m, 2H), 7.12 (dd, J = 9.4, 4.7 Hz, 1H), 6.97 -
1
3
.05 (m, 1H), 5.65 (s, 2H)); C NMR (101MHz, CDCl
3
) δ = 155.7, 155.1, 130.9, 129.5, 129.3, 129.1,
28.7, 128.7, 124.7, 121.2, 120.9, 117.3, 117.1, 116.9, 116.6, 116.4, 115.3, 115.1, 99.0; LRMS (+EI,
•+
GCMS): Found 310.1; HRMS (+EI): Calculated [C H F O ] : 310.0800: Found: 310.0809.
12
19
2
2
Compound 20 / 4-Phenyldibenzo[d,f][1,3]dioxepine. Prepared by general procedure 2.
Chromatography was performed with CH
2
Cl
2
in hexane fraction as eluent (gradient, 0 to 10%).
1
Isolated as a colourless waxy solid, 52.6 mg, 0.192 mmol, 38% yield. MP: H NMR (400MHz,
CDCl ) δ = 7.64 (dd, J = 1.8, 7.6 Hz, 1 H), 7.62 - 7.58 (m, 1 H), 7.58 - 7.53 (m, 2 H), 7.48 - 7.42 (m,
3
2
2
1
H), 7.42 - 7.38 (m, 2 H), 7.32 (s, 2 H), 7.31 - 7.26 (m, 1 H), 7.20 (dd, J = 1.2, 7.8 Hz, 1 H), 5.52 (s,
13
H); C NMR (101MHz, CDCl ) δ = 153.8, 151.5, 137.9, 134.7, 132.2, 130.9, 130.3, 129.5, 129.2,
3
29.1, 128.1, 128.0, 127.3, 125.0, 124.8, 121.0, 101.0; HRMS (+EI, GCMS): Found 274.1; HRMS
+
(
+EI): Calculated (C19
H
14
O
2
): 274.0988; Found: 274.0998.
Compound 21 / 2-(Dibenzo[d,f][1,3]dioxepin-4-yl)pyrazine. Prepared by general procedure 1.
Chromatography was performed with MeOH in CH Cl as eluent (gradient, 0.5 to 1.0%). Isolated as a
2
2
1
pale-beige gum, 98 mg, 0.356 mmol, 71% yield. H NMR (400MHz, CDCl ): δ = 9.06 (s, 1 H), 8.69
3

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(
s, 1 H), 8.53 (d, J = 2.3 Hz, 1 H), 7.80 - 7.75 (m, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.63 (d, J = 7.4 Hz,
1
3
1
H), 7.44 - 7.34 (m, 3 H), 7.29 (t, J = 7.4 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 5.64 (s, 2 H); C NMR
(
101MHz, CDCl ): δ = 154.0, 152.3, 151.7, 145.9, 144.2, 142.7, 132.2, 130.3, 130.3, 130.1, 129.4,
3
129.1, 125.3, 124.9, 121.0, 116.2, 100.9; LRMS (+EI, GCMS): Found 276.0; HRMS (+EI):
•+
12 2 2
Calculated [C17H N O ] : 276.0893; Found: 276.0900.
Compound 22 / 4-(2,5-Dimethoxyphenyl)dibenzo[d,f][1,3]dioxepine. Prepared by general
procedure 1. Chromatography was performed with EtOAc in hexane fraction as eluent (gradient, 2 to
5
%). A second column was required for complete isolation; CH
2
Cl
2
in hexane fraction (gradient, 40 to
1
0%). Isolated as a colourless waxy solid, 96.2 mg, 0.288 mmol, 57% yield. H NMR (400MHz,
5
CDCl
3
): δ = 7.62 (dd, J = 1.8, 7.6 Hz, 2 H), 7.34 - 7.25 (m, 2 H), 7.25 - 7.20 (m, 2 H), 7.13 (dd, J =
7.8, 1.2Hz, 1 H), 6.92 - 6.85 (m, 2 H), 6.82 (d, J = 2.0 Hz, 1 H), 5.52 (s, 2 H), 3.77 (s, 3 H), 3.71 (s, 3
1
H); C NMR (101MHz, CDCl
3
3
): δ = 154.0, 153.3, 152.7, 151.2, 131.5, 131.2, 130.6, 129.9, 129.2,
129.0, 128.2, 128.1, 124.5, 124.3, 120.9, 117.0, 113.5, 111.9, 100.2, 56.2, 55.7; LRMS (+EI, GCMS):
•
+
18 4
Found 334.2; HRMS (+EI): Calculated [C21H O ] ; 334.1205; Found: 334.1205.
Compounds 23a and 23b. Prepared by general procedure 1. After initial separation of two main
components containing 23a and 23b, (Initial yield: 112 mg, 70% yield, ratio of 1-naphthyl to 2-
naphthyl = 7:3, respectively). Further separated with CH
3a. The earlier-eluting fraction was subjected to chromatography with toluene in hexane fraction
gradient, 15-30%) to deliver the 2-naphthyl isomer 23b, which was not able to be completely
2 2
Cl in hexane (gradient, 12-20%) to deliver
2
(
separated from a coupled but not cyclized compound with a mass of 326 (as determined by GCMS).
1
Compound 23a / 4-(Naphthalen-1-yl)dibenzo[d,f][1,3]dioxepine. MP: 143-145 °C; H NMR
(
400MHz, CDCl
3
): δ = 7.90 (dd, J = 3.9, 8.2 Hz, 2 H), 7.69 (ddd, J = 1.8, 3.7, 7.4 Hz, 2 H), 7.63 (d, J
=
1
8.6 Hz, 1 H), 7.57 - 7.52 (m, 1 H), 7.48 (t, J = 7.4 Hz, 1 H), 7.46 - 7.41 (m, 1 H), 7.39 (d, J = 7.8 Hz,
13
H), 7.37 - 7.27 (m, 4 H), 7.14 (dd, J = 1.4, 7.6 Hz, 1 H), 5.32 (s, 2 H); C NMR (101MHz,
CDCl
3
): δ 154.0, 152.2, 136.1, 133.5, 133.4, 132.4, 131.8, 131.3, 130.9, 129.1, 129.0, 128.3, 128.1,

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127.9, 127.1, 126.2, 126.0, 125.8, 125.2, 124.8, 124.7, 121.0, 101.0. LRMS (+EI, GCMS): Found
•
+
3
24.2; HRMS (+EI): Calculated [C H O ] : 324.1145; Found: 324.1149
16
23
2
1
Compound 23b 4-(Naphthalen-2-yl)dibenzo[d,f][1,3]dioxepine. H NMR (400MHz, CDCl ): δ =
3
8.00 (s, 1 H), 7.86 - 7.92 (m, 3 H), 7.60 - 7.71 (m, 3 H), 7.47 - 7.54 (m, 3 H), 7.34 - 7.40 (m, 2 H),
1
3
7
.30 (d, J = 7.83 Hz, 1 H), 7.18 (d, J = 7.83 Hz, 1 H), 5.48 - 5.52 (m, 2 H);
): δ = 153.8, 151.6, 135.4, 134.6, 133.3, 132.5, 132.3, 130.5, 129.2, 129.0, 128.4, 128.1, 128.1,
27.9, 127.6, 127.4, 127.1, 126.1, 126.0, 125.1, 124.8, 121.0, 100.9; LRMS (+EI, GCMS): Found
C NMR (101MHz,
CDCl
3
1
3
•+
16 2
24.2; HRMS (+EI): Calculated [C23H O ] : 324.1145; Found: 324.1149.
Compounds 24a and 24b. Prepared by general procedure 1. Chromatography was performed on
silica gel with toluene in hexane fraction as eluent (gradient, 20 to 30%) delivered first 44a then 44b,
as well as some of the 4-phenyl coupled but not cyclised side product (15%). Caution: Products
somewhat volatile from toluene.
Compound 24a / 1-Phenyldibenzo[d,f][1,3]dioxepine. Isolated as a colourless oil, 47 mg, 0.172
1
mmol, 34% yield. H NMR: δ = 7.77 (dd, J = 9.8, 8.6 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.48 (dd, J =
7.8, 5.1 Hz, 3H), 7.40 - 7.42 (m, 1H), 7.35 (td, J = 5.1, 1.6 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.26 (d,
1
3
J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 5.66 (d, J = 0.8 Hz, 2H); C NMR (CHLOROFORM-
d ,101MHz): δ = 155.8, 155.7, 141.8, 139.7, 139.7, 129.6, 129.1, 128.9, 128.8, 128.6, 127.7, 124.4,
•
+
122.9, 122.9, 120.9, 119.2, 98.4; HRMS (+EI): HRMS (+EI): Calculated [C19
14 2
H O ] : 274.0988;
Found: 274.0992.
Compound 24b / 3-Phenyldibenzo[d,f][1,3]dioxepine. Isolated as a colourless solid, 24.5 mg, 0.091
1
mmol, 18% yield. H NMR: δ = 7.41 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.4, 1.2 Hz, 1H), 7.24 - 7.28
(
m, 4H), 7.22 - 7.23 (m, 1H), 7.18 - 7.21 (m, 3H), 6.86 (ddd, J = 7.8, 6.3, 2.0 Hz, 1H), 6.66 - 6.69 (m,
1
3
1
1
2
H), 5.64 - 5.66 (m, 2H); C NMR: δ = 153.3, 141.9, 140.6, 131.9, 131.8, 131.0, 129.9, 128.8, 128.6,
•+
14 2
28.2, 128.1, 127.9, 126.9, 124.2, 121.0, 120.2, 102.7; HRMS (+EI): Calculated [C19H O ] :
74.0988; Found: 274.0997.

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Compound 43 / 4-((2-Bromophenoxy)methoxy)-1,1'-biphenyl. Prepared by general procedure 4.
Chromatography was performed with CH Cl in hexane fraction as eluent (gradient, 8% to 20%).
2
2
1
Isolated as a colourless oil, 108 mg, 0.304 mmol, 61% yield. H NMR (400MHz, CDCl ): δ = 7.54 (d,
3
J = 9.0 Hz, 5H), 7.39 - 7.44 (m, 2H), 7.29 - 7.34 (m, 1H), 7.26 - 7.28 (m, 2H), 7.20 - 7.24 (m, 2H),
1
.90 - 6.95 (m, 1H), 5.81 (s, 2H); C NMR (101MHz, CDCl
3
6
3
): δ = 156.3, 153.4, 140.5, 135.6, 133.5,
128.7, 128.5, 128.2, 126.9, 126.8, 123.7, 116.7, 116.6, 113.0, 91.5; HRMS (+EI): Calculated
•
+
[
C H BrO ] : 354.0250; Found: 354.0253
19 15 2
Compound 44 / 2-(4-((2-Bromophenoxy)methoxy)phenyl)pyrazine. Prepared by general
procedure 3. Chromatography was performed with acetone in hexane fraction as eluent (gradient,
1
2.5% to 17.5%). Isolated as an off-white amorphous solid, 124 mg, 0.347 mmol, 69% yield. H
1
NMR (400MHz, CDCl ): δ = 8.98 (d, J = 0.8 Hz, 1H), 8.59 (dd, J = 2.3, 1.6 Hz, 1H), 8.46 (d, J = 2.3
3
Hz, 1H), 7.98 - 8.03 (m, 2H), 7.55 (dd, J = 7.8, 1.2 Hz, 1H), 7.25─7.32 (m, 4H), 6.90─6.97 (m, 1H),
1
3
5
.84 (s, 2H); C NMR (101MHz, CDCl ): δ = 158.4, 153.3, 152.3, 144.1, 142.4, 141.8, 133.6, 130.7,
3
•
+
1
28.5, 128.4, 124.0, 116.9, 116.8, 113.2, 91.2; HRMS (+EI): Calculated [C H BrN O ] : 356.0155;
17 13 2 2
Found: 356.0162.
Compound 45 / 4'-((2-Bromophenoxy)methoxy)-2,5-dimethoxy-1,1'-biphenyl. Prepared by
general procedure 3. Chromatography was performed with EtOAc in hexane fraction as eluent
(
2 2
gradient, 2 to 5%). A second column was required for complete isolation; CH Cl in hexane fraction
(
gradient, 25 to 50%). Isolated as a colourless solid, 105 mg, 0.253 mmol, 50% yield. MP: 62–64 °C;
1
H NMR (400MHz, CDCl
3
): δ = 7.56 (dd, J = 8.0, 0.9 Hz, 1H), 7.50─7.53 (m, 2H), 7.25─7.31 (m,
2
H), 7.22 (d, J = 8.5 Hz, 2H), 6.88─6.96 (m, 3H), 6.84 (dd, J = 8.6, 3.4 Hz, 1H), 5.79─5.84 (m, 2H),
1
3
5
.81 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H); C NMR (101MHz, CDCl
3
): δ = 156.1, 153.7, 153.5, 150.7,
133.5, 132.7, 131.0, 130.7, 128.5, 123.7, 116.7, 116.6, 116.0, 113.0, 112.8, 112.5, 91.5, 56.3, 55.8;
•+
4
HRMS (+EI): Calculated [C21H19BrO ] ; 414.0461; Found: 414.0469.
Compounds 46a and 46b. Prepared by general procedure 3. Chromatography was performed on
silica gel with CH Cl in hexane fraction as eluent (gradient, 5 to 10%), by which the 1-naphthyl and
2
2

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2-naphthyl isomers were separable save a small mixed fraction between the two. The second
compound was further cleaned by running on silica gel with toluene in hexane (gradient, 10 to 25%).
Isolated as colourless solids, 176 mg, 0.43 mmol, 87% yield; 1-Np to 2-Np ratio = 6:4.
Compound 46a / 1-(4-((2-Bromophenoxy)methoxy)phenyl)naphthalene. Isolated as a colourless
1
solid, 85 mg, 0.21 mmol, 42% yield. MP: 80–82 °C; H NMR (400MHz, CDCl
3
): δ = 7.90 (d, J =
8.2 Hz, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.47 - 7.54 (m, 2H), 7.39 - 7.47 (m,
1
3
4
H), 7.30 - 7.36 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 5.87 (s, 2H); C NMR
): δ = 156.3, 153.5, 139.6, 135.1, 133.8, 133.6, 131.7, 131.3, 128.6, 128.3, 127.5,
27.0, 126.0, 126.0, 125.8, 125.4, 123.8, 116.7, 116.3, 116.3, 113.1, 91.6; HRMS (+EI): Calculated
(
101MHz, CDCl
3
1
•+
23 2
[C H17BrO ] : 404.0406; Found: 404.0410.
Compound 46b / 2-(4-((2-Bromophenoxy)methoxy)phenyl)naphthalene. Isolated as a colourless
1
solid, 69 mg, 0.172 mmol, 34% yield. MP: 73-75 °C; H NMR (400MHz, CDCl
3
): δ = 7.99 (s, 1H),
7.88 (q, J = 8.2 Hz, 3H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 7.66 - 7.70 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H),
1
3
7
.44 - 7.52 (m, 2H), 7.26 - 7.31 (m, 4H), 6.91 - 6.97 (m, 1H), 5.84 (s, 2H); C NMR (101MHz,
CDCl
3
): δ = 156.5, 137.9, 135.6, 135.6, 133.7, 133.5, 132.4, 128.6, 128.5, 128.4, 128.1, 127.6, 126.3,
•
+
1
2
25.8, 125.4, 125.3, 123.8, 116.8, 116.8, 113.1, 91.6; HRMS (+EI): Calculated [C23H17BrO ] :
404.0406; Found: 404.0408.
Acknowledgments
This work was supported by a Vice-Chancellor’s Research Fellowship from the Queensland
University of Technology. Mass spectra were acquired by Ms Anithahini (Anitha) Jeyasingham with
support from Prof. Stephen Blanksby and QUT’s Central Analytical Facility (CARF). K.-S. M.
acknowledges valuable mentoring from Prof. Steven Bottle and Prof. Stefan Bräse.
Electronic Supplementary Information

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1
13
Full H and C NMR spectra for 26 new compounds and a representation showing the set-up
for coupling of solid at room-temperature arenes (Figure S 1) is compiled in a word
document. This material is available on the internet at DOI: 10.XXXX
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3
17x123mm (300 x 300 DPI)