Straightforward convergent access to 2-arylated polysubstituted benzothiazoles

Article abstract of DOI:10.1016/j.tet.2020.130982

A modular access to 2,4 disubstituted benzothiazoles has been achieved though the intermediacy of 4-bromo-2-iodobenzothiazole. The difference in reactivity of both halogens was advantageously exploited to achieve sequential Suzuki-Miyaura cross-coupling g

Full text of DOI:10.1016/j.tet.2020.130982

Journal Pre-proof
Straightforward convergent access to 2-arylated polysubstituted benzothiazoles
Omar Sadek, David M. Perrin, Emmanuel Gras
PII:
S0040-4020(20)30077-6
https://doi.org/10.1016/j.tet.2020.130982
TET 130982
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 December 2019
Revised Date: 23 January 2020
Accepted Date: 26 January 2020
Please cite this article as: Sadek O, Perrin DM, Gras E, Straightforward convergent access to 2-arylated
polysubstituted benzothiazoles, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.130982.
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Straightforward convergent access to 2-arylated
polysubstituted benzothiazoles
Omar Sadek,1,2 David M. Perrin,2 Emmanuel Gras*1,3
Addresses:
1) LCC, CNRS UPR 8241, Université de Toulouse, UPS, INPT, 205 route de Narbonne
31077 Toulouse Cedex 4
2) Chemistry Department, 2036 Main Mall, UBC, Vancouver, BC, V6T 1Z1, Canada
3) ITAV, CNRS USR 3505, Université de Toulouse, UPS, 1 place Pierre Potier, 31106
Toulouse Cedex 1
Email : Emmanuel Gras - emmanuel.gras@lcc-toulouse.fr
Abstract:
A modular access to 2,4 disubstituted benzothiazoles has been achieved though the
intermediacy of 4-bromo-2-iodobenzothiazole. The difference in reactivity of both
halogens was advantageously exploited to achieve sequential Suzuki-Miyaura cross-
coupling giving access to a range of polyaromatic derivatives featuring a central
benzothiazole core.
Keywords:
Orthogonal Reaction; Suzuki-Miyaura cross coupling; benzothiazole; boronic
derivatives.
Introduction
The benzothiazole core is considered a privileged fused bicyclic heterocycle in light of
its applications in pharmaceutical, agrochemical, and materials chemistry.[1] This has
driven the development of increasingly efficient methodologies towards the synthesis of
functionalised 2-arylated benzothiazole scaffolds.[2] More recently, these scaffolds have
found applications in organocatalyzed (de)hydrosilylation reactions where they function
1

as carbon-centred Lewis acids in the activation of Si–H σ bonds.[3] Substituted
benzothiazoles are also involved in important applications in organic light-emitting
devices (OLEDs).[4] Similar to other benzazoles,[5] they quite commonly exhibit
interesting photochemical properties including processes such as Excited State
Intramolecular Proton Transfer (ESIPT).[6] These molecules have also been intensively
studied for their dual action potential as metal chelators and as intercalating compounds
targeting pathological peptidic aggregates that of interest for imaging various dementias
e.g. Alzheimer’s Disease.[7]
S
S
N
Pt
O
N
OTf
N
Carbon Lewis Acid
S
OLED
N
I
HO
S
N
N
HO
I
Intercalating metal chelator
ESIPT Fluorescent Probe
Figure 1: Benzothiazole scaffolds integrated into various applications
Considering that the nitrogen atom of the benzothiazole is key in all the applications
mentioned and illustrated above, we focused our attention on modulating its
environment by introducing substituents on position 2 and 4 of the benzothiazole core in
a convergent fashion. Although numerous strategies have been designed to access
substituted benzothiazoles, in nearly all cases, strategies have required non-versatile
and non-modular syntheses.[1a] One major path relies on the cyclisation of
functionalised arylthioamides or arylthioureas. Such starting materials require time-
2

consuming methods to generate thioamides (or thioureas) prior to cyclisation, most
commonly from the corresponding amide with Lawesson’s reagent. Alternatively,
benzothiazoles can also be accessed by condensing aldehydes with 2-
aminothiophenols in the presence of an oxidant (air being the mildest) or reaction with
activated esters and/or acid halides. However, drawbacks with these approaches are
readily appreciated by considering the poor shelf-life of many aldehydes, the high-
reactivity of acid halides, as well as the poor availability of functionalized 2-
aminothiophenols, which are themselves air-sensitive and easily decomposed.
A more facile and highly convergent approach, based on readily available and stable
building blocks, would be to leverage the extensive portfolio of boronic acids to access
polysubstituted benzothiazole derivatives through Suzuki-Miyaura cross coupling
starting with a suitable 2-iodobenzothioazole as a readily accessed coupling partner.
Moreover, taking advantage of the C-2 activated position of the heterocycle might prove
sufficiently selective for orthogonal coupling thus providing diversely polysubstituted
benzothiazoles in a highly convergent and straightforward fashion. Herein, we present a
preliminary report that establishes this strategy as a viable route to polysubsituted
benzothiazoles. To test this hypothesis, we envisioned a practical and convergent
strategy involving 4-bromo-2-iodobenzothiazole 3 (Scheme 1) as a key intermediate
that would enable regio/chemoselective coupling to deliver a series of C2/C4 arylated
benzothiazoles. This strategy is attractive as it is highly modular as it allows for
considerable synthetic versatility considering the expansive library of aryl boronic acids
and derivatives available, both commercially and synthetically, as suitable coupling
partners.[8] Herein, we describe the swift synthesis of versatile intermediate 3,
3

substituted with two different halogens that, as part of our design, demonstrates efficient
access to the said benzothiazoles via chemoselective and regioselective
functionalisation with various aromatic substituents.
Results and Discussion
Synthesis of di-halogenated intermediate
We sought a simple, efficient, and high-yielding synthetic route with an eye to utilizing
affordable and common laboratory reagents. Starting from commercially-available 2-
bromoaniline, thiourea 1 was obtained following standard protocol.[9] Subsequent
Hugershoff cyclization with Br2 yielded the desired 2-amino-4-bromobenzothiazole (2) in
excellent yield,[10] as usually observed for Hugershoff cyclization.[11] Although metal-free
conditions have been recently reported,[12] we found out that one-pot iodination of 2,
under Sandmeyer conditions using catalytic amount of CuI, provided 4-bromo-2-iodo-
benzothiazole (3) in excellent yield (Scheme 1). Key intermediate 3 is obtained in three
synthetic steps in 63% global yield without further optimization. This represents a
significant improvement over the 5-step approach from the less available 2,3-
dibromoaniline as reported in patent literature.[13]
S
N
S
N
S
2
NH2
I
a
c
b
NH2
N
NH2
4
Br
H
Br
Br
Br
1 (75%)
2 (93%)
3 (90%)
Scheme 1 Synthesis of 4-bromo-2-iodobenzothiazole. a, BzCl, NH4SCN, acetone, reflux, 1 hour. b, Br2,
CHCl3, reflux 1.5 hours. c, (i) p-TsOH·H2O, MeCN, room temperature, (ii) t-BuONO, -5 °C, 30 minutes,
(iii) KI, cat. CuI, H2O, 0 °C then room temperature, 18 hours.
4

Functionalisation of key benzothiazole intermediate
Given the well-established reactivity differences between C(sp2)-I and C(sp2)-Br bonds
with respect to oxidative addition at a transition metal centre, 3 should submit to
chemoselective and regioselective Suzuki-Miyaura cross-coupling with various aryl
boron derivatives (Scheme 2).[14] Indeed, products of selective mono-arylation of 3 were
obtained by initial cross-coupling at C-2, at moderate reaction temperature (90 °C),
selective arylation could be achieved while safeguarding the C-Br bond intact for further
functionalization (vide infra). Notably, 2-hydroxyphenyl-boronic acid, 2-aminophenyl-
boronic acid, and N-Boc-indole-2-boronic acid could be coupled to 3, furnishing 2-aryl-4-
bromobenzthiazoles 4, 5 and 6, respectively in good yields. Notably, if desired, one-pot,
double cross-coupling with 2-aminophenylboronic acid was found to be highly efficient,
providing the corresponding 2,4-dianiline (7) in 87% yield.
S
N
S
N
N
Boc
a
HO
Br
Br
c
6 (72%)
4 (73%)
S
N
I
d
b
Br
S
N
S
3
N
H2N
7 (87%)
H2N
5 (82%)
H2N
Br
Scheme 2. Selective coupling at position 2 and double cross-coupling
a, 2-hydroxyphenylboronic acid, Pd(PPh3)4, Na2CO3, DMF/H2O, microwave, 90 °C, 1 hour. b, 2-
aminophenylboronic acid, Pd(PPh3)4, XantPhos, Na2CO3, 1,4-dioxane/H2O, microwave, 90 °C, 1 hour. c,
N-Boc-indole-2-boronic acid, Pd(PPh3)4, Cs2CO3, 1,4-dioxane/H2O, microwave, 90 °C, 1 hour.
d) 2-aminophenylboronic acid, Pd(PPh3)4, Na2CO3, DMF/H2O, microwave, 120 °C, 5 hour.
5

The aniline in benzothiazole 5 was shown to efficiently undergo selective mono-N-
methylation using Re-catalysed reaction in MeOH, while conserving the C-Br bond and
avoiding tedious separation with polymethylated products, providing 10 in good yield.
(Scheme 3).[16]
S
a
S
N
N
HN
Br
H2N
Br
10 (78%)
5
Scheme 3. Monomethylation of 5
a) Re(NH(CH2CH2PPh2)2)(CO)3Br, Cs2CO3, MeOH, 140 °C, 5 days.
To capitalize on the extant C-Br bond, compounds 4,6, and 10 could be further
functionalised in step-wise fashion, at C-4, via cross-coupling with various arylboronic
acids or trifluoroborates. For example, reaction of 4 with potassium N-Boc-indole-2-
trifluoroborate, under conditions reported by Molander et al.,[15] or with 2-
aminophenylboronic acid furnished 2,4-diarylbenzthiazoles 8 and 9, respectively, in
good yields. Benzothiazole derivative 10 could be further cross-coupled with 2-
hydroxyphenylboronic acid to furnish 2,4-diarylbenzothiazole 11 in good yield. Finally, 4-
bromo-2-indolebenzothiazole 6, after Boc-deprotection of 6 to 6a, could be coupled with
2-hydroxyphenylboronic acid to provide 12 in high yield.
6

S
N
S
N
S
N
HO
8 (69%)
c
HN
NH
HO
a
HN
Br
Br
10
11 (78%)
S
N
S
S
N
S
N
HO
b
Br
N
N
H
4
d, e
N
Boc
OH
HO
H2N
6
12 (70%)
9 (82%)
Scheme 4. Secondary coupling at position 4 yielding 2,4-disubstituted benzothiazoles.
a, potassium N-Boc-indole-2-trifluoroborate, Pd(OAc)2, SPhos, Na2CO3, EtOH, 85 °C, 5 hours. b, 2-
aminophenylboronic acid, Pd(PPh3)4, Na2CO3, DMF/H2O, microwave, 120 °C, 1 hour. c, 2-
hydroxyphenylboronic acid, Pd(PPh3)4, Na2CO3, DMF/H2O, 120 °C, 18 hours. d, TFA/DCM (1:1), room
temperature, 2 hours. e, 2-hydroxyphenylboronic acid, Pd(PPh3)4, Na2CO3, DMF/H2O, 120 °C, 1 hour.
Photophysical Properties
Given the increasing interest and application of the absorptive and emissive properties
of benzothiazoles, we briefly studied the photophysical properties of these novel
benzothiazoles. As a general trend, these benzothiazoles exhibit similar absorption
spectra, consisting of large bands in the UV region of the spectrum; they absorb
strongly with absorption maxima ranging from 339 to 405 nm that are attributed to
characteristic π-π* transitions. However, on closer inspection it becomes evident that the
nature of the aromatic group at C-2 determines the absorption profile, while the
substitution at C-4 delivers fine-tuning of the absorption maximum (Figures 2, 3 and 4).
These compounds were also found to be fluorescent, with broad emission bands
ranging from 403 to 519 nm, corresponding to Stokes shifts (∆SS) varying from 39 to 180
nm (Figure 5). The large ∆SS are only observed for compounds 4, 8 and 9 which feature
7

2-hydroxylphenyl at C-2, allowing for the possibility of ESIPT which induces significant
structural reorganisation in the excited state, accounting for the large ∆SS. In contrast to
the relationship observed in absorption, the substituent at C-4 has no effect on emission
profiles or maxima.
Figure 2: UV Absorption spectra of 4,8 and 9.
8

Figure 3: UV Absorption spectra of 12 and 6a.
Figure 4: UV Absorption spectra of 5, 7, 10 and 11.
Figure 5: Fluorescence spectra of 4, 5, 6a, 7, 8, 9, 10, 11 and 12.
9

Table 1 Photophysical properties of compounds 4-12
Compound
λ
abs (nm)
log
ε
(M-1 cm-1)
λ
em (nm)
∆
ss (nm - cm-1)
180 - 10231
66 -3971
4
5
339
4.1
519
376
4.0
442
6a
7
368
4.4
407
39 - 2604
65 - 3979
155 - 8727
174- 10005
61- 3232
373
4.0
438
8
351
4.1
506
9
339
4.2
513
10
11
12
405
4.1
466
405
3.6
471
66 - 3460
43 - 2964
360
4.5
403
Conclusion
In conclusion, here we have demonstrated the facile synthesis of a wide variety of 2-
aryl-4-bromo and 2,4-diarylbenzothiazole derivatives via selective Suzuki-Miyaura
cross-coupling with key benzothiazole intermediate 3. This scaffold has proven
versatile, allowing selective structural elaboration firstly at the C-2 position, in high
yields, followed by functionalisation at the C-4 position; the scaffold can also be di-
functionalised in one-pot at both the C-2 and C-4 positions. This strategy gives rapid
access to a diverse family of benzothiazoles with tuneable photophysical properties.
Although our synthesis is somewhat limited in scope, we suggest that this reaction
manifold should be readily amenable to preparing a large number of tricyclic
compounds starting with (hetero)arylboronic acids. Hence, in this preliminary report, we
acknowledge this methodology serves as a proof of concept for its expansion towards
10

the functionalisation of other positions on the benzothiazole core in a similar fashion. It
is readily anticipated more densely functionalized bromoanilines should readily submit
to this reaction scheme. The novel benzothiazoles derivatives reported here accessible
through 3, or derivatives thereof, are further anticipated to be of interest for
photophysical studies in both solution and the solid-state, as well as their investigation
as Lewis acid catalysts and as chelators for various metal cations. Studies towards
these goals are currently underway.
Experimental section:
General Information
Solvents and Reagents
All chemicals were purchased from commercial sources and used as received unless
otherwise noted. Solvents used were all commercial grade and used as received with
no drying, all reactions were performed in oven-dried glassware under ambient
atmosphere unless otherwise stated. Deuterated solvents for NMR spectroscopic
analysis were purchased from Euriso-top.
Analysis
NMR experiments were performed in deuterated solvents. 1H NMR, 13C NMR, 11B NMR
19
and F spectra were recorded on 300 Avance (300 MHz), 400 Avance (400 MHz) and
400 AvanceIII (400 MHz) Bruker spectrometers. All spectra were recorded at ambient
temperature (298 K). Chemical shifts (δ) are reported in parts per million (ppm) relative
to the residual protium in the solvents (1H) or the solvent carbon (13C) as internal
standards. Multiplicity of signals is indicated using the following abbreviations: s
(singlet), b (broad), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt
(doublet of triplet), td (triplet of doublet), hept (heptet) and m (multiplet). Reactions were
monitored using Merck Silica gel 60 F254 glass backed plates. TLC plates were
11

visualized by UV fluorescence (λ= 254, 365 nm) and KMNO4 stain. Flash column
chromatography was performed using VWR Chemicals Silica gel 60 – 200 µm or on an
automated Interchim puriFlash system using pre-packed Interchim 30 µm Silica gel
cartridges. IR spectra were recorded on a PerkinElmer Spectrum One or Frontier FT-IR
spectrometer with frequencies expressed in cm-1. UV/Vis spectra were recorded on an
Agilent 8453 Spectroscopy System using a 10 mm Quartz cuvette. Fluorescence
spectra were recorded on a HORIBA Jobin Yvon FluoroMax-4 Spectrofluorometer.
High-resolution mass spectra (HRMS) were recorded using either electrospray
ionization (ESI) or desorption chemical ionization (DCI) using a Waters GCT Premier or
Sciex QTRAP 4500 AB or Thermo Fisher Scientific DSQ II spectrometers.
Synthetic procedures and characterisation data for 1 – 12
2-bromophenylthiourea (1)
A two-necked 250 mL round-bottom flask was charged with a stir bar, condenser,
NH4SCN (10.9250 g, 0.13 mol) and acetone (50 mL). Benzoyl chloride (13.93 mL, 0.12
mol) was added dropwise via syringe to the rapidly stirring reaction mixture. The mixture
was heated at reflux for 15 minutes, and then cooled back down to room temperature.
In an addition funnel, 2-bromoaniline (22.63 mL, 0.1 mol) was dissolved in acetone (25
mL), this solution was added dropwise to the vigorously stirring reaction mixture over 15
minutes; the reaction mixture was then heated at reflux for 1 hour. The crude mixture
was then dropped onto excess water and vigorously stirred. A yellow precipitate formed
and was collected by filtration and washed with water until washes were colourless. The
precipitate was then washed with cold MeOH/H2O solution (1:1). In a 1L Erlenmeyer
flask, 10% aq. NaOH solution (400 mL) was prepared and heated to 80 °C. The washed
precipitate was then added to this base solution for hydrolysis. The precipitate dissolved
into the base solution producing a clear yellow solution, this was stirred at 80 °C for 15
minutes. The solution was then acidified to pH 2 using concentrated HCl (37%, 12 M),
producing a white precipitate. The solution was then basified to pH 9 using a 25% aq.
NH4OH solution producing a white precipitate which was collected by filtration and
washed with water until washes were neutral. The product, a white powder, was then
12

dried under high vacuum (17.3748 g, 75%). IR νmax/cm-1 (neat film): 3425, 3253, 3245,
3124, 3002, 1619, 1500, 1466, 1427, 1290, 1063, 1039, 1025, 818, 758, 706. 1H NMR
(400 MHz, Acetone-d6) δ 8.66 (bs, 1H), 7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.66 (dd, J = 8.0,
1.4 Hz, 1H), 7.40 (td, J = 7.9, 1.4 Hz, 1H), 7.20 (td, J = 7.8, 1.6 Hz, 1H), 7.09 (bs, 2H).
13C NMR (101 MHz, Acetone-d6) δ 184.2 (Cq), 138.2 (Cq), 133.8 (CH), 130.1 (CH),
128.9 (CH), 128.9 (CH), 121.1 (Cq). HRMS-ESI (m/z): found [M79Br+H]+ 230.9595,
calc’d C7H8N2S79Br requires 230.9592, found [M81Br+H]+ 232.9574, calc’d C7H8N2S81Br
requires 232.9572.
2-amino-4-bromobenzothiazole (2)
A 50 mL, two-necked, round-bottom flask was charged with a stir bar, 2-
bromophenylthiourea (2.3204 g, 10 mmol) and CHCl3 (10 mL). Bromine (0.51 mL, 10
mmol) was dissolved in CHCl3 (5 mL) in an addition funnel and affixed to the main neck
of the round-bottom flask, the second neck was connected to a base trap to neutralize
HBr fumes developed during the reaction. The flask was cooled to 0 °C in an ice-bath
and the bromine solution was added dropwise to the vigorously stirring reaction mixture
(note: often the sides needed to be scraped down as the bromine solution would
coagulate on the bottom and sides of the flask). The addition funnel was then replaced
with a condenser and the reaction mixture heated at reflux for 1.5 hours until complete
conversion of starting material was determined by TLC; with external heat HBr gas
evolution became rapid. During the reaction, a fine yellow precipitate evolved in a clear
red/brown solution. After cooling to room temperature, all solvent was removed under
reduced pressure. The remaining residue was dissolved in EtOAc (100 mL) and washed
with sat’d aq. NaHCO3 (2 x 100 mL), 5% aq. Na2S2O3 (2 x 50 mL) and brine (2 x 50
mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure and further dried under high vacuum overnight to furnish the
product as a yellow powder (2.1296 g, 93%). IR νmax/cm-1 (neat film): 3446, 3277, 3073,
1
2926, 1635, 1531, 1415, 1269, 882, 750, 725. H NMR (400 MHz, Acetone-d6) δ 7.64
(d, J = 7.7 Hz, 1H), 7.51 (bs, 2H), 7.45 (d, J = 7.8 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H). 13C
NMR (101 MHz, Acetone-d6) δ 168.2 (Cq), 151.8 (Cq), 132.9 (Cq), 129.7 (CH), 123.1
13

(CH), 121.0 (CH), 111.9 (CH). HRMS-ESI (m/z): found [M79Br+H]+ 228.9440, calc’d
C7H6N2S79Br requires 228.9435, [M81Br+H]+ 230.9418, calc’d C7H6N2S81Br requires
230.9419.
4-bromo-2-iodobenzothiazole (3)
A 500 mL round-bottom flask was charged with a stir bar, 2-amino-4-
bromobenzothiazole (9.85 g, 42 mmol), p-TsOH·H2O (24.9 g, 129 mmol) and MeCN
(172 mL). The heterogenous reaction mixture was stirred and cooled in an ice-brine
bath to -5 °C, at which point t-BuONO (15.3 mL, 129 mmol) was added dropwise, over
10 minutes, via an addition funnel; after the addition was complete the reaction mixture
was stirred at -5 °C for 30 minutes. An additional funnel was then charged with a water
(43 mL) solution of KI (21.4 g, 129 mmol) and CuI (819 mg, 4.3 mmol). The KI solution
was added dropwise to the vigorously stirred reaction mixture at 0 °C over 20 minutes;
the reaction mixture was then allowed to warm to room temperature overnight. The
crude reaction mixture was concentrated under reduced pressure to ~70 mL and then
dropped on sat’d aq. NaHCO3 (150 mL), the phases separated, and the aqueous phase
extracted with EtOAc (4 x 150 mL). The combined organic phases were then washed
with a 5% aqueous Na2S2O3 solution (4 x 150 mL). The organic phase was dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure to furnish the
product
as
a
brown
powder
(13.1607 g, 90%). IR νmax/cm-1 (neat film): 3089, 3064, 2931, 2851, 1442, 1391, 1203,
952, 842, 764, 732. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J = 8.1, 1.0 Hz, 1H), 7.72
(dd, J = 7.8, 1.0 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ
152.0 (Cq), 139.8 (Cq), 129.7 (CH), 126.9 (CH), 121.1 (CH), 114.6 (Cq), 112.8 (Cq).
HRMS-ESI (m/z): found [M79Br+H]+ 339.8298, calc’d C7H4NS79BrI requires 339.8293,
[M81Br+H]+ 341.8279, calc’d C7H4NS81BrI requires 341.8272.
14

2-(2-hydroxyphenyl)-4-bromobenzothiazole (4)
A 10 mL µwave vial was charged with a stir bar, 4-bromo-2-iodobenzothiazole (35 mg,
0.1 mmol), 2-hydroxyphenylboronic acid (20.5 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 10
mol%), Na2CO3 (74 mg, 0.7 mmol), DMF (0.8 mL) and water (0.2 mL). The reaction
mixture was stirred at room temperature for 5 minutes, while bubbling the reaction
mixture with Ar. The vial was then loaded into a microwave reactor and heated at 90 °C
for 1 hour, after which TLC (cyclohexane/CH2Cl2, 3:2) showed complete conversion of
starting material. The crude was dropped onto brine (10 mL) and the phases separated,
the aqueous phase was extracted with EtOAc (3 x 15 mL) and the combined organic
phases washed with brine (2 x 10 mL). The organic phase was dried over anhydrous
MgSO4, then filtered and concentrated on Celite. The crude was purified on Silica gel
flash column chromatography using 100% cyclohexane to 4:1 cyclohexane/CH2Cl2 as
the eluent. Fractions were collected and concentrated to furnish the product as an off-
white powder which was further dried under high vacuum (23 mg, 73%). IR νmax/cm-1
(neat film): 3045, 2922, 2851, 1586, 1482, 1266, 1218, 1091, 977, 743. 1H NMR (400
MHz, Chloroform-d) δ 7.79 (dd, J = 8.0, 1.0 Hz, 1H), 7.66 (dd, J = 7.8, 1.0 Hz, 1H), 7.63
(dd, J = 7.9, 1.6 Hz, 1H), 7.39 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H),
7.11 (dd, J = 8.4, 1.2 Hz, 1H), 6.94 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H). 13C NMR (101 MHz,
Chloroform-d) δ 169.8 (Cq), 158.2 (Cq), 150.3 (Cq), 133.4 (CHArom, Cq), 130.1 (CHArom),
128.5 (CHArom), 126.5 (CHArom), 120.7 (CHArom), 119.7 (CHArom), 118.2 (CHArom), 116.5
(Cq), 115.8 (Cq). HRMS-DCI-CH4 (m/z): found [M]+ 305.9602, calc’d C13H9NOS79Br+
requires 305.9588.
2-(2-aminophenyl)-4-bromobenzothiazole (5)
A 10 mL microwave vial was charged with a stir bar, 4-bromo-2-iodobenzothiazole (34.1
mg, 0.1 mmol), 2-aminophenylboronic acid (21.8 mg, 0.15 mmol), Na2CO3 (48 mg, 0.45
mmol), Pd(PPh3)4 (12 mg, 10 mol%), 1,4-dioxane (0.8 mL) and water (0.2 mL). The vial
was purged with Ar and loaded into a microwave reactor and heated at 90 °C for 1 hour.
The reaction mixture was cooled to room temperature before being transferred to a
15

separatory funnel with sat’d aq. NaHCO3 (10 mL), the aqueous phase was extracted
with EtOAc (3 x 10 mL). The combined aqueous phases were washed with brine (3 x 20
mL), then dried over anhydrous MgSO4, filtered and the filtrate concentrated onto Celite
under reduced pressure. The crude material was purified by Silica gel flash column
chromatography using an eluent of 100% cyclohexane to cyclohexane/EtOAc (4:1).
Desired fractions were collected and concentrated under reduced pressure, and further
under high vacuum overnight to furnish the desired compound as a yellow powder (25
mg, 82%). IR νmax/cm-1 (neat film): 3460, 3295, 3063, 2924, 1615, 1594, 1494, 1449,
1227, 964, 735. 1H NMR (300 MHz, Chloroform-d) δ 7.79 (dd, J = 8.0, 1.0 Hz, 1H), 7.66
(dd, J = 8.0, 1.4 Hz, 1H), 7.64 (dd, J = 7.8, 1.0 Hz, 1H), 7.24 (ddd, J = 8.5, 7.1, 1.5 Hz,
1H), 7.20 (t, J = 7.9 Hz, 1H), 6.82 (dd, J = 8.3, 0.8 Hz, 1H), 6.74 (ddd, J = 8.2, 7.2, 1.1
13
Hz, 1H). C NMR (75 MHz, Chloroform-d) δ 169.7 (Cq), 152.0 (Cq), 147.0 (Cq), 134.1
(Cq), 132.2 (CHArom), 130.3 (CHArom), 129.5 (CHArom), 125.8 (CHArom), 120.4 (CHArom),
117.3 (CHArom), 117.1 (CHArom), 116.1 (Cq), 114.9 (Cq). HRMS-ESI (m/z): found
[M79Br+H]+ 304.9752, calc’d C13H10N2SBr+ requires 304.9748.
tert-butyl 2-(4-bromobenzothiazol-2-yl)-1H-indole-1-carboxylate (6)
A 35 mL microwave vial was charged with a stir bar, 4-bromo-2-iodobenzothiazole (34.3
mg, 0.1 mmol), N-Boc-indole-2-boronic acid (32 mg, 0.12 mmol), Pd(PPh3)4 (65 mg, 50
mol%), Cs2CO3 (84.7 mg, 0.26 mmol), 1,4-dioxane (7.7 mL) and water (0.3 mL). The
reaction mixture was degassed (3 x freeze-pump-thaw) and then purged with Ar. The
vial was loaded into a microwave reactor and programmed to be heated at 90 °C for 1
hour, after which the crude was dropped onto water (10 mL) and the phases separated.
The aqueous phase was extracted with EtOAc (3 x 10 mL), the combined organic
phases were dried over anhydrous MgSO4, filtered and concentrated onto Celite. The
crude residue was purified by Silica gel flash column chromatography using 100%
cyclohexane to cyclohexane/EtOAc (9.5:0.5). Desired fractions were collected and
concentrated to furnish the desired product as a yellow oil which was further dried under
vacuum overnight (31 mg, 72%). IR νmax/cm-1 (neat film): 3066, 2978, 2930, 1735, 1442,
1368, 1321, 1221, 1157, 1132, 1006, 739. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (dd,
16

J = 8.3, 0.9 Hz, 1H), 7.84 (dd, J = 8.0, 1.1 Hz, 1H), 7.71 (dd, J = 7.8, 1.1 Hz, 1H), 7.59
(dt, J = 7.8, 1.0 Hz, 1H), 7.40 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.30 – 7.22 (m, 2H), 7.03
(s, 1H), 1.34 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 161.0 (Cq), 151.8 (Cq), 149.5
(Cq), 138.3 (Cq), 136.3 (Cq), 131.4 (Cq), 130.1 (CHArom), 128.3 (Cq), 126.5 (CHArom),
126.3 (CHArom), 123.5 (CHArom), 121.6 (CHArom), 120.8 (CHArom), 117.1 (Cq), 115.5
(CHArom), 115.1 (CHArom), 84.5 (Cq), 27.8 (CH3t-Bu). HRMS-DCI(CH4) (m/z): found [M]+
428.0194, calc’d C20H1779BrN2O2S requires 428.0194.
4-bromo-2-(1H-indol-2-yl)benzothiazole (6a)
A 10 mL round-bottom flask was charged with a stir bar, tert-butyl 2-(4-
bromobenzo[d]thiazol-2-yl)-1H-indole-1-carboxylate (150 mg, 0.35 mmol) and CH2Cl2 (1
mL). Trifluoroacetic acid (TFA) (1 mL) was added via syringe dropwise and the reaction
mixture stirred at room temperature for 2 hours. All solvent was removed under reduced
pressure and the residue dissolved in CH2Cl2 (10 mL) and dropped onto sat’d aq.
NaHCO3. The phases were separated, and the aqueous phase extracted with CH2Cl2 (3
x 10 mL). The combined organic phases were dried over anhydrous MgSO4, filtered and
concentrated onto Celite. The crude residue was purified by Silica gel flash column
chromatography using 100% cyclohexane to cyclohexane/EtOAc (9:1). Desired
fractions were collected and concentrated to furnish the desired product as a yellow
powder which was further dried under vacuum overnight (111.3 mg, 97%). IR νmax/cm-1
(neat film): 3398, 3380, 3058, 2960, 2921, 2852, 1588, 1557, 1459, 1439, 1397, 1339,
1302, 1142, 1035, 917, 788, 766, 747, 733, 668. 1H NMR (400 MHz, Chloroform-d) δ
9.54 (bs, 1H, N-H), 7.81 (dd, J = 8.0, 1.1 Hz, 1H), 7.68 (ddd, J = 8.0, 2.2, 1.0, 2H), 7.45
(dq, J = 8.3, 0.9 Hz, 1H), 7.31 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H),
7.19 – 7.13 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 160.5 (Cq), 151.9 (Cq), 137.2
(Cq), 135.6 (Cq), 131.0 (Cq), 130.1 (CHArom), 128.5 (Cq), 126.2 (CHArom), 125.1 (CHArom),
121.9 (CHArom), 121.01 (CHArom), 120.95 (CHArom), 116.5 (Cq), 111.8 (CHArom), 106.2
79
(CHArom). HRMS-DCI(CH4) (m/z): found [M+H]+ 328.9749, calc’d C15H9 BrN2S requires
328.9748.
17

2,2'-(benzothiazole-2,4-diyl)dianiline (7)
A 10 mL microwave vial was charged with a stir bar, 4-bromo-2-iodobenzothiazole (34
mg, 0.1 mmol), 2-aminophenylboronic acid (41.1 mg, 0.3 mmol), Na2CO3 (106 mg, 1
mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), DMF (0.6 mL) and water (0.2 mL). The crude
mixture was then degassed (3 x freeze-pump-thaw) and purged with Ar. The vial was
loaded into a microwave reactor and heated at 120 °C for 5 hours. The reaction mixture
was cooled to room temperature before being transferred to a separatory funnel with
sat’d aq. NaHCO3 (10 mL), the aqueous phase was extracted with EtOAc (3 x 15 mL).
The combined organic phases were washed with brine (3 x 20 mL), then dried over
anhydrous MgSO4, filtered and the filtrate concentrated onto Celite under reduced
pressure. The crude material was purified using Silica gel flash chromatography using
an eluent of 100% cyclohexane to 70:30 cyclohexane/EtOAc. Desired fractions were
collected and concentrated under reduced pressure, and further under high vacuum
overnight to furnish the desired compound as a red powder (27.6 mg, 87%). IR νmax/cm-
1 (neat film): 3457, 3372, 3305, 3055, 3024, 2924, 2853, 1698, 1614, 1593, 1494, 1223,
963, 748. 1H NMR (300 MHz, Acetone-d6) δ 8.03 (dq, J = 5.8, 3.6 Hz, 1H), 7.68 (dd, J =
8.0, 1.5 Hz, 1H), 7.50 (dd, J = 4.6, 0.8 Hz, 2H), 7.28 – 7.10 (m, 3H), 6.95 (bs, 2H), 6.91
– 6.83 (m, 2H), 6.74 (td, J = 7.4, 1.2 Hz, 1H), 6.66 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 4.46
(bs, 2H). 13C NMR (75 MHz, Acetone-d6) δ 156.5 (Cq), 152.6 (Cq), 148.8 (Cq), 146.4
(Cq), 134.9 (Cq), 134.6 (Cq), 132.5 (CHArom), 131.9 (CHArom), 130.7 (CHArom), 129.5
(CHArom), 128.4 (CHArom), 126.2 (CHArom), 125.4 (Cq), 121.6 (CHArom), 117.8 (CHArom),
117.5 (CHArom), 116.9 (CHArom), 116.4 (CHArom), 114.9 (Cq). HRMS-ESI (m/z): found
[M+H]+ 318.1062, calc’d C19H16N3S+ requires 318.1065.
Potassium N-Boc-indole-2-trifluoroborate
A 25 mL round-bottom flask was charged with a stir bar, N-(tert-butoxycarbonyl)indole-
2-boronic acid (1.1653 g, 4.5 mmol) and MeOH (1.3 mL). The reaction mixture was
stirred until all boronic acid had dissolved then aq. KHF2 (4.5 M, 3.3 mL, 14.9 mmol)
was added dropwise; the reaction became a pink slurry, additional MeOH was added to
18

ensure efficient stirring. The reaction mixture was stirred at room temperature for 2
hours after which complete conversion was determined by 11B NMR. All solvent was
removed under reduced pressure and the white residue left to dry under high vacuum
for 6 hours. The crude was triturated with acetone (3 x 20 mL) and filtered to remove
insoluble solids. The acetone filtrate was concentrated to saturation then dropped onto
pentane to precipitate the desired salt as a white powder which was collected by
filtration, washed with pentane then dried under high vacuum overnight (1.4246 g,
>99%). 1H NMR (400 MHz, DMSO-d6) δ 8.07 – 7.95 (m, 1H), 7.42 – 7.35 (m, 1H), 7.05
(pd, J = 7.1, 1.5 Hz, 2H), 6.40 (d, J = 0.8 Hz, 1H), 1.57 (s, 9H). 19F NMR (376 MHz,
DMSO-d6) δ -135.84 – -136.78 (m). 11B NMR (128 MHz, DMSO-d6) δ 1.46 (bs). LRMS-
ESI (m/z): [M-K]- 284. Characterisation data matches previous literature reports.[15]
2-(4-(1H-indol-2-yl)benzothiazol-2-yl)phenol (8)
A 10 mL microwave vial was charged with a stir bar, 2-(4-bromobenzo[d]thiazol-2-
yl)phenol (31.4 mg, 0.1 mmol), potassium N-(tert-butoxycarbonyl)indole-2-trifluoroborate
(41.3 mg, 0.12 mmol), Pd(OAc)2 (2.6 mg, 10 mol%) and SPhos (10.3 mg, 25 mol%).
The vial was placed under vacuum and purged with Ar (x 3) before EtOH (1 mL) was
added. The vial was loaded into a microwave reactor and heated at 85 °C for 5 hours.
The crude was dropped onto brine (10 mL) and extracted with EtOAc (3 x 10 mL). The
combined organic phases were dried over anhydrous MgSO4, filtered and all solvent
removed under reduced pressure. The residue was dissolved in CH2Cl2 (1 mL) and TFA
(1 mL) and stirred at room temperature for 2 hours. Solvent was removed under
reduced pressure and the residue dissolved in CH2Cl2 (10 mL) and washed with sat’d
aq. NaHCO3 (2 x 10 mL) until pH was basic (~8) then brine (10 mL). The organic phase
was dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude
residue was purified on Si gel flash column chromatography using an eluent of 100%
cyclohexane to 8.5:1.5 cyclohexane/EtOAc. Desired fractions were collected and
concentrated to furnish the desired product as an orange powder which was further
dried under high vacuum overnight (23.6 mg, 69%). IR νmax/cm-1 (neat film): 3441, 3357,
3054, 2956, 2919, 2846, 1621, 1583, 1481, 1450, 1418, 1301, 1222, 747. 1H NMR (400
19

MHz, Chloroform-d) δ 11.91 (s, 1H, O-H), 9.32 (s, 1H, N-H), 7.83 (dd, J = 7.6, 1.1 Hz,
1H), 7.80 (dd, J = 8.0, 1.1 Hz, 1H), 7.70 (td, J = 7.8, 7.4, 1.3 Hz, 2H), 7.51 (dq, J = 8.1,
0.9 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.40 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.29 – 7.22 (m,
1H), 7.17 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.12 (dd, J = 8.4, 1.1 Hz, 1H), 7.09 (dd, J =
2.2, 0.9 Hz, 1H), 6.98 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H). 13C NMR (101 MHz, Chloroform-d)
δ 169.6 (Cq), 157.5 (Cq), 148.1 (Cq), 137.0 (Cq), 135.4 (Cq), 134.2 (Cq), 133.3 (CHArom),
128.76 (CHArom), 128.7 (Cq), 126.3 (Cq), 126.0 (CHArom), 125.1 (CHArom), 123.0 (CHArom),
121.0 (CHArom), 120.47 (CHArom), 120.43 (CHArom), 120.1 (CHArom), 118.0 (CHArom), 117.0
(Cq), 111.5 (CHArom), 102.4 (CHArom). HRMS-ESI (m/z): found [M+H]+ 343.0902, calc’d
C21H15N2OS requires 343.0905.
2-(2-hydroxyphenyl)-4-(2-aminophenyl)benzothiazole (9)
A 10 mL microwave vial was charged with a stir bar, 2-(2-hydroxyphenyl)-4-
bromobenzothiazole (33.6 mg, 0.1 mmol), 2-aminophenylboronic acid (28.7 mg, 0.21
mmol), Pd(PPh3)4 (12 mg, 10 mol%), Na2CO3 (78 mg, 0.7 mmol), DMF (0.8 mL) and
water (0.2 mL). The reaction mixture was degassed (3 x freeze-pump-thaw) then
purged with Ar. The vial was loaded into a microwave reactor and programmed to be
heated at 120 °C for 1 hour, after which the crude was dropped onto water (10 mL) and
the phases separated. The aqueous phase was extracted with EtOAc (3 x 10 mL), the
combined organic phases were dried over anhydrous MgSO4, filtered and concentrated
onto Celite. The crude residue was purified by Silica gel flash column chromatography
using cyclohexane/EtOAc (4:2 to 1:1). Desired fractions were collected and
concentrated to furnish the desired product as a yellow powder which was further dried
under vacuum overnight (28.7 mg, 82%). IR νmax/cm-1 (neat film): 3466, 3371, 3211,
3057, 3021, 2920, 2250, 1936, 1612, 1577, 1482, 1467, 1219, 1151, 977, 726. 1H NMR
(400 MHz, Chloroform-d) δ 12.27 (bs, 1H, O-H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.68 (dd,
J = 7.8, 1.6 Hz, 1H), 7.56 (dd, J = 7.4, 1.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.36 (ddd, J
= 8.6, 7.2, 1.6 Hz, 1H), 7.31 – 7.20 (m, 2H), 7.04 (dd, J = 8.3, 1.2 Hz, 1H), 6.98 – 6.84
(m, 3H), 3.76 (bs, 2H, N-H2). 13C NMR (101 MHz, Chloroform-d) δ 169.2 (Cq), 158.0
(Cq), 150.0 (Cq), 144.0 (Cq), 133.6 (Cq), 133.4 (Cq), 133.0 (CHArom), 131.3 (CHArom),
20

129.5 (CHArom), 128.4 (CHArom), 128.2 (CHArom), 126.1 (CHArom), 124.4 (Cq), 120.9
(CHArom), 119.6 (CHArom), 118.7 (CHArom), 118.0 (CHArom), 116.9 (Cq), 116.2 (CHArom).
HRMS-ESI (m/z): found [M+H]+ 319.0905, calc’d C19H15N2OS requires 319.0905.
2-(2-methylaminophenyl)-4-bromobenzothiazole (10)[16]
An oven dried 10 mL Pyrex Wheaton vial was charged with a stir bar, [Re] (23 mg,
0.025 mmol, 5 mol%), Cs2CO3 (188.9 mg, 0.6 mmol, 100 mol%), 2-(2-aminophenyl)-4-
bromobenzothiazole (174.5 mg, 0.6 mmol) and dry MeOH (2 mL). The vial was purged
with Ar, then the reaction mixture degassed (3 x freeze-pump-thaw) and left under an
atmosphere of Ar before being sealed with a Teflon lined cap. The vial was then placed
in an oil bath at 140 °C and reaction progress moni tored by TLC (9:1
cyclohexane/EtOAc). After 5 days, the reaction mixture was cooled to rt, diluted with
EtOAc and passed through a Silica plug in a Pasteur pipette and eluted with EtOAc.
The residue was concentrated onto Celite and purified using Silica gel flash column
chromatography using 100% cyclohexane to cyclohexane/CH2Cl2 (7:3). Desired
fractions were collected and concentrated under reduced pressure to furnish the desired
product as a yellow powder, which was further dried under high vacuum overnight
(142.3 mg, 78%). IR νmax/cm-1 (neat film): 3275, 3098, 3056, 2924, 2890, 2859, 2820,
1
1612, 1575, 1525, 1499, 1454, 1305, 1218, 1173, 954, 732. H NMR (400 MHz,
Chloroform-d) δ 9.05 (bs, 1H, N-H), 7.78 (dd, J = 7.9, 1.0 Hz, 1H), 7.69 (dd, J = 7.9, 1.5
Hz, 1H), 7.63 (dd, J = 7.8, 1.0 Hz, 1H), 7.36 (ddd, J = 8.6, 7.1, 1.5 Hz, 1H), 7.19 (t, J =
7.9 Hz, 1H), 6.80 (dd, J = 8.5, 1.1 Hz, 1H), 6.69 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.08 (d,
J = 3.9 Hz, 3H, CH3). 13C NMR (101 MHz, Chloroform-d) δ 170.0 (Cq), 151.8 (Cq), 148.9
(Cq), 134.0 (Cq), 132.8 (CHArom), 130.6 (CHArom), 129.4 (CHArom), 125.7 (CHArom), 120.4
(CHArom), 115.8 (Cq), 115.1 (CHArom), 114.2 (Cq), 111.2 (CHArom), 30.0 (CH3). HRMS-ESI
(m/z): found [M79Br+H]+ 318.9892, calc’d C14H12N2S79Br requires 318.9905.
2-(2-methylaminophenyl)-4-(2-hydroxyphenyl)benzothiazole (11)
21

A 10 mL round-bottom flask with condenser was charged with a stir bar, 2-(4-
bromobenzo[d]thiazol-2-yl)-N-methylaniline (101.9 mg, 0.32 mmol),
2-hydroxyphenylboronic acid (71 mg, 0.5 mmol), Pd(PPh3)4 (36 mg, 10 mol%), Na2CO3
(212 mg, 2 mmol), DMF (2.4 mL) and water (0.6 mL). The reaction mixture was
degassed (3 x freeze-pump-thaw) and then purged with Ar. The flask was placed in an
oil bath at 120 °C for 18 hours. The crude was drop ped onto water (10 mL) and the
phases separated. The aqueous phase was extracted with EtOAc (3 x 10 mL), the
combined organic phases were dried over anhydrous MgSO4, filtered and concentrated
onto Celite. The crude residue was purified by Silica gel flash column chromatography
using 100% cyclohexane to cyclohexane/EtOAc (4:1). Desired fractions were collected
and concentrated to furnish the desired product as a yellow foam which was further
dried under vacuum overnight (82.7 mg, 78%). IR νmax/cm-1 (neat film): 3343, 3060,
1
2922, 2817, 1608, 1575, 1492, 1448, 1312, 1216, 1172, 961, 748. H NMR (400 MHz,
Chloroform-d) δ 8.27 (bs, 1H, N-H), 7.91 (dd, J = 7.8, 1.3 Hz, 1H), 7.74 (dd, J = 7.9, 1.5
Hz, 1H), 7.56 (dd, J = 7.5, 1.3 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.43 – 7.32 (m, 2H), 7.18
(dd, J = 8.1, 1.2 Hz, 1H), 7.11 (td, J = 7.5, 1.3 Hz, 1H), 6.92 (bs, 1H, O-H), 6.75 (d, J =
8.5 Hz, 1H), 6.70 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 2.92 (s, 3H, CH3). 13C NMR (101 MHz,
Chloroform-d) δ 171.1 (Cq), 153.8 (Cq), 150.5 (Cq), 148.5 (Cq), 133.4 (Cq), 133.0
(CHArom), 131.8 (Cq), 131.6 (CHArom), 130.8 (CHArom), 129.9 (CHArom), 128.2 (CHArom),
126.7 (Cq), 125.8 (CHArom), 121.2 (CHArom), 120.7 (CHArom), 118.0 (CHArom), 115.4
(CHArom), 114.1 (Cq), 111.4 (CHArom), 29.8 (CH3). HRMS-DCI(CH4) (m/z): found [M+H]+
333.1048, calc’d C20H17N2OS requires 333.1062.
2-(2-(1H-indol-2-yl)benzo[d]thiazol-4-yl)phenol (12)
A 10 mL microwave vial was charged with a stir bar, tert-butyl 2-(4-
bromobenzo[d]thiazol-2-yl)-1H-indole-1-carboxylate (33.1 mg, 0.077 mmol), 2-
hydroxyphenylboronic acid (23.3 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 10 mol%), Na2CO3
(64 mg, 0.6 mmol), DMF (0.8 mL) and water (0.2 mL). The reaction mixture was
degassed (3 x freeze-pump-thaw) and then purged with Ar. The vial was loaded into a
microwave reactor and heated at 120 °C for 1 h. The crude was dropped onto water (10
22

mL) and the phases separated. The aqueous phase was extracted with EtOAc (3 x 10
mL), the combined organic phases were dried over anhydrous MgSO4, filtered and
concentrated. The crude was dissolved in CH2Cl2 (1 mL) and TFA (1 mL) and stirred at
room temperature for 2 hours. Solvent was removed under reduced pressure and the
crude dissolved in CH2Cl2 (10 mL). The organic phase was washed with sat’d aq.
NaHCO3 (2 x 10 mL) until pH was basic (~8) and finally with brine (10 mL). The organic
phase was dried over anhydrous MgSO4, then filtered and concentrated onto Celite.
The crude residue was purified by Silica gel flash column chromatography using 100%
cyclohexane to cyclohexane/EtOAc (4:1). Desired fractions were collected and
concentrated to furnish the desired product as a yellow powder which was further dried
under vacuum overnight (18.4 mg, 70%). IR νmax/cm-1 (neat film): 3348, 3061, 2927,
1
2846, 2248, 1584, 1549, 1458, 1340, 1230, 1141, 1024, 905, 728. H NMR (400 MHz,
Chloroform-d) δ 9.27 (s, 1H, N-H), 7.90 (dd, J = 7.9, 1.2 Hz, 1H), 7.67 (dq, J = 8.1, 1.0
Hz, 1H), 7.61 (dd, J = 7.6, 1.2 Hz, 1H), 7.56 – 7.47 (m, 2H), 7.45 – 7.36 (m, 2H), 7.31
(ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.25 – 7.19 (m, 2H), 7.19 – 7.08 (m, 2H). 13C NMR (101
MHz, Chloroform-d) δ 161.3 (Cq), 154.3 (Cq), 149.8 (Cq), 137.5 (Cq), 134.4 (Cq), 133.4
(Cq), 131.6 (CHArom), 130.2 (Cq), 130.1 (CHArom), 129.2 (CHArom), 128.4 (Cq), 127.1 (Cq),
126.4 (CHArom), 125.5 (CHArom), 121.9 (CHArom), 121.6 (CHArom), 121.2 (CHArom), 121.0
(CHArom), 119.7 (CHArom), 112.0 (CHArom), 107.2 (CHArom). HRMS-ESI (m/z): found
[M+H]+ 343.0904, calc’d C21H15N2OS requires 343.0905.
Declaration of competing interest
We have no competing interest to declare
Acknowledgements
Financial support from the Université de Toulouse III-Paul Sabatier (Ph.D. Funding
O.S.), French Canadian Research Fund, and Centre National de la Recherche
Scientifique (CNRS) is gratefully acknowledged. Procedures provided in the
supplementary information are related to the PhD Thesis of Omar Sadek “Exploiting
23

boron-fluorine bonds for fluorination and synthesis of potential bi-modal imaging
agents.” Coordination chemistry. Université Paul Sabatier - Toulouse III; University of
British Columbia. Library, 2018. English.
Supporting Information
Supporting information including 1H and 13C NMR spectra are provided.
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Highlights :
Straightforward access to orthogonally dihalogenated benzothiazole core.
Orthogonal Suzuki-Miyaura cross coupling allowing a convergent approach to a
benzothiazole based chemical space.
Synthesis driven taming of photophysical properties.

Declaration of interests
☐
☑ 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.
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: