A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles

Article abstract of DOI:10.1016/j.bmc.2017.01.022

A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.

Full text of DOI:10.1016/j.bmc.2017.01.022

Accepted Manuscript
A Continuous Flow Synthesis and Derivatization of 1,2,4-Thiadiazoles
Marcus Baumann, Ian R. Baxendale
PII:
S0968-0896(17)30090-1
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.01.022
BMC 13501
Reference:
Bioorganic & Medicinal Chemistry
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Received Date:
Revised Date:
Accepted Date:
2 December 2016
12 January 2017
14 January 2017
Please cite this article as: Baumann, M., Baxendale, I.R., A Continuous Flow Synthesis and Derivatization of 1,2,4-
Thiadiazoles, Bioorganic & Medicinal Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.01.022
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A Continuous Flow Synthesis and
Derivatisation of 1,2,4-Thiadiazoles
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Marcus Baumann and Ian R. Baxendale
Department of Chemistry, University of Durham, South Road, DH1 3LE. Durham, United Kingdom.

Bioorganic & Medicinal Chemistry
A Continuous Flow Synthesis and Derivatization of 1,2,4-Thiadiazoles
Marcus Baumanna,  and Ian R. Baxendalea
aDepartment of Chemistry, University of Durham, South Road, DH1 3LE. Durham, United Kingdom.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A continuous flow process is presented that enables the efficient synthesis and derivatization of
1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile
yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order
to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities
of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of
this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based
nucleophiles. This synthetic approach was subsequently applied to generate a series of
bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural
diversification on this important heterocyclic scaffold.
Available online
Keywords:
Flow Synthesis
Microreactors
Heterocycles
2009 Elsevier Ltd. All rights reserved.
Thiadiazoles
Medicinal Chemistry
1. Introduction
sulfenylchloride (5, Scheme 1).15 Although very versatile this
reagent poses several safety risks as it is unstable and readily
decomposes into highly corrosive and malodorous species.16 In
order to mitigate these hazards we decided to harness the benefits
of flow reactor technology17-26 to study the safe and efficient use
of trichloromethane sulfenylchloride en route to 5-chloro-1,2,4-
thiadiazoles that would allow further functionalization reactions
to take place at the activated 5-position of this scaffold.
Thiadiazoles represent a unique subclass of bioactive five-
membered aromatic heterocycles containing one sulfur and two
nitrogen atoms.1-4 The presence of these heteroatoms increases
both the membrane permeability as well as the ability to act as
versatile hydrogen bond acceptors. Due to the spacial similarity
of vinyl groups to ring embedded sulfur atoms thiadiazoles can
be considered isosteres of diazines5,6 adding to their potential to
serve as fragments of bioactive structures.7-10 Thiadiazoles can
occur in four distinct regioisomeric forms (1-4) enriching their
structural diversity with respect to local polarization and vector
space occupied by both carbon bound substituents R1 and R2
(Figure 1).
2. Results and Discussion
In order to safely employ trichloromethane sulfenylchloride
we opted to utilize a Vapourtec R-series flow system27 as it is
amenable to using either the injection sample loops (for small
scale reactions) or pumping directly from reagent bottles (for
scale up operations).
Figure 1: Regioisomerism of thiadiazoles (1-4).
Amongst the possible thiadiazole isoforms the 1,2,4-
thiadiazole scaffold is an important structure as it resembles the
ubiquitous pyrimidine moiety. The synthesis of 1,2,4-thiadiazoles
can be accomplished by a variety of methods including oxidative
ring closure,11,12 multicomponent reactions13 or [3+2]-
cycloadditions.14 A further option which is more amenable to
subsequent functionalization on the heterocyclic scaffold is
Scheme 1: Flow reactor set-up.
Stock solutions of trichloromethane sulfenylchloride (5, 0.45
M in EtOAc) and hydrated benzamidine hydrochloride salt (6,
0.4 M in 1.5 M aqueous NaOH) were freshly prepared before
each set of experiments and used up within 2-3 h. As depicted in
Scheme 1 the reagent solutions were loaded into the sample loops
(PTFE, 2-5 mL each) and subsequently pumped at equal flow
———
based on reacting various amidines with trichloromethane
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

rates to unite at a T-piece (PEEK, 1.3 mm ID). The initial mixing
resulted in an emulsion that then separated into individual
droplets due to the biphasic nature of the solvent system. This
stream was then directed through two tubular coiled reactors
(PTFE, 10 mL each, ambient temperature, no active cooling)
followed by a 75 psi back-pressure regulator prior to be collected
into a round-bottom flask.
competent nucleophiles analogously delivering interesting sulfide
linked architectures in good yield (Figure 2). Finally, we found
that 5-phenoxy substituted 1,2,4-thiadiazoles can be generated by
treating a solution of 7 (0.5 M, THF) at room temperature with
phenols in the presence of polymer-substituted BEMP as base
leading to the clean and high-yielding formation of the desired
adduct 21 (Figure 2).
Using this set-up allowed us to rapidly screen a selection of
conditions and quickly confirm the viability of preparing the
desired 5-chloro-1,2,4-thiadiazole building block 7 in a short
residence time of only 5 minutes with yields up to 80%.
Importantly the improved heat transfer offered by this flow
approach meant that the reaction can be performed at ambient
temperature without decomposition or run-away phenomena
being observed. Although the desired reaction reaches
completion in <5 minutes we elected to use a residence time of
30 minutes in order to further ensure complete hydrolysis of any
residual reagent 5 in addition to any of its hazardous by-products
in the alkaline aqueous co-solvent. This is very selective as the
desired product 7 resides preferentially in the organic phase
which minimizes its hydrolysis to the corresponding 5-hydroxy
derivative (8). This is more difficult to achieve in a batch process
showcasing another benefit of this flow process. Encouraged by
these results we decided to test the scale up of 7 by processing a
20-fold amount of starting materials in an analogous fashion (20
mmol scale). Pleasingly this directly translated into an efficient
access to multi-gram quantities of the desired 5-chloro-1,2,4-
thiadiazole 7 which was isolated in pure form after aqueous
extraction and filtration over a short plug of silica with hexanes
as the eluent yielding 3.25 g of 7 (83%).
Figure 2: Structures of sulfur- and oxygen-linked products 18-
21.
The connectivity of selected reaction products (13 and 20) was
confirmed by single crystal X-ray diffraction experiments (Figure
3). This also revealed an interesting π-stacking phenomenon
between the thiadiazole ring and a nearby aryl moiety in the case
of sulfide linked entities (e.g. 20).
With sufficient quantities of compound 7 in hand we
proceeded to study its functionalization via reaction with
different nucleophiles in a simple parallel batch process. We
therefore dissolved aliquots of 7 in CH2Cl2 (1.0 mmol, 2.5 M)
and added the desired nucleophile (1.1 equiv.) and triethylamine
as base (1.1 equiv.). The reactions were stirred at 25 °C until
complete conversion of 7 was indicated by tlc (typically 2-8 h)
followed by evaporation and purification by silica gel
chromatography. Pleasingly, this approach allowed us to quickly
generate a small selection of reaction products based on various
nitrogen nucleophiles including aliphatic as well as variable
cyclic amine species (Scheme 2).
Figure 3: X-ray crystal structures of 13 (left) and 20 (right).
In an extension of our studies we decided to investigate the
formation of 5-chloro-1,2,4-thiadiazole building blocks that
would enable functionalization in a bidirectional sense. To this
end we opted to incorporate bromo-substituents located at
different positions of the phenyl moiety enabling future
diversification by means of metal mediated amination or cross-
coupling reactions (Figure 4).
Figure 4: Key scaffold for bidirectional diversification.
The required bromophenylamidine substrates (22-24) were
prepared by reacting ortho-, meta- and para-bromobenzonitrile
(0.5 M, THF) with a solution of NaHMDS (1.5 M, 1.2 equiv.,
THF, 1 h, rt) rendering after treatment with aqueous hydrochloric
acid the desired bromophenylamidine HCl-salts 22-24 (see
experimental section for full details). Having gained a quick
access to these substrates we applied them towards the flow-
synthesis of the corresponding thiadiazole derivatives (Scheme
3). In order to avoid any potential solubility issues we modified
the initial set-up by first mixing trichloromethane
sulfenylchloride (5, stream 1, 0.45 M, EtOAc) with the
bromophenylamidine HCl-salt (22-24, stream 2, 0.4 M, H2O)
prior to adding a stream containing NaOH (stream 3, 1.5 M,
Scheme 2: Functionalization of 7 with amine nucleophiles.
Furthermore, we established that substituted thioimidazoles
obtained via a Marckwald multicomponent reaction28 are equally

automated melting point system with a heating rate of 1 °C/min
and are uncorrected.
H2O). The resulting biphasic reaction mixture was then again
directed through two flow coils maintained at ambient
temperature (residence time 30 minutes) before being collected
and purified by aqueous work-up and silica column
chromatography. Pleasingly this approach enabled the rapid and
high yielding generation of three regioisomeric building blocks
(25-27) that can be exploited towards expanded thiadiazole
libraries.
4.2 Synthetic procedures
In order to synthesise 5-chloro-1,2,4-thiadiazole 7 stock
solutions of 5 (0.45 M in EtOAc) and hydrated benzamidine
hydrochloride salt (6, 0.4 M in 1.5 M aqueous NaOH) were
prepared and injected into the sample loops (2-5 mL) of a
Vapourtec R-series flow system. Both streams were pumped at
equal flow rates (0.33 mL/min) and directed into two successive
tubular flow reactors (10 mL each, rt) after being combined at a
T-piece. Upon exiting the second flow reactor the combined
reaction stream passed a back-pressure regulator (75 psi) before
being collected into a flask. After aqueous extraction (3 x 10 mL
water) the organic layer was dried over anhydrous sodium
sulfate, filtered and evaporated to dryness. The organic residue
was further purified by silica column chromatography using
EtOAc/hexanes (5/95 to 10/90) as eluent yielding the desired
thiadiazole 7 after evaporation of all volatiles as a yellow oil.
Small amounts of hydrolysis product 8 were isolated as white
solid.
4.2.1 5-Chloro-3-phenyl-1,2,4-thiadiazole (7).
At 1 mmol scale: Yellow oil; yield: 80%. 1H-NMR (400 MHz,
CDCl3): δ 8.22-8.28 (m, 2H), 7.45-7.70 (m, 3H). 13C-NMR (101
MHz, CDCl3): δ 172.9 (C), 172.1 (C), 131.9 (C), 130.9 (CH),
128.8 (2CH), 128.1 (2CH). IR (neat, ν/cm-1): 1471 (s), 1439 (s),
1319 (m), 1273 (s), 1112 (m), 1057 (s), 781 (m), 706 (s), 688 (s),
650 (m). HRMS (ES-TOF+) calculated for C8H6N2ClS 196.9940,
found 196.9941.
Scheme 4: Flow synthesis of thiadiazoles 25-27.
3. Conclusion
In conclusion we have developed a flow process for
converting benzamidine HCl-salts into valuable 1,2,4-thiadiazole
derivatives based on safely utilizing trichloromethane
sulfenylchloride as a versatile reagent. Exploiting the 5-chloro
substituent we subsequently demonstrated the simple generation
of a small set of 1,2,4-thiadiazole derivatives bearing different
nitrogen-, sulfur- or oxygen-nucleophiles by means of efficient
SNAr reactions. Finally, we extended our methodology to also
access reaction products containing a bromophenyl moiety that
together with the 5-chloro functionality allows for orthogonal and
regiospecific diversification of the 1,2,4-thiadiazole system.
4.2.1 3-Phenyl-1,2,4-thiadiazole-5-ol (8).
Isolated as a by-product. White solid; melting range: 204.6-
1
207.0 °C; yield: 10-20%. H-NMR (400 MHz, d6-DMSO): δ
13.41 (br s, 1H), 7.90-7.99 (m, 2H), 7.49-7.55 (m, 3H). 13C-NMR
(101 MHz, d6-DMSO): δ 180.0 (C), 155.1 (C), 131.8 (CH), 129.4
(2CH), 129.0 (C), 127.0 (2CH). IR (neat, ν/cm-1): 2800-3200
(br), 1642 (s), 1542 (m), 1504 (m), 1463 (m), 1434 (m), 1175
(m), 919 (m), 778 (s), 733 (m), 689 (s), 593 (s), 466 (m). HRMS
(ES-TOF+) calculated for C8H7N2OS 179.0279, found 179.0282.
For derivatizing 5-chloro-3-phenyl-1,2,4-thiadiazole (7) with
different nucleophiles a solution of 7 (1.0 equiv., 2.5 M, DCM)
was prepared. The desired nucleophile (1.1 equiv.) and
triethylamine (1.1 equiv.) were added to this solution. The
resulting reaction mixture was stirred at 25 °C until complete
consumption of the substrates was observed by tlc (2-8 h). After
aqueous extraction (3 x 10 mL water) the organic layer was dried
over anhydrous sodium sulfate, filtered and evaporated to
dryness furnishing the desired product which was furthermore
purified by silica column chromatography (EtOAc/hexanes 10/90
to 30/70).
4. Experimental protocols
4.1 General methods and materials
Unless otherwise stated, all solvents, substrates and reagents
were used as purchased without further purification.
1H-NMR spectra were recorded on 400 MHz instruments and
are reported relative to residual solvent: CHCl3 (δ 7.26 ppm) or
DMSO (δ 2.50 ppm). 13C-NMR spectra were recorded on the
same instrument and are reported relative to CHCl3 (δ 77.16
ppm) or DMSO (δ 39.52 ppm). Data for 1H-NMR are reported as
follows: chemical shift (δ/ ppm) (integration, multiplicity,
coupling constant (Hz)). Multiplicities are reported as follows: s
= singlet, d = doublet, t = triplet, q = quartet, p = pentet, m =
multiplet, br. s = broad singlet, app = apparent. Data for 13C-
NMR are reported in terms of chemical shift (δ/ ppm) and
multiplicity (C, CH, CH2 or CH3). DEPT-135, COSY, HSQC,
HMBC and NOESY experiments were used in the structural
assignment. IR spectra were recorded neat (ATR sampling) with
the intensities of the characteristic signals being reported as weak
(w, <20% of tallest signal), medium (m, 21-70% of tallest signal)
or strong (s, >71% of tallest signal). Low and high resolution
mass spectrometry was performed using the indicated techniques
on instruments equipped with Acquity UPLC and a lock-mass
electrospray ion source. Melting points were recorded on an
4.2.2 N-(2-(Cyclohex-1-en-1-yl)ethyl)-3-phenyl-1,2,4-
thiadiazole-5-amine (9).
1
White solid; melting range: 138.0-140.5 °C; yield: 86%. H-
NMR (400 MHz, CDCl3): δ 8.13-8.18 (m, 2H), 7.39-7.45 (m,
3H), 6.32 (br s, 1H), 5.49 (br s, 1H), 3.31 (app q, J = 6.6 Hz, 2H),
2.28 (app t, J = 6.6 Hz, 2H), 1.95-2.05 (m, 2H), 1.85-1.93 (m,
2H), 1.56-1.62 (m, 2H), 1.48-1.55 (m, 2H). 13C-NMR (101 MHz,
CDCl3): δ 184.5 (C), 170.0 (C), 133.5 (C), 133.3 (C), 129.9
(CH), 128.5 (2CH), 127.9 (2CH), 124.8 (CH), 44.3 (CH2), 37.2
(CH2), 27.7 (CH2), 25.2 (CH2), 22.7 (CH2), 22.2 (CH2). IR (neat,
ν/cm-1): 3235 (m), 2923 (m), 1575 (s), 1459 (m), 1426 (m), 1349
(s), 1299 (m), 1071 (m), 1017 (m), 779 (m), 703 (s), 576 (m).

HRMS (ES-TOF+) calculated for C16H20N3S 286.1378, found
286.1371.
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication CCDC-1519611.
4.2.3 N-Benzyl-3-phenyl-1,2,4-thiadiazol-5-amine (10).
4.2.7 (Rac)-(2R,4R,5S)-2-Ethyl 4-methyl 4-methyl-1-(3-
phenyl-1,2,4-thiadiazol-5-yl)-5-(thiophen-2yl)pyrrolidine-2,4-
dicarboxylate (14).
1
White solid; melting range: 101.6-103.8 °C; yield: 82%. H-
NMR (400 MHz, CDCl3): δ 8.13-8.18 (m, 2H), 7.37-7.43 (m,
3H), 7.30-7.36 (m, 5H), 6.76 (br s, 1H), 4.49 (d, J = 5.6 Hz, 2H).
13C-NMR (101 MHz, CDCl3): δ 184.5 (C), 169.9 (C), 136.2 (C),
133.2 (C), 129.9 (CH), 128.9 (2CH), 128.5 (2CH), 128.2 (CH),
127.9 (2CH), 127.7 (2CH), 50.5 (CH2). IR (neat, ν/cm-1): 3215
(m), 3029 (w), 1739 (w), 1559 (s), 1467 (m), 1430 (m), 1345 (s),
1217 (w), 1027 (w), 707 (s). HRMS (ES-TOF+) calculated for
C15H14N3S 268.0908, found 268.0900.
Yellow oil; yield: 79%. 1H-NMR (400 MHz, CDCl3): δ 8.15-8.10
(m, 2H), 7.42-7.34 (m, 4H), 7.30 (dd, J = 5.0, 1.2 Hz, 1H), 6.98
(dd, J = 5.1, 3.6 Hz, 1H), 4.84 (s, 1H), 4.74 (dd, J = 10.2, 6.9 Hz,
1H), 4.42-4.28 (m, 2H), 3.45 (s, 3H), 3.08 (dd, J = 13.1, 10.3 Hz,
1H), 2.35 (dd, J = 13.1, 7.0 Hz, 1H), 1.56 (s, 3H), 1.35 (t, J = 7.1
Hz, 3H). 13C-NMR (101 MHz, CDCl3): δ 181.0 (C), 171.9 (C),
170.8 (C), 169.3 (C), 138.6 (C), 133.2 (C), 128.8 (CH), 128.4
(2CH), 128.1 (CH), 128.0 (2CH), 126.9 (CH), 126.6 (CH), 71.2
(CH), 62.3 (CH), 61.8 (CH2), 55.2 (C), 52.2 (CH3), 36.8 (CH2),
23.4 (CH3), 14.3 (CH3). IR (neat, ν/cm-1): 2971 (w), 1739 (s),
1537 (m), 1465 (m), 1434 (m), 1351 (s), 1230 (m), 1204 (m),
1131 (m), 708 (s). HRMS (ES-TOF+) calculated for
C22H24N3O4S2 458.1208, found 458.1208.
4.2.4 N-(2-Morpholinoethyl)-3-phenyl-1,2,4-thiadiazol-5-
amine (11).
1
Colourless oil; yield: 76%. H-NMR (400 MHz, CDCl3): δ
8.13-8.19 (m, 2H), 7.35-7.45 (m, 3H), 6.40 (br s, 1H), 3.70-3.77
(m, 4H), 3.35-3.42 (m, 2H), 2.66-2.71 (m, 2H), 2.47-2.55 (m,
4H). 13C-NMR (101 MHz, CDCl3): δ 184 (C), 170.2 (C), 133.3
(C), 129.9 (CH), 128.5 (2CH), 127.9 (2CH), 66.9 (2CH2), 56.2
(CH2), 53.2 (2CH2), 42.1 (CH2). IR (neat, ν/cm-1): 3269 (w), 2970
(w), 1739 (s), 1561 (s), 1430 (m), 1349 (s), 1217 (s), 1117 (m),
707 (s). HRMS (ES-TOF+) calculated for C14H19N4SO 291.1280,
found 291.1279.
4.2.8 5-(4-Methylpiperazin-1-yl)-3-phenyl-1,2,4-thiadiazole
(15).
Off-white solid; melting range: 222.1-225.0 °C; yield: 87%.
1H-NMR (400 MHz, CDCl3): δ 8.17-8.21 (m, 2H), 7.38-7.43 (m,
3H), 3.62 (app t, J = 5.2 Hz, 4H), 2.54 (app t, J = 5.2 Hz, 4H),
2.35 (s, 3H). 13C-NMR (101 MHz, CDCl3): δ 185.1 (C), 170.3
(C), 133.5 (C), 129.8 (CH), 128.4 (2CH), 128.0 (2CH), 54.0
(2CH2), 48.8 (2CH2), 46.2 (CH3). IR (neat, ν/cm-1): 1590 (w),
1523 (s), 1504 (s), 1440 (m), 1368 (s), 1345 (s), 1131 (m), 1028
(m), 743 (s), 702 (m), 683 (s), 644 (m). HRMS (ES-TOF+)
calculated for C13H17N4S 261.1174, found 261.1186.
4.2.5 (Rac)-Methyl 4-methyl-2-((3-phenyl-1,2,4-thiadiazol-5-
yl)amino)pentanoate (12).
1
Yellow oil; yield: 73%. H-NMR (400 MHz, CDCl3): δ 8.12-
8.19 (m, 2H), 7.37-7.44 (m, 3H), 6.15 (d, J = 8.4 Hz, 1H), 4.45-
4.50 (m, 1H), 3.79 (s, 3H), 1.70-1.82 (m, 3H), 0.99 (t, J = 6.1 Hz,
6H). 13C-NMR (101 MHz, CDCl3): δ 183.0 (C), 173.0 (C), 169.8
(C), 133.1 (C), 129.9 (CH), 128.4 (2CH), 128.0 (2CH), 57.2
(CH), 52.6 (CH3), 41.8 (CH2), 24.8 (CH), 22.7 (CH3), 22.0 (CH3).
IR (neat, ν/cm-1): 3297 (w), 2957 (m), 1744 (s), 1551 (s), 1469
(s), 1433 (s), 1345 (s), 1273 (m), 1205 (s), 1171 (m), 708 (s).
HRMS (ES-TOF+) calculated for C15H20N3O2S 306.1276, found
306.1276.
4.2.9 3-Phenyl-5-(4-(pyrrolidin-1-yl)piperidin-1-yl)-1,2,4-
thiadiazole (16).
1
Pale yellow oil; yield: 83%. H-NMR (400 MHz, CDCl3): δ
8.15-8.20 (m, 2H), 7.35-7.43 (m, 3H), 3.96 (br d, J = 12.2 Hz,
2H), 3.24 (ddd, J = 13.1, 11.3, 3.2 Hz, 2H), 2.55-2.70 (m, 4H),
2.30-2.37 (m, 1H), 1.95-2.05 (m, 2H), 1.75-1.85 (m, 4H), 1.66-
1.74 (m, 2H). 13C-NMR (101 MHz, CDCl3): δ 184.9 (C), 170.3
(C), 133.5 (C), 129.8 (CH), 128.4 (2CH), 128.0 (2CH), 60.7
(CH), 51.3 (2CH2), 47.7 (2CH2), 30.2 (2CH2), 23.3 (2CH2). IR
(neat, ν/cm-1): 2957 (m), 2787 (m), 1743 (w), 1556 (s), 1466 (s),
1432 (s), 1356 (s), 1329 (m), 1294 (s), 1150 (m), 1117 (m), 933
(w), 785 (w), 706 (s). HRMS (ES-TOF+) calculated for
C17H23N4S 315.1643, found 315.1647.
4.2.6 5-(Azetidin-1-yl)-3-phenyl-1,2,4-thiadiazole (13).
1
Colourless solid; melting range: 103.5-104.3 °C; yield: 84%. H-
NMR (400 MHz, CDCl3): δ 8.15-8.25 (m, 2H), 7.37-7.45 (m,
3H), 4.18 (app t, J = 7.6 Hz, 4 H), 2.50 (app p, J = 7.6 Hz, 2H).
13C-NMR (101 MHz, CDCl3): δ 184.3 (C), 170.4 (C), 133.4 (C),
129.8 (CH), 128.4 (2CH), 128.1 (2CH), 53.7 (2CH2), 17.8 (CH2).
IR (neat, ν/cm-1): 3045 (w), 2949 (w), 2870 (w), 1745 (w), 1575
(s), 1463 (s), 1432 (s), 1352 (s), 1283 (m), 702 (s). HRMS (ES-
TOF+) calculated for C11H12N3S 218.0752, found 218.0757.
Crystal data for 13: C11H11N3S, M = 217.29, triclinic, space
group P -1, a = 7.3473(4), b = 12.0606(7), c = 12.6147(7) Å, α =
71.093(5),  = 75.062(5), γ = 81.387(5)°, U = 1019.08(11) Å3,
F(000) = 456, Z = 4, Dc = 1.416 mg m-3,  = 0.284 mm-1 (Mo-
K,  = 0.71073 Å), T = 120(1)K. 15847 reflections were
collected on an Agilent Xcalibur diffractometer (Sapphire-3 CCD
detector, fine-focus tube, graphite monochromator) yielding 5660
unique data (Rmerg = 0.034). The structure was solved by direct
method and refined by full-matrix least squares on F2 for all data
using SHELXTL and OLEX2 software.29,30 All non-hydrogen
atoms were refined with anisotropic displacement parameters, H-
atoms were placed into calculated positions and refined in riding
mode. Final wR2(F2) = 0.1035 for all data 271 refined
parameters), conventional R1 (F) = 0.0383 for 4524 reflections
with I  2, GOF = 1.021. Crystallographic data for the structure
4.2.10 3-Phenyl-5-(4-phenylpiperazin-1-yl)-1,2,4-thiadiazole
(17).
Pale yellow solid; melting range: 135.0-135.6 °C. Yield: 85%.
1H-NMR (400 MHz, CDCl3): δ 8.20-8.27 (m, 2H), 7.40-7.47 (m,
3H), 7.29-7.35 (m, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.96 (t, J = 8.4
Hz, 1H), 3.74-3.79 (m, 4H), 3.32-3.36 (m, 4H). 13C-NMR (101
MHz, CDCl3): δ 185.2 (C), 170.4 (C), 150.9 (C), 133.5 (C),
129.9 (CH), 129.4 (2CH), 128.5 (2CH), 128.0 (2CH), 120.9
(CH), 117.0 (2CH), 49.1 (2CH2), 48.8 (2CH2). IR (neat, ν/cm-1):
2822 (w), 1599 (m), 1554 (s), 1502 (m), 1466 (s), 1433 (s), 1355
(s), 1297 (m), 1230 (s), 1028 (m), 944 (m), 759 (m), 707 (s), 692
(m). HRMS (ES-TOF+) calculated for C18H19N4S 323.1330,
found 323.1331.
4.2.11 (1-Methyl-2-((3-phenyl-1,2,4-thiadiazol-5-yl)thio)-
1H-imidazol-5-yl)methanol (18).
1
Colourless oil; yield: 82%. H-NMR (400 MHz, CDCl3): δ 8.15-
8.19 (m, 2H), 7.39-7.45 (m, 3H), 7.10 (s, 1H), 4.62 (s, 2H), 4.35

(br s, 1H), 3.72 (s, 3H). 13C-NMR (101 MHz, CDCl3): δ 185.1
(C), 172.7 (C), 136.1 (C), 134.5 (C), 132.2 (C), 130.6 (CH),
129.5 (CH), 128.7 (2CH), 128.2 (2CH), 54.4 (CH2), 31.8 (CH3).
IR (neat, ν/cm-1): 3100-3500 (br), 2932 (w), 2871 (w), 1465 (s),
1436 (s), 1319 (s), 1275 (s), 1112 (m), 1051 (m), 1025 (s), 953
(w), 823 (w), 782 (w), 708 (s), 692 (m). HRMS (ES-TOF+)
calculated for C13H13N4S2O 305.0531, found 305.0533.
For preparing bromobenzimidamide HCl-salts 22-24 the
corresponding bromobenzonitriles (10 mmol, 1.0 equiv., 0.8 M,
THF) were treated at ambient temperature with a solution of
NaHMDS (1.5 M, THF, 1.2 equiv., 8 mL). The resulting reaction
mixture was stirred at ambient temperature for 1 h before being
quenched by addition of water (5 mL). After addition of aqueous
hydrochloric acid (1 M, 15 mL) the aqueous layer was separated
and evaporated to about 15% of its original volume resulting in
crystallization of the desired HCl-salts 22-24 which were isolated
in pure form as beige solids after filtration and drying at high
vacuum.
4.2.12 (1-Butyl-2-((3-phenyl-1,2,4-thiadiazol-5-yl)thio)-1H-
imidazol-5-yl)methanol (19).
1
Colourless oil; yield: 76%. H-NMR (400 MHz, CDCl3): δ 8.18-
8.24 (m, 2H), 7.40-7.51 (m, 3H), 7.13 (s, 1H), 4.65 (s, 2H), 4.09
(app t, J = 7.8 Hz, 2H), 3.63 (br s, 1H), 1.62-1.75 (m, 2H), 1.33
(hex, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C-NMR (101
MHz, CDCl3): δ 185.1 (C), 172.4 (C), 135.3 (C), 134.9 (C),
132.3 (C), 130.5 (CH), 129.8 (CH), 128.7 (2CH), 128.2 (2CH),
54.6 (CH2), 45.4 (CH2), 33.1 (CH2), 20.0 (CH2), 13.6 (CH3). IR
(neat, ν/cm-1): 3000-3500 (br), 2959 (m), 2929 (m), 2873 (w),
1467 (s), 1436 (s), 1320 (s), 1276 (s), 1114 (w), 1055 (m), 1027
(m), 786 (w), 709 (s). HRMS (ES-TOF+) calculated for
C16H19N4S2O 347.1000, found 347.1006.
4.2.15 2-Bromobenzimidamide hydrochloride (22).
1
Beige solid; yield: 77%. H-NMR (400 MHz, d6-DMSO): δ 9.70
(s, 2H), 9.64 (s, 2H), 7.79-7.85 (m, 1H), 7.54-7.65 (m, 3H). 13C-
NMR (101 MHz, d6-DMSO): δ 166.3 (C), 133.6 (CH), 133.5
(CH), 132.2 (C), 130.0 (CH), 128.4 (CH), 120.1 (C). IR (neat,
ν/cm-1): 3216 (br m), 3042 (br s), 1669 (s), 1595 (m), 1454 (m),
1425 (m), 1040 (m), 727 (s), 677 (m). HRMS (ES-TOF+)
calculated for C7H8N2Br 198.9871, found 198.9866.
4.2.16 3-Bromobenzimidamide hydrochloride (23).
4.2.13 (1-(2,6-Difluorobenzyl)-2-((3-phenyl-1,2,4-thiadiazol-
5-yl)thio)-1H-imidazol-5-yl)methanol (20).
1
Beige solid; yield: 81%. H-NMR (400 MHz, d6-DMSO): δ 9.74
(s, 2H), 9.50 (s, 2H), 8.12 (t, J = 1.8 Hz, 1H), 7.88-7.96 (m, 2H),
7.56 (t, J = 8.1 Hz, 1H). 13C-NMR (101 MHz, d6-DMSO): δ
165.0 (C), 136.9 (CH), 131.5 (CH), 131.3 (CH), 130.4 (C), 127.8
(CH), 122.4 (C). IR (neat, ν/cm-1): 3239 (br s), 3027 (br s), 1673
(s), 1519 (s), 1465 (s), 1080 (m), 884 (m), 796 (m), 710 (s), 659
(s). HRMS (ES-TOF+) calculated for C7H8N2Br 198.9871, found
198.9873.
Colourless solid; melting range: 155.5-158.1 °C; yield: 70%. 1H-
NMR (400 MHz, d6-DMSO): δ 8.10-8.15 (m, 2H), 7.50-7.55 (m,
3H), 7.32 (tt, J = 8.5, 6.6 Hz, 1H), 7.23 (s, 1H), 7.03 (app t, J =
8.3 Hz, 2H), 5.47 (s, 2H), 5.37 (t, J = 5.4 Hz, 1H), 4.55 (d, J =
5.4 Hz, 2H). 13C-NMR (101 MHz, d6-DMSO): δ 185.4 (C), 171.4
(C), 161.1 (2CF, dd, J = 249, 8 Hz), 137.7 (C), 134.4 (C), 132.2
(C), 131.6 (CH, app t, J = 11 Hz), 131.2 (CH), 129.5 (2CH),
129.1 (CH), 128.1 (2CH), 112.3 (2CH, m), 111.9 (C, app t, J =
18 Hz), 53.8 (CH2), 37.7 (CH2). 19F-NMR (376 MHz, d6-DMSO):
δ -114. IR (neat, ν/cm-1): 3000-3450 (br), 1628 (w), 1467 (s),
1438 (s), 1424 (m), 1321 (m), 1277 (m), 1236 (m), 1049 (s),
1026 (s), 987 (s), 902 (m), 868 (m), 789 (s), 702 (s). HRMS (ES-
TOF+) calculated for C19H15N4S2F2O 417.0655, found 417.0648.
Crystal data for 20: C19H14N3S, M = 416.46, monoclinic, space
group P 21/c, a = 37.5101(19), b = 7.0468(4), c = 14.0246(7) Å, 
= 100.807(2) °, U = 3641.3(3) Å3, F(000) = 1712, Z = 8, Dc =
1.519 mg m-3,  = 0.331 mm-1 (Mo-K,  = 0.71073 Å), T =
120(1)K. 50305 reflections were collected on an Bruker
D8Venture diffractometer (Photon 100 CMOS detector, IμS-
microsource, focusing mirrrors) yielding 8358 unique data (Rmerg
= 0.057). The structure was solved by direct method and refined
as a 2-component twin by full-matrix least squares on F2 for all
data using SHELXTL and OLEX2 software.29,30 H-atoms were
placed into calculated positions and refined in riding mode. Final
wR2(F2) = 0.1919 for all data (487 refined parameters),
conventional R1 (F) = 0.0770 for 7497 reflections with I  2,
GOF = 1.021. Crystallographic data for the structure have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC-1519612.
4.2.17 4-Bromobenzimidamide hydrochloride (24).
1
Beige solid; yield: 85%. H-NMR (400 MHz, d6-DMSO): δ 9.58
(br s, 2H), 9.42 (br s, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.81 (d, J =
8.0 Hz, 2H). 13C-NMR (101 MHz, d6-DMSO): δ 165.4 (C), 132.5
(2CH), 130.7 (2CH), 128.1 (C), 127.7 (C). IR (neat, ν/cm-1):
3322 (br s), 3135 9br s), 1669 (s), 1593 (s), 1480 (m), 1428 (m),
1071 (m), 1009 (m), 841 (m), 776 (m), 695 (s), 623 (s). HRMS
(ES-TOF+) calculated for C7H8N2Br 198.9871, found 198.9873.
In order to synthesise 5-chloro-1,2,4-thiadiazoles 25-27 stock
solutions of 5 (0.45 M in EtOAc) and the desired substrates 22-
24 (0.4 M in water) were prepared and injected into the sample
loops of a Vapourtec R-series flow system. Both streams (0.17
mL/min each) were combined in a T-piece and subsequently
mixed with a stream of aqueous NaOH (1.5 M, 0.33 mL/min)
prior to entering two successive tubular flow reactors (10 mL
each, rt). Upon exiting the second flow reactor the combined
reaction stream passed a back-pressure regulator (75 psi) before
being collected into a flask. After aqueous extraction (3 x 10 mL
water) the organic layer was dried over anhydrous sodium
sulfate, filtered and evaporated to dryness. The organic residue
was further purified by silica column chromatography using
EtOAc/hexanes (1/99 to 20/80) as eluent yielding the desired
thiadiazoles (25-27) in pure form after evaporation of all
volatiles.
4.2.14 5-(4-Bromophenoxy)-3-phenyl-1,2,4-thiadiazole (21).
1
Colourless solid; melting range: 82.3-84.9 °C; yield: 93%. H-
NMR (400 MHz, CDCl3): δ 8.13-8.22 (m, 2H), 7.60 (d, J = 8.9
Hz, 2H), 7.40-7.48 (m, 3H), 7.30 (d, J = 8.9 Hz, 2H). 13C-NMR
(101 MHz, CDCl3): δ 190.6 (C), 169.2 (C), 153.9 (C), 133.3
(2CH), 132.6 (C), 130.6 (CH), 128.6 (2CH), 127.9 (2CH), 121.9
(2CH), 120.1 (C). IR (neat, ν/cm-1): 3060 (w), 1510 (m), 1480
(m), 1455 (m), 1334 (m), 1247 (m), 1189 (m), 1067 (m), 1009
(m), 827 (m), 777 (m), 701 (s), 687 (s). HRMS (ES-TOF+)
calculated for C14H10N2SBrO 332.9697, found 332.9696.
4.2.18 3-(2-Bromophenyl)-5-chloro-1,2,4-thiadiazole (25).
Yellow oil; yield: 82%. 1H-NMR (400 MHz, CDCl3): δ 7.85 (dd,
J = 7.7, 1.8 Hz, 1H), 7.71 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (td, J =
7.6, 1.3 Hz, 1H), 7.31 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H). 13C-NMR
(101 MHz, CDCl3): δ 172.8 (C), 171.2 (C), 134.2 (CH), 133.0
(C), 132.3 (CH), 131.4 (CH), 127.4 (CH), 121.9 (C). IR (neat,
ν/cm-1): 3058 (w), 1591 (w), 1468 (m), 1451 (s), 1292 (s), 1251

17. Movisyan, M.; Delbeke, E.I.P; Berton, J.K.E.T.; Battilocchio, C.;
Ley, S.V.; Stevens, C.V. Chem. Soc. Rev. 2016, 45, 4892-4928.
18. McQuade, D.T.; Seeberger, P.H. J. Org. Chem. 2013, 78, 6384-
6389.
19. Baumann, M.; Baxendale, I.R. Beilstein J. Org. Chem. 2015, 11,
1194-1219.
20. Baxendale, I.R. J. Chem. Technol. Biotechnol. 2013, 88, 519-552.
21. Ley, S.V. Chem. Rec. 2012, 12, 378-390.
22. Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47,
4583-4592.
23. Malet-Sanz, L.; Susanne, F. J. Med. Chem. 2012, 55, 4062-4098.
24. Baumann, M.; Baxendale, I.R.; Ley, S.V. Mol. Div. 2011, 15, 613-
630.
25. McMullen, J.P.; Jensen, K.F. Annu. Rev. Anal. Chem. 2010, 3, 19-
42.
(m), 1060 (s), 1026 (m), 899 (m), 766 (m), 734 (s). HRMS (TOF
AP+) calculated for C8H5N2SBrCl 274.9045, found 274.9051.
4.2.19 3-(3-Bromophenyl)-5-chloro-1,2,4-thiadiazole (26).
1
Yellow oil; yield: 79%. H-NMR (400 MHz, CDCl3): δ 8.38 (t, J
= 1.8 Hz, 1H), 8.14 (dt, J = 7.8, 1.3 Hz, 1H), 7.59 (ddd, J = 7.9,
2.0, 1.1 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H). 13C-NMR (101 MHz,
CDCl3): δ 173.4 (C), 170.5 (C), 133.9 (CH), 133.6 (C), 131.1
(CH), 130.3 (CH), 126.6 (CH), 122.9 (C). IR (neat, ν/cm-1): 3069
(w), 1568 (w), 1469 (s), 1458 (s), 1427 (m), 1281 (s), 1057 (s),
907 (m), 792 (m), 726 (s), 677 (s). HRMS (TOF AP+) calculated
for C8H5N2SBrCl 274.9045, found 274.9073.
26. Webb, D.; Jamison, T.F. Chem. Sci. 2010, 1, 675-680.
27. https://www.vapourtec.com/ (accessed on 19/11/2016).
28. Baumann, M.; Baxendale, I.R. Org. Lett. 2014, 16, 6076-6079.
29. Sheldrick, G.M. Acta Cryst. 2008, A64, 112-122.
30. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.;
Puschmann, H. J. Appl. Cryst. 2009, 42, 339-341.
4.2.20 3-(4-Bromophenyl)-5-chloro-1,2,4-thiadiazole (27).
1
Off-white amorphous solid; yield: 85%. H-NMR (400 MHz,
CDCl3): δ 8.11 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H). 13C-
NMR (101 MHz, CDCl3): δ 173.3 (C), 171.1 (C), 132.1 (2CH),
130.8 (C), 129.6 (2CH), 125.6 (C). IR (neat, ν/cm-1): 2924 (w),
1715 (w), 1591 (m), 1461 (m), 1397 (m), 1305 (m), 1272 (m),
1109 (m), 1058 (s), 1007 (m), 894 (m), 829 (s), 732 (s). HRMS
(TOF AP+) calculated for C8H4N2SBrCl 273.8967, found
273.8989.
5. Acknowledgement
We gratefully acknowledge financial support by the Royal
Society (to MB and IRB) for undertaking this study. We also
want to express our gratitude to Dr Andrej Batsanov and Dr
Dmitry Yufit (both Department of Chemistry, University of
Durham) for solving the single crystal X-ray structures of
compounds 13 and 20.
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