Thiolation of Pyridine-2-sulfonamides using Magnesium Thiolates

Article abstract of DOI:10.1055/s-0039-1690199

The thiolation of pyridine-2-sulfonamides using magnesium thiolates is reported. The ortho-functionalizations of these sulfonamides using TMPMgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) followed by electrophilic quenching produced a range of 3-functiona

Full text of DOI:10.1055/s-0039-1690199

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
paper
A
en
B. Heinz et al.
Paper
Synthesis
Thiolation of Pyridine-2-sulfonamides using Magnesium Thiolates
Benjamin Heinz
1) E-X
(1.2–1.6 equiv)
THF, 0–25 °C
MgCl•LiCl
TMPMgCl•LiCl
(1.2 equiv)
E
Moritz Balkenhohl
N
Paul Knochel*
0
0
0
0-0
0
0
1-7
9
1
3-
4
3
3
2
N
S
N
S
N
THF, 0 °C, 2 h
N
SR
2) RSMgCl•LiCl
(1.2 equiv)
0–25 °C, 12 h
O
O
O
O
Ludwig-Maximilians-Universität München, Department Chemie,
Butenandtstr. 5–13, Haus F, 81377 München, Germany
paul.knochel@cup.uni-muenchen.de
19 examples
50–95% yield
R = alkyl
Received: 05.08.2019
Accepted: 19.08.2019
Published online: 03.09.2019
DOI: 10.1055/s-0039-1690199; Art ID: ss-2019-c0439-op
actions.5 However, several of these methods require harsh
reaction conditions or the use of a transition-metal catalyst.
Recently, we have described the amination of pyridine-2-
sulfonamides, sulfonic acids, or -2-phosphorodiamidates
using magnesium amides.6 In the case of pyridine-sulfon-
amides and -phosphorodiamidates, an ortho-functionaliza-
tion followed by an amination using magnesium amides
was described.6a,b We envisioned that other nucleophiles
may also undergo substitution reactions on pyridine sul-
fonamides, which would increase the scope and synthetic
utility of the present method. Thus, in the course of these
investigations, alternative nucleophilic reagents were test-
ed. Carbon-centered nucleophiles such as phenylmagne-
sium bromide, diphenylmagnesium, or more reactive
phenyllithium did not lead to the desired C–C coupling
products in synthetically useful yields. Presumably, this was
due to a too weak precomplexation to the pyridine nitrogen
or a too high reactivity of the employed metal species.6a
However, when a thiol such as 2-propanethiol was treated
with iPrMgCl·LiCl at 0 °C for 15 min and 25 °C for 15 min in
THF, the magnesium thiolate iPrSMgCl·LiCl was formed.
This thiolate (2.0 equiv) reacted with pyridine-2-sulfon-
amide 1 at 25 °C for 12 h to give the thiolated pyridine 2a in
63% yield (Scheme 1). This result led us to investigate the
reaction scope.
Abstract The thiolation of pyridine-2-sulfonamides using magnesium
thiolates is reported. The ortho-functionalizations of these sulfon-
amides using TMPMgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) fol-
lowed by electrophilic quenching produced a range of 3-functionalized
pyridine-2-sulfonamides, which were subsequently converted into the
corresponding thioethers. Finally, symmetric or asymmetric diorgano-
disulfides were employed as electrophiles in a one-pot ortho-
functionalization–thiolation procedure, leading to pyridine 2,3-disubsti-
tuted dithioethers.
Key words pyridine, thiols, magnesium, thioethers, N-heterocycles
Thioethers play an important role in modern organic
synthesis and material sciences.1 They are used in the
preparation and stabilization of a range of nanoparticles,2
and can act as directing groups in regioselective alkenyla-
tion and alkynylation reactions.3 Moreover, thioethers are
present in various pharmaceuticals and natural products
(Figure 1).4
N
Me
SMe
Thus, other thiols, such as ethane-, butane- or cyclohex-
ane-thiol led to the thioethers 2b–d in 72–83% yield. An al-
lylic thiol was also employed under these mild reaction
conditions to give 2e in 68% yield.7 However, 1,3-propan-
edithiol did not lead to the desired symmetrical dithioether 2f.
Sterically hindered metal amide bases such as TMPMgCl·LiCl8
or TMPZnCl·LiCl9 (TMP = 2,2,6,6-tetramethylpiperidyl) have
proven to be excellent reagents for directed metalation reac-
tions. A well-known directed ortho-metalation group (DMG)
is the sulfonamide group, which has allowed the prepara-
tion of a range of ortho-functionalized pyridine-2-sulfon-
amides.6a,10 Herein, we have used this approach to prepare a
N
S
SMe
N
N
N
SMe
Et
Et
S
N
N
N
N
H
H
H
Simetryn
(herbicide)
Thioridazine
(antipsychotic)
Cyclobrassinin
Figure 1 Thioethers present in various pharmaceuticals and natural
products
To date, pyridine-thioethers have been prepared via al-
kylation of mercaptopyridine, platinum-catalyzed reduc-
tive couplings, or via nucleophilic aromatic substitution re-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B. Heinz et al.
Paper
Synthesis
TMPMgCl•LiCl
(1.2 equiv)
MgCl•LiCl
E
RSMgCl•LiCl (2.0 equiv)
0 °C to 25 °C, 12 h
EX
N
N
N
S
N
SR
THF, 0 °C, 2 h
N
S
N
SO2NR2
N
SO2NR2
O
S
O
O
1
O
1
2a–e
3
4a–k
I
Br
SMe
N
N
S
N
S
N
N
N
S
2a: 63%
2b: 72%
2c: 76%
N
S
N
S
N
O
O
O
O
O
O
4a: 82%
4b: 94%
4c: 76%
N
S
N
S
S
N
N
S
Ph
2f: 0%
2d: 83%
2e: 68%
OH
O
Scheme 1 Thiolation of pyridine-2-sulfonamide 1 using magnesium
thiolates
O
N
S O
N
S
N
S
N
O
N
N
O
O
wide variety of 3-functionalized pyridine-2-sulfonamides,
which should also be available reactants for thiolation reac-
tions. Thus, pyridine-2-sulfonamide 1 was dissolved in THF
(0.2 M) and was magnesiated with TMPMgCl·LiCl (1.2
equiv) at 0 °C for 2 h (Scheme 2). Reaction of the resulting
pyridine-3-magnesium species of type 3 with iodine or
(BrCl2C)2 led to the halogenated pyridines 4a–b in 81–94%
yield. Quenching of the magnesiated pyridine with
MeSSO2Me or benzaldehyde, gave the thioether 4c or the al-
cohol 4d in 76% or 81% yield, respectively.
4d: 81%
4e: 92%a
4f: 86%a
O
O
S
O
O
O
O
N
S
N
S
N
Cl
O
O
N
S O
N
N
4g: 83%a
4h: 70%a
tBu
4i: 88%a
CO2Et
Transmetalation of the magnesium species of type 3 to
copper using a 1 M CuCN·2LiCl solution in THF (1.2 equiv)
paved the way for allylation reactions. Thus, after reaction
with allyl bromide or 3-bromocyclohexene, the allylated
pyridines 4e–f were obtained in 86–92% yield. Typical
quench reactions of copper organometallics also include re-
actions with acyl chlorides. Therefore, mixing the resulting
copper species with cyclopropanecarbonyl chloride, thio-
phenecarbonyl chloride, or 4-chlorobenzoyl chloride, af-
forded the ketones 4g–i in 70–88% yield. Finally, palladium-
catalyzed Negishi cross-couplings11 were performed after
transmetalation of the magnesium reagent of type 3 to zinc,
using a 1 M ZnCl2 solution in THF (1.2 equiv). Treatment of
the generated zinc species with 4-iodo-tert-butylbenzene
(0.8 equiv) or ethyl 4-iodobenzoate (0.8 equiv) in the pres-
ence of Pd(dba)2 (3 mol%) and tfp (6 mol%)12 produced the
biaryl derivatives 4j–k in 67–90% yield (Scheme 2).
O
O
N
S
N
O
N
S
N
O
4j: 90%b
4k: 67%b
Scheme 2 Directed ortho-metalation and functionalization of pyri-
dine-2-sulfonamide 1 using TMPMgCl·LiCl. a CuCN·2LiCl solution (1 M,
1.2 equiv) was used for transmetalation. b Pd(dba)2 (3 mol%) and tfp (6
mol%) after transmetalation with a 1 M ZnCl2 solution was used as cata-
lyst system.
Yet, when the sensitive allyl-substituted pyridines 4e–f
were treated with a range of thiolates, the expected thio-
ethers 5g–j were obtained in 58–95% yield.
In the next step, the 3-functionalized pyridine-2-sulfon-
amides of type 4 were treated with various magnesium thi-
olates to obtain the desired pyridine thioethers. Thus, mix-
ing halopyridines 4a–b with magnesium thiolates (includ-
ing allyl magnesium thiolate) at 0 °C, gave the thioethers
5a–e in 75–91% yield (Scheme 3). When thioether 4c was
treated with cyclohexylmagnesium thiolate, the dithioether
5f was obtained in 82% yield. Unfortunately, reaction of the
alcohol 4d with an excess of a thiolate did not lead to the
desired substitution product in satisfactory yields (<20%).
The prepared ketones 4g–i also tolerated the basic reac-
tion conditions. Thus, after standard thiolation, thioethers
5k–m were obtained in 81–86% yield. When biaryls 4j–k
were mixed with magnesium thiolates, the desired 2,3-di-
functionalized pyridines 5n–o were obtained in 55–95%
yield (Scheme 3).
Finally, quench reactions of the magnesium amides of
type 3 with symmetrical and asymmetrical disulfides were
investigated. Interestingly, reaction of 3 with dimethyl di-
sulfide (1.5 equiv) directly led to dithioether 6a in 84% yield
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

C
B. Heinz et al.
Paper
Synthesis
E
S
MgCl•LiCl
E
TMPMgCl•LiCl
(1.2 equiv)
RSMgCl•LiCl (1.2 equiv)
0 to 25 °C, 12 h
N
N
N
S
N
N
S
N
N
SR
THF, 0 °C, 2 h
O
O
O
O O
O
4a–l
5a–p
1
RSSR'
(1.5 equiv)
I
I
I
I
S
SR
SR
N
S
N
S
N
SiPr
N
SBu
N
12 h, 25 °C
N
N
SR'
O
O
6a–d
5a: 88%
5d: 82%
+ R'SMgCl•LiCl (7)
5b: 75%
5c: 91%
S
Br
SMe
SMe
SMe
SBu
SBu
N
S
Me
N
N
SBu
N
S
N
N
S
N
SBu
5e: 81%
5f: 82%
5g: 71%
5h: 90%
6a: 84%
6c: 75%
SBu
O
Me
S
O
6b: 50%
N
S
N
S
N
S
N
SEt
N
SiPr
S
SBu
5i: 95%
5j: 64%
5k: 81%
5l: 81%
Me
Me
8
tBu
CO2Et
O
S
6d: 50%
Scheme 4 Quenching of ortho-magnesiated pyridine-2-sulfonamides
of type 3 with symmetrical and asymmetrical disulfides
N
Cl
N
S
N
S
was performed using aluminum plates covered with silica gel (Merck
60, F-254) and visualized by UV detection. Purification by column
chromatography was performed using Merck silica gel 60 (40–63 mm
230–400 mesh ASTM from Merck). THF was continuously heated at
reflux and freshly distilled from sodium benzophenone ketyl under
N2. Yields refer to isolated yields of compounds estimated to be >95%
pure as determined by 1H NMR spectroscopy (25 °C) and capillary GC
analysis. Melting points were measured with a Büchi B 540 apparatus
and are uncorrected. NMR spectra were recorded in CDCl3. Mass spec-
tra and HRMS were recorded with Finnigan MAT 90 or Finnigan MAT
95 instruments using electron ionization (EI). IR spectra were record-
ed with a PerkinElmer spectrum BX-59343 instrument. For detection,
a Smiths Detection DuraSamplIR II Diamond ATR sensor was used.
Gas chromatographic analyses were performed with a Hewlett-Pack-
ard 6890 instrument (5% phenylmethylpolysiloxane; length: 15 m;
diameter: 0.25 mm; film thickness: 0.25 m). 2,2,6,6-Tetrameth-
ylpiperidine (TMPH) was distilled prior to use, and CuCN, ZnCl2, and
LiCl were obtained from Merck.
5m: 86%
5n: 95%
5o: 55%
Scheme 3 Thiolation of ortho-functionalized pyridine-2-sulfonamides
using magnesium thiolates
(Scheme 4). First, the magnesium organometallic of type 3
reacts with the disulfide (RSSR′), giving rise to a magne-
sium thiolate 7 (R′SMgCl·LiCl). This thiolate (7) may then
substitute the sulfonamide moiety, leading to the formation
of 6a. Reaction of 3 with dibutyl disulfide or ditolyl disul-
fide gave 6b–c in 50–75% yield. Employing the unsymmet-
rical disulfide 8 gave the pyridine 6d in 50% yield, as identi-
fied by 2D NMR spectroscopy.13
In summary, the thiolation of pyridine-2-sulfonamides
using magnesium thiolates was reported. Directed ortho-
metalations and functionalizations were also carried out,
which, after subsequent thiolations, led to 3-functionalized
pyridine-2-thioethers in high yields. Additionally, a one-pot
ortho-functionalization–thiolation procedure was devel-
oped by using symmetrical or asymmetrical disulfides as
electrophiles in ortho-magnesiation reactions.
CuCN·2LiCl Solution14
CuCN·2LiCl solution (1.0 M in THF) was prepared by drying CuCN
(7.17 g, 80 mmol) and LiCl (6.77 g, 160 mmol) in a Schlenk flask un-
der vacuum at 140 °C for 5 h. After cooling, anhyd. THF (80 mL) was
added and stirring was continued until all salts were dissolved (24 h).
ZnCl2 Solution
ZnCl2 solution (1.0 M in THF) was prepared by drying ZnCl2 (136.3 g,
100 mmol) in a Schlenk flask under vacuum at 140 °C for 5 h. After
cooling, anhyd. THF (100 mL) was added and stirring was continued
until all salts were dissolved (12 h).
Unless otherwise indicated, all reactions were carried out with mag-
netic stirring and in flame-dried glassware under argon. Syringes
used to transfer reagents and solvents were purged with argon thrice
prior to use. Reactions were monitored by GC or GC-MS or by TLC. TLC
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

D
B. Heinz et al.
Paper
Synthesis
iPrMgCl·LiCl15
Synthesis of 2-(Isopropylthio)pyridine (2a)
Mg turnings (110 mmol) and anhyd. LiCl (100 mmol) were placed in
an argon-flushed flask, and THF (50 mL) was added. A solution of iPrCl
(100 mmol) in THF (50 mL) was slowly added at 25 °C. The reaction
started within a few minutes. After the addition, the reaction mixture
was stirred for 12 h at 25 °C. The gray solution of iPrMgCl·LiCl was
cannulated into another argon-filled flask and removed in this way
from excess Mg. iPrMgCl·LiCl was titrated with I2 prior to use.
Pyridine 2a was prepared via GP1 using 1 (113 mg, 0.50 mmol),
iPrMgCl·LiCl (0.65 mL, 1.00 mmol) and propane-2-thiol (0.09 mL,
1.00 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 2a.
Yield: 48.0 mg (0.31 mmol, 63%); colorless oil.
IR (Diamond-ATR, neat): 3045, 2962, 1577, 1555, 1451, 1413, 1123,
1053, 755, 724 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.44 (dd, J = 5.0, 1.8 Hz, 1 H), 7.47 (dd,
J = 8.2, 7.4 Hz, 1 H), 7.16 (dd, J = 8.0, 1.0 Hz, 1 H), 6.99–6.95 (m, 1 H),
4.03–3.98 (m, 1 H), 1.41 (dd, J = 6.8, 0.6 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 159.5, 149.5, 135.9, 122.8, 119.3, 35.1,
23.2.
TMPMgCl·LiCl8
In a dry and argon-flushed Schlenk flask, TMPH (14.8 g, 105 mmol)
was added to iPrMgCl·LiCl (71.4 mL, 100 mmol, 1.40 M in THF) at
25 °C and the mixture was stirred for 3 d at 25 °C. The freshly pre-
pared TMPMgCl·LiCl was titrated prior to use at 0 °C with benzoic
acid using 4-(phenylazo)diphenylamine as indicator.
MS (EI, 70 eV): m/z (%) = 153 (25), 138 (35), 120 (100), 111 (39), 67
(22).
Thiolation of Pyridine-2-sulfonamides; General Procedure 1 (GP1)
HRMS (EI): m/z calcd. for C8H11NS: 153.0612; found: 153.0606.
iPrMgCl·LiCl (2.0 equiv) was added to a solution of thiol (2.0 equiv) in
THF (5.0 mL/mmol of thiol) at 0 °C. The solution was stirred at 0 °C for
15 min, then 15 min at 25 °C, followed by addition to a solution/sus-
pension of pyridine-2-sulfonamide (1.0 equiv) in THF (5.0 mL/mmol
of sulfonamide) at 0 °C. The reaction mixture was stirred at 25 °C un-
til completion. The reaction was quenched with sat. aq. ammonium
chloride solution, extracted with EtOAc and dried over sodium sul-
fate. After filtration, the solvent was removed in vacuo. The crude
product was purified by flash chromatography using the appropriate
eluent.
Synthesis of 2-(Butylthio)pyridine (2b)
Pyridine 2b was prepared via GP1 using 1 (57.0 mg, 0.25 mmol),
iPrMgCl·LiCl (0.33 mL, 0.50 mmol) and butane-1-thiol (0.06 mL, 0.50
mmol). After workup, the crude product was purified via flash chro-
matography (isohexane/EtOAc = 10:0.3) to give 2b.
Yield: 30.0 mg (0.18 mmol, 72%); colorless oil.
IR (Diamond-ATR, neat): 2961, 2918, 2252, 1579, 1454, 1414, 1126,
904, 724, 649 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.44 (dd, J = 4.9, 1.9 Hz, 1 H), 7.48 (dd,
J = 8.1, 7.4 Hz, 1 H), 7.18 (dt, J = 8.1, 1.0 Hz, 1 H), 7.00–6.96 (m, 1 H),
3.21–3.16 (m, 2 H), 1.72 (tt, J = 8.6, 6.8 Hz, 2 H), 1.55–1.44 (m, 2 H),
0.96 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.7, 149.4, 135.8, 122.1, 119.2, 31.4,
29.9, 22.1, 13.7.
ortho-Functionalization of Pyridine-2-sulfonamides; General Pro-
cedure 2 (GP2)
To a solution of sulfonamide (1.0 equiv) in THF (5.0 mL/mmol of sul-
fonamide), a solution of TMPMgCl·LiCl (1.2–1.6 equiv) was added at
0 °C. The reaction mixture was stirred at 0 °C until completion of the
metalation (checked via iodolysis), then a solution of the electrophile
(1.2–1.6 equiv) in THF (5.0 mL/mmol of electrophile) was added at
0 °C. The reaction mixture was stirred at 25 °C until completion. The
reaction was quenched with sat. aq. ammonium chloride solution,
and the mixture was extracted with EtOAc and dried over sodium sul-
fate. After filtration, the solvent was removed in vacuo. The crude
product was purified by flash chromatography using the appropriate
eluent.
MS (EI, 70 eV): m/z (%) = 167 (14), 138 (56), 125 (100), 124 (33), 120
(16), 111 (38), 78 (15).
HRMS (EI): m/z calcd. for C9H13NS: 167.0769; found: 167.0762.
Synthesis of 2-(Cyclohexylthio)pyridine (2c)
Pyridine 2c was prepared via GP1 using 1 (565 mg, 3.00 mmol),
iPrMgCl·LiCl (3.84 mL, 6.00 mmol) and cyclohexanethiol (0.76 mL,
6.00 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 2c.
2-(Piperidin-1-ylsulfonyl)pyridine (1)
Adapted from a reported procedure;6a pyridine-2-sulfonyl chloride
(1.11 g, 6.25 mmol) was dissolved in CH2Cl2 (20 mL), then piperidine
(1.81 mL, 18.7 mmol) was added at 0 °C and the reaction mixture was
stirred at 25 °C for 12 h. The reaction was quenched with aq. sat. am-
monium chloride solution, and the mixture was extracted with EtOAc
(3 × 75 mL) and dried over sodium sulfate. After filtration, the solvent
was removed in vacuo. The crude product was purified by flash chro-
matography (isohexane/EtOAc = 6:4) to give 1.
Yield: 443 mg (2.29 mmol, 76%); colorless oil.
IR (Diamond-ATR, neat): 2927, 2851, 1578, 1555, 1449, 1412, 1122,
984, 755, 725 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.44 (dd, J = 4.9, 1.0 Hz, 1 H), 7.47 (dd,
J = 8.0, 1.9 Hz, 1 H), 7.17 (dt, J = 8.0, 1.1 Hz, 1 H), 6.97 (dd, J = 7.4,
1.1 Hz, 1 H), 3.89–3.72 (m, 1 H), 2.15–2.05 (m, 2 H), 1.86–1.74 (m,
2 H), 1.70–1.62 (m, 1 H), 1.55–1.44 (m, 4 H), 1.38–1.28 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 159.3, 149.5, 135.9, 122.9, 119.3, 42.9,
33.3, 26.0, 25.8.
Yield: 1.41 g (6.23 mmol, 98%); light-yellow solid.
1H NMR (400 MHz, CDCl3):  = 8.74–8.68 (m, 1 H), 7.97–7.86 (m, 2 H),
7.52–7.44 (m, 1 H), 3.32–3.24 (m, 4 H), 1.68–1.57 (m, 4 H), 1.54–1.45
(m, 2 H).
MS (EI, 70 eV): m/z (%) = 193 (21), 138 (29), 112 (37), 111 (77), 78
(18), 67 (18).
HRMS (EI): m/z calcd. for C11H14NS: 193.0925; found: 193.0919.
The spectra matched those reported.6a
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

E
B. Heinz et al.
Paper
Synthesis
Synthesis of 2-(Ethylthio)pyridine (2d)
Yield: 143 mg (0.47 mmol, 94%); colorless solid.
1H NMR (400 MHz, CDCl3):  = 8.50 (dd, J = 4.6, 1.4 Hz, 1 H), 8.06 (dd,
J = 8.0, 1.4 Hz, 1 H), 7.30 (dd, J = 8.0, 4.6 Hz, 1 H), 3.59–3.53 (m, 4 H),
1.73–1.60 (m, 6 H).
Pyridine 2d was prepared via GP1 using 1 (113 mg, 0.5 mmol),
iPrMgCl·LiCl (0.65 mL, 1.00 mmol) and ethanethiol (0.07 mL,
1.00 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 2d.
The spectra matched those reported.6a
Yield: 58.0 mg (0.42 mmol, 83%); colorless oil.
IR (Diamond-ATR, neat): 3045, 2969, 2928, 1578, 1556, 1454, 1413,
Synthesis of 3-(Methylthio)-2-(piperidin-1-ylsulfonyl)pyridine
(4c)
1126, 756, 723 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.44–8.38 (m, 1 H), 7.49–7.40 (m, 1 H),
7.15 (dt, J = 8.1, 1.0 Hz, 1 H), 6.97–6.89 (m, 1 H), 3.16 (q, J = 7.4 Hz,
2 H), 1.37 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.5, 149.6, 135.9, 122.3, 119.3, 24.5,
14.7.
Pyridine 4c was prepared via GP2 using 1 (113 mg, 0.50 mmol),
TMPMgCl·LiCl (0.48 mL, 0.60 mmol) and S-methyl methanesul-
fonothioate (0.08 mL, 0.75 mmol). After workup, the crude product
was purified via flash chromatography (isohexane/EtOAc = 7:3) to
give 4c.
Yield: 104 mg (0.38 mmol, 76%); light-yellow solid; mp 108–100 °C.
MS (EI, 70 eV): m/z (%) = 139 (73), 138 (22), 124 (58), 111 (20), 106
IR (Diamond-ATR, neat): 2939, 2856, 1549, 1429, 1333, 1320, 1167,
(100), 79 (18).
1130, 1042, 945, 775, 708 cm–1
.
HRMS (EI): m/z calcd. for C7H9NS: 139.0449; found: 139.0456.
1H NMR (400 MHz, CDCl3):  = 8.34 (dd, J = 4.5, 1.4 Hz, 1 H), 7.68 (dd,
J = 8.2, 1.4 Hz, 1 H), 7.39 (dd, J = 8.1, 4.5 Hz, 1 H), 3.53–3.49 (m, 4 H),
2.51 (s, 3 H), 1.72–1.65 (m, 4 H), 1.63–1.57 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 154.0, 143.4, 136.9, 134.2, 125.9, 47.8,
25.8, 24.0, 15.4.
Synthesis of 2-(Allylthio)pyridine (2e)
Pyridine 2e was prepared via GP1 using 1 (113 mg, 0.5 mmol),
iPrMgCl·LiCl (0.65 mL, 1.00 mmol) and prop-2-ene-1-thiol (0.08 mL,
1.00 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 2e.
MS (EI, 70 eV): m/z (%) = 152 (15), 125 (18), 124 (13), 84 (100), 79
(13), 44 (17), 43 (18).
Yield: 51.0 mg (0.34 mmol, 68%); colorless oil.
HRMS (EI): m/z [M – H]+ calcd. for C11H15O2N2S2+: 271.0580; found:
271.0586.
IR (Diamond-ATR, neat): 3308, 3080, 2920, 1693, 1634, 1578, 1555,
1453, 1413, 1281, 1123, 985, 918, 756 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.51–8.38 (m, 1 H), 7.56–7.45 (m, 1 H),
7.20 (dt, J = 8.1, 1.0 Hz, 1 H), 7.06–6.91 (m, 1 H), 6.07–5.91 (m, 1 H),
5.31 (dq, J = 17.0, 1.5 Hz, 1 H), 5.18–5.12 (m, 1 H), 3.86 (dt, J = 6.8,
1.2 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 158.6, 149.5, 135.9, 133.9, 122.3,
119.5, 117.5, 33.0.
Synthesis of Phenyl[2-(piperidin-1-ylsulfonyl)pyridin-3-yl ]meth-
anol (4d)
Pyridine 4d was prepared via GP2 using 1 (113 mg, 0.50 mmol),
TMPMgCl·LiCl (0.48 mL, 0.60 mmol) and benzaldehyde (0.08 mL,
0.75 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 8:2) to give 4d.
MS (EI, 70 eV): m/z (%) = 150 (10), 136 (100), 124 (10), 118 (21), 117
(14).
Yield: 134 mg (0.40 mmol, 81%); colorless solid.
1H NMR (400 MHz, CDCl3):  = 8.42 (dd, J = 4.7, 1.6 Hz, 1 H), 7.61 (dd,
J = 7.9, 1.7 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.38–7.27 (m, 4 H), 6.75 (d, J =
4.0 Hz, 1 H), 3.64–3.49 (m, 4 H), 1.73–1.61 (m, 5 H).
13C NMR (101 MHz, CDCl3):  = 157.1, 147.1, 140.8, 139.4, 138.8,
128.4, 127.6, 126.6, 126.4, 69.2, 48.1, 25.9, 23.9.
HRMS (EI): m/z calcd. for C8H9NS: 151.0456; found: 151.0449.
Synthesis of 3-Iodo-2-(piperidin-1-ylsulfonyl)pyridine (4a)
Pyridine 4a was prepared via GP2 using 1 (226 mg, 1.00 mmol),
TMPMgCl·LiCl (1.16 mL, 1.2 mmol) and iodine (381 mg, 1.50 mmol).
After workup, the crude product was purified via flash chromatogra-
phy (isohexane/EtOAc = 8:2) to give 4a.
The spectra matched those reported.16
Synthesis of 3-Allyl-2-(piperidin-1-ylsulfonyl)pyridine (4e)
Yield: 289 mg (0.82 mmol, 82%); colorless solid.
Pyridine 4e was prepared via GP2 using 1 (452 mg, 2.00 mmol) and
TMPMgCl·LiCl (1.92 mL, 2.40 mmol). After the metalation was com-
plete, a 1 M CuCN·2LiCl solution in THF (2.40 mL, 2.40 mmol) was
added at –20 °C. After stirring at –20 °C for 30 min, allyl bromide
(0.28 mL, 3.00 mmol) was added and the reaction mixture was stirred
for 12 h at 25 °C. After workup, the crude product was purified via
flash chromatography (isohexane/EtOAc = 8:2) to give 4e.
1H NMR (400 MHz, CDCl3):  = 8.41 (dd, J = 4.7, 1.6 Hz, 1 H), 7.93 (dd,
J = 7.8, 1.6 Hz, 1 H), 6.71 (dd, J = 7.8, 4.7 Hz, 1 H), 3.85 (tt, J = 10.2,
3.7 Hz, 1 H), 2.16–2.09 (m, 2 H), 1.85–1.78 (m, 2 H), 1.70–1.62 (m,
1 H), 1.57–1.45 (m, 4 H), 1.40–1.30 (m, 1 H).
The spectra matched those reported.6a
Synthesis of 3-Bromo-2-(piperidin-1-ylsulfonyl)pyridine (4b)
Yield: 488 mg (1.83 mmol, 92%) as a colorless solid.
Pyridine 4b was prepared via GP2 using 1 (113 mg, 0.50 mmol),
TMPMgCl·LiCl (0.48 mL, 0.60 mmol) and 1,2-dibromo-1,1,2,2-tetra-
chloroethane (195 mg, 0.75 mmol). After workup, the crude product
was purified via flash chromatography (isohexane/EtOAc = 8:2) to
give 4b.
1H NMR (400 MHz, CDCl3):  = 8.40 (dd, J = 4.6, 1.6 Hz, 1 H), 7.71 (dd,
J = 7.8, 1.6 Hz, 1 H), 7.36 (dd, J = 7.8, 4.6 Hz, 1 H), 6.05–5.93 (m, 1 H),
5.15 (dq, J = 14.0, 1.7 Hz, 2 H), 3.84 (d, J = 6.8 Hz, 2 H), 3.54 (t, J =
5.4 Hz, 4 H), 1.71–1.59 (m, 6 H).
The spectra matched those reported.6a
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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Synthesis
Synthesisof3-(Cyclohex-2-en-1-yl)-2-(piperidin-1-ylsulfonyl)pyr-
idine (4f)
Yield: 118 mg (0.35 mmol, 70%); yellow solid; mp 111–112 °C.
IR (Diamond-ATR, neat): 3104, 2939, 2856, 1651, 1411, 1337, 1170,
1128, 1046, 942, 883, 850, 730 cm–1
1H NMR (400 MHz, CDCl3):  = 8.82 (dd, J = 4.7, 1.7 Hz, 1 H), 7.83 (dd,
J = 7.8, 1.7 Hz, 1 H), 7.76 (dd, J = 4.9, 1.2 Hz, 1 H), 7.57 (dd, J = 7.8,
4.7 Hz, 1 H), 7.30 (dd, J = 3.8, 1.2 Hz, 1 H), 7.10 (dd, J = 4.9, 3.8 Hz,
1 H), 3.39–3.27 (m, 4 H), 1.64–1.57 (m, 4 H), 1.57–1.50 (m, 2 H).
Pyridine 4f was prepared via GP2 using 1 (113 mg, 0.50 mmol) and
TMPMgCl·LiCl (0.48 mL, 0.60 mmol). After the metalation was com-
plete, a 1 M CuCN·2LiCl solution in THF (0.60 mL, 0.60 mmol) was
added at –20 °C. After stirring at –20 °C for 30 min, 3-bromocyclohex-
1-ene (0.10 mL, 0.75 mmol) was added and the reaction mixture was
stirred for 12 h at 25 °C. After workup, the crude product was purified
via flash chromatography (isohexane/EtOAc = 9:1) to give 4f.
.
13C NMR (101 MHz, CDCl3):  = 185.5, 154.0, 150.3, 144.0, 136.9,
135.7, 135.3, 128.4, 125.7, 47.4, 25.5, 23.7.
Yield: 132 mg (0.43 mmol, 86%); colorless oil.
MS (EI, 70 eV): m/z (%) = 188 (12), 161 (24), 160 (14), 111 (10), 84
(100), 83 (11).
IR (Diamond-ATR, neat): 2937, 2858, 1560, 1445, 1331, 1318, 1167,
1155, 1124, 1050, 945, 909, 748, 730, 702 cm–1
.
HRMS (EI): m/z calcd. for C15H16O3N2S2: 336.0602; found: 336.0604.
1H NMR (400 MHz, CDCl3):  = 8.37 (dd, J = 4.6, 1.7 Hz, 1 H), 7.79 (dd,
J = 7.9, 1.7 Hz, 1 H), 7.36 (dd, J = 7.9, 4.6 Hz, 1 H), 6.00–5.91 (m, 1 H),
5.63–5.52 (m, 1 H), 4.45–4.37 (m, 1 H), 3.56 (t, J = 5.3 Hz, 4 H), 2.32–
2.21 (m, 1 H), 2.13–2.05 (m, 2 H), 1.79–1.57 (m, 8 H), 1.49–1.39 (m,
1 H).
13C NMR (101 MHz, CDCl3):  = 157.0, 145.6, 141.7, 138.9, 129.66,
128.9, 126.0, 48.0, 36.2, 32.0, 26.0, 24.8, 24.1, 21.2.
Synthesis of (4-Chlorophenyl)[2-(piperidin-1-ylsulfonyl)pyridin-
3-yl ]methanone (4i)
Pyridine 4i was prepared via GP2 using 1 (113 mg, 0.50 mmol) and
TMPMgCl·LiCl (0.48 mL, 0.60 mmol). After the metalation was com-
plete, a 1 M CuCN·2LiCl solution in THF (0.60 mL, 0.60 mmol) was
added at –20 °C. After stirring at –20 °C for 30 min, 4-chlorobenzoyl
chloride (0.10 mL, 0.75 mmol) was added and the reaction mixture
was stirred for 12 h at 25 °C. After workup, the crude product was pu-
rified via flash chromatography (isohexane/EtOAc = 6:4) to give 4i.
MS (ESI): m/z (%) = 307 (100).
HRMS (ESI): m/z [M + H]+ calcd. for C16H23O2N2S+: 307.1480; found:
307.1474.
Yield: 160 mg (0.44 mmol, 88%); yellow solid; mp 137–138 °C.
Synthesis of Cyclopropyl[2-(piperidin-1-ylsulfonyl)pyridin-3-
yl]methanone (4g)
IR (Diamond-ATR, neat): 2941, 2856, 1676, 1586, 1399, 1339, 1279,
1172, 1091, 924, 751, 730 cm–1
.
Pyridine 4g was prepared via GP2 using 1 (57.0 mg, 0.25 mmol) and
TMPMgCl·LiCl (0.24 mL, 0.30 mmol). After the metalation was com-
plete, a 1 M CuCN·2LiCl solution in THF (0.30 mL, 0.30 mmol) was
added at –20 °C. After stirring at –20 °C for 30 min, cyclopropanecar-
bonyl chloride (0.04 mL, 375 mol) was added and the reaction mix-
ture was stirred for 12 h at 25 °C. After workup, the crude product
was purified via flash chromatography (isohexane/EtOAc = 6:4) to
give 4g.
1H NMR (400 MHz, CDCl3):  = 8.83 (dd, J = 4.7, 1.7 Hz, 1 H), 7.74 (dd,
J = 7.8, 1.7 Hz, 1 H), 7.71–7.69 (m, 2 H), 7.58 (dd, J = 7.8, 4.7 Hz, 1 H),
7.45–7.41 (m, 2 H), 3.33–3.29 (m, 4 H), 1.66–1.59 (m, 4 H), 1.57–1.51
(m, 2 H).
13C NMR (101 MHz, CDCl3):  = 192.3, 154.1, 150.3, 140.5, 136.7,
135.4, 135.0, 131.2, 129.1, 125.8, 47.4, 25.5, 23.7.
MS (EI, 70 eV): m/z (%) = 218 (15), 188 (10), 216 (36), 182 (22), 154
(10), 153 (16), 111 (10), 84 (100), 83 (16).
Yield: 61 mg (0.21 mmol, 83%); yellow oil.
HRMS (EI): m/z calcd. for C17H17O3N2ClS: 364.0648; found: 364.0629.
IR (Diamond-ATR, neat): 2939, 2856, 1689, 1576, 1446, 1377, 1336,
1324, 1207, 1167, 1128, 1050, 986, 941, 716, 692 cm–1
.
Synthesis of 3-[4-(tert-Butyl)phenyl]-2-(piperidin-1-ylsulfo-
nyl)pyridine (4j)
1H NMR (400 MHz, CDCl3):  = 8.73 (dd, J = 4.7, 1.7 Hz, 1 H), 7.76 (dd,
J = 7.8, 1.7 Hz, 1 H), 7.53 (dd, J = 7.8, 4.7 Hz, 1 H), 3.41–3.36 (m, 4 H),
2.43 (tt, J = 7.8, 4.5 Hz, 1 H), 1.69–1.61 (m, 4 H), 1.59–1.53 (m, 2 H),
1.41–1.35 (m, 2 H), 1.22–1.16 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 203.7, 153.7, 149.7, 138.2, 136.3,
126.0, 47.6, 25.6, 23.8, 23.4, 13.7.
Pyridine 4j was prepared via GP2 using 1 (113 mg, 0.50 mmol) and
TMPMgCl·LiCl (0.48 mL, 0.60 mmol). After the metalation was com-
plete, a 1 M ZnCl2 solution in THF (0.60 mL, 0.60 mmol) was added at
0 °C. After stirring at 0 °C for 30 min, 1-(tert-butyl)-4-iodobenzene
(0.09 mL, 0.50 mmol), tfp (5.00 mg, 0.02 mmol) and Pd(dba)2
(6.00 mg, 0.01 mmol) were added and the reaction mixture was
stirred for 12 h at 25 °C. After workup, the crude product was purified
via flash chromatography (isohexane/EtOAc = 9:1) to give 4j.
MS (ESI): m/z (%) = 295 (100).
HRMS (ESI): m/z [M + H]+ calcd. for C14H19O3N2S+: 295.1116; found:
295.1110.
Yield: 161 mg (0.45 mmol, 90%); colorless solid; mp 134–135 °C.
Synthesis of [2-(Piperidin-1-ylsulfonyl)pyridin-3-yl](thiophen-2-
yl) methanone (4h)
IR (Diamond-ATR, neat): 2946, 2861, 2254, 1445, 1356, 1167, 1126,
947, 904, 724, 649 cm–1
.
Pyridine 4h was prepared via GP2 using 1 (113 mg, 0.50 mmol) and
TMPMgCl·LiCl (0.48 mL, 0.60 mmol). After the metalation was com-
plete, a 1 M CuCN·2LiCl solution in THF (0.60 mL, 0.60 mmol) was
added at –20 °C. After stirring at –20 °C for 30 min, 2-thiophenecar-
bonyl chloride (0.08 mL, 0.75 mmol) was added and the reaction mix-
ture was stirred for 12 h at 25 °C. After workup, the crude product
was purified via flash chromatography (isohexane/EtOAc = 7:3) to
give 4h.
1H NMR (400 MHz, CDCl3):  = 8.56 (dd, J = 4.6, 1.7 Hz, 1 H), 7.75 (dd,
J = 7.8, 1.7 Hz, 1 H), 7.49–7.41 (m, 5 H), 3.42 (t, J = 4.8 Hz, 4 H), 1.59
(dd, J = 7.6, 3.2 Hz, 6 H), 1.36 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 156.4, 151.2, 146.7, 141.0, 137.7,
134.0, 129.0, 125.6, 125.0, 47.7, 34.7, 31.4, 25.9, 24.0.
HRMS (ESI): m/z [M + H]+ calcd. for C20H27O2N2S+: 359.1788; found:
359.1788.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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Synthesis
Synthesis of Ethyl 4-[2-(Piperidin-1-ylsulfonyl)pyridin-3-yl]ben-
zoate (4k)
HRMS (EI): m/z calcd. for C8H10NIS: 278.9579; found: 278.9574.
Pyridine 4k was prepared via GP2 using 1 (113 mg, 0.50 mmol) and
TMPMgCl·LiCl (0.48 mL, 0.60 mmol). After the metalation was com-
plete, a 1 M ZnCl2 solution in THF (0.60 mL, 0.60 mmol) was added at
0 °C. After stirring at 0 °C for 30 min, ethyl 4-iodobenzoate (0.09 mL,
0.50 mmol), tfp (5.00 mg, 0.02 mmol) and Pd(dba)2 (6.00 mg,
0.01 mmol) were added and the reaction mixture was stirred for 12 h
at 25 °C. After workup, the crude product was purified via flash chro-
matography (isohexane/EtOAc = 8:2) to give 4k.
Synthesis of 2-(Butylthio)-3-iodopyridine (5c)
Pyridine 5c was prepared via GP1 using 4a (88 mg, 0.25 mmol),
iPrMgCl·LiCl (0.32 mL, 0.50 mmol) and butane-1-thiol (0.06 mL,
0.50 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 5c.
Yield: 67 mg (0.23 mmol, 91%); colorless oil.
IR (Diamond-ATR, neat): 3036, 2956, 2927, 2870, 1558, 1424, 1377,
1141, 1113, 1058, 1000, 780, 742, 726, 636 cm–1
.
Yield: 117 mg (0.31 mmol, 67%); yellow solid; mp 188–190 °C.
1H NMR (400 MHz, CDCl3):  = 8.40 (dd, J = 4.7, 1.6 Hz, 1 H), 7.92 (dd,
J = 7.7, 1.6 Hz, 1 H), 6.71 (dd, J = 7.8, 4.7 Hz, 1 H), 3.22–3.10 (m, 2 H),
1.71 (tt, J = 8.6, 6.8 Hz, 2 H), 1.53–1.43 (m, 2 H), 0.95 (t, J = 7.3 Hz,
3 H).
13C NMR (101 MHz, CDCl3):  = 162.1, 148.2, 145.7, 119.9, 93.8, 32.4,
31.0, 22.2, 13.8.
IR (Diamond-ATR, neat): 2944, 2858, 2255, 1711, 1612, 1446, 1334,
1275, 1166, 1112, 904, 723, 648 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.61 (dd, J = 4.7, 1.6 Hz, 1 H), 8.14–8.10
(m, 2 H), 7.73 (dd, J = 7.8, 1.7 Hz, 1 H), 7.57–7.53 (m, 2 H), 7.50 (dd, J =
7.8, 4.6 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 3.43 (t, J = 4.9 Hz, 4 H), 1.61
(d, J = 7.9 Hz, 6 H), 1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.2, 156.4, 147.4, 141.5, 140.5,
136.6, 130.3, 129.3, 125.5, 61.0, 47.7, 25.8, 23.9, 14.3.
MS (EI, 70 eV): m/z (%) = 264 (25), 251 (100), 250 (13), 237 (75), 233
(17), 166 (60), 136 (10), 124 (66), 110 (26).
HRMS (EI): m/z calcd. for C9H12NIS: 292.9735; found: 292.9728.
MS (ESI): m/z (%) = 375 (100).
HRMS (ESI): m/z [M + H]+ calcd. for C19H23O4N2S+: 375.1373; found:
375.1374.
Synthesis of 2-(Allylthio)-3-iodopyridine (5d)
Pyridine 5d was prepared via GP1 using 4a (176 mg, 0.50 mmol),
iPrMgCl·LiCl (0.65 mL, 1.00 mmol) and prop-2-ene-1-thiol (0.08 mL,
1.00 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 5d.
Synthesis of 2-(Cyclohexylthio)-3-iodopyridine (5a)
Pyridine 5a was prepared via GP1 using 4a (176 mg, 0.50 mmol),
iPrMgCl·LiCl (0.65 mL, 1.00 mmol) and cyclohexanethiol (0.11 mL,
1.00 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3 + 1% Et3N) to give 5a.
Yield: 113 mg (0.41 mmol, 82%); yellow oil.
IR (Diamond-ATR, neat): 3305, 2918, 1557, 1424, 1377, 1223, 1141,
1113, 1058, 1001, 917, 783, 725 cm–1
.
Yield: 141 mg (0.44 mmol, 88%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.41 (dd, J = 4.7, 1.6 Hz, 1 H), 7.93 (dd,
J = 7.8, 1.6 Hz, 1 H), 6.73 (dd, J = 7.7, 4.7 Hz, 1 H), 6.04–5.93 (m, 1 H),
5.32 (dq, J = 17.0, 1.4 Hz, 1 H), 5.16–5.11 (m, 1 H), 3.82 (dt, J = 6.9,
1.2 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 161.2, 148.2, 145.8, 133.4, 120.2,
117.9, 93.6, 35.5.
IR (Diamond-ATR, neat): 3035, 2925, 2849, 1558, 1447, 1423, 1376,
1140, 1110, 1058, 998, 780, 740, 726, 637 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.38 (dd, J = 4.7, 1.6 Hz, 1 H), 7.91 (dd,
J = 7.8, 1.6 Hz, 1 H), 6.69 (dd, J = 7.8, 4.7 Hz, 1 H), 3.87–3.77 (m, 1 H),
2.14–2.06 (m, 2 H), 1.82–1.75 (m, 2 H), 1.71–1.62 (m, 1 H), 1.55–1.40
(m, 4 H), 1.40–1.29 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 161.9, 148.2, 145.8, 119.9, 94.0, 45.2,
32.9, 26.2, 25.9.
MS (EI, 70 eV): m/z (%) = 262 (100), 244 (14), 150 (42), 135 (13), 117
(35), 109 (11), 82 (11), 78 (13).
HRMS (EI): m/z calcd. for C8H8NIS: 276.9422; found: 276.9417.
MS (EI, 70 eV): m/z (%) = 286 (12), 238 (18), 237 (100), 192 (69), 110
(20).
Synthesis of 2-(Butylthio)-3-bromopyridine (5e)
HRMS (EI): m/z calcd. for C11H14NIS: 318.9892; found: 318.9886.
Pyridine 5e was prepared via GP1 using 4b (77 mg, 0.25 mmol),
iPrMgCl·LiCl (0.32 mL, 0.50 mmol) and butane-1-thiol (0.06 mL,
0.50 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 5e.
Synthesis of 3-Iodo-2-(isopropylthio)pyridine (5b)
Pyridine 5b was prepared via GP1 using 4a (176 mg, 0.50 mmol),
iPrMgCl·LiCl (0.65 mL, 1.00 mmol) and propane-2-thiol (0.09 mL,
1.00 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3 + 1% TEA) to give 5b.
Yield: 67 mg (0.23 mmol, 91%); colorless oil.
IR (Diamond-ATR, neat): 3042, 2955, 2926, 2870, 1564, 1428, 1383,
1144, 1118, 1058, 1009, 782, 744, 725 cm–1
.
Yield: 104 mg (0.37 mmol, 75%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.37 (dd, J = 4.7, 1.5 Hz, 1 H), 7.69 (dd,
J = 7.8, 1.6 Hz, 1 H), 6.86 (dd, J = 7.9, 4.7 Hz, 1 H), 3.24–3.14 (m, 2 H),
1.71 (tt, J = 8.4, 6.8 Hz, 2 H), 1.48 (dt, J = 14.7, 7.4 Hz, 2 H), 0.95 (t, J =
7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.2, 147.4, 139.0, 119.6, 119.1, 31.0,
30.7, 22.1, 13.7.
IR (Diamond-ATR, neat): 3039, 2965, 2928, 2865, 1560, 1378, 1238,
1142, 1053, 1001, 905, 783, 725, 648 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.42 (dd, J = 4.7, 1.6 Hz, 1 H), 7.94 (dd,
J = 7.7, 1.6 Hz, 1 H), 6.72 (dd, J = 7.8, 4.7 Hz, 1 H), 3.98 (p, J = 6.9 Hz,
1 H), 1.45 (d, J = 6.9 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 162.1, 148.2, 145.8, 119.9, 93.9, 37.4,
22.8.
MS (EI, 70 eV): m/z (%) = 218 (33), 216 (32), 205 (92), 203 (100), 191
(65), 189 (68), 166 (90), 124 (91), 110 (53).
MS (EI, 70 eV): m/z (%) = 237 (32), 152 (100), 110 (22).
HRMS (EI): m/z calcd. for C9H12NBrS: 244.9874; found: 244.9870.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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Paper
Synthesis
Synthesis of 2-(Cyclohexylthio)-3-(methylthio)pyridine (5f)
Synthesis of 3-Allyl-2-(isopropylthio)pyridine (5i)
Pyridine 5f was prepared via GP1 using 4c (78 mg, 0.28 mmol),
iPrMgCl·LiCl (0.36 mL, 0.56 mmol) and cyclohexanethiol (0.08 mL,
0.56 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 5f.
Pyridine 5i was prepared via GP1 using 4e (80.0 mg, 0.30 mmol),
iPrMgCl·LiCl (0.39 mL, 0.60 mmol) and propane-2-thiol (0.06 mL,
0.60 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 5i.
Yield: 55 mg (0.23 mmol, 82%); colorless oil.
Yield: 55.0 mg (0.28 mmol, 95%); colorless oil.
IR (Diamond-ATR, neat): 2923, 2850, 1557, 1447, 1430, 1374, 1262,
IR (Diamond-ATR, neat): 3047, 2963, 2926, 2865, 1640, 1577, 1559,
1450, 1399, 1302, 1240, 1174, 1135, 1100, 1072, 993, 916, 785, 752,
1130, 1067, 1033, 997, 887, 780, 733 cm–1
.
699 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.23 (dd, J = 4.8, 1.6 Hz, 1 H), 7.37 (dd,
J = 7.8, 1.6 Hz, 1 H), 6.95 (dd, J = 7.7, 4.8 Hz, 1 H), 3.96 (tt, J = 10.2,
3.8 Hz, 1 H), 2.45 (s, 3 H), 2.13–2.06 (m, 2 H), 1.81–1.74 (m, 2 H),
1.67–1.58 (m, 1 H), 1.52–1.41 (m, 4 H), 1.37–1.27 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 157.5, 145.6, 133.2, 133.0, 119.3, 43.3,
33.2, 26.1, 25.9, 15.8.
1H NMR (400 MHz, CDCl3):  = 8.32 (dd, J = 4.8, 1.8 Hz, 1 H), 7.37–7.32
(m, 1 H), 6.94 (dd, J = 7.5, 4.8 Hz, 1 H), 6.02–5.88 (m, 1 H), 5.18–5.05
(m, 2 H), 4.11 (p, J = 6.8 Hz, 1 H), 3.35 (dd, J = 6.6, 1.6 Hz, 2 H), 1.41
(dd, J = 6.8, 1.0 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 158.2, 147.0, 135.5, 134.7, 133.2,
119.0, 117.1, 36.3, 34.8, 34.7, 23.2.
MS (EI, 70 eV): m/z (%) = 225 (10), 224 (100), 206 (13), 157 (37), 156
(10), 154 (11), 142 (68), 124 (68).
MS (EI, 70 eV): m/z (%) = 160 (11), 150 (100), 136 (76), 118 (39), 117
(14).
HRMS (EI): m/z calcd. for C12H17NS2: 239.0802; found: 239.0796.
HRMS (EI): m/z calcd. for C11H15NS: 193.0925; found: 193.0919.
Synthesis of 3-Allyl-2-(cyclohexylthio)pyridine (5g)
Synthesis of 3-(Cyclohex-2-en-1-yl)-2-(ethylthio)pyridine (5j)
Pyridine 5g was prepared via GP1 using 4e (80.0 mg, 0.30 mmol),
iPrMgCl·LiCl (0.39 mL, 0.60 mmol) and cyclohexanethiol (0.08 mL,
0.60 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 5g.
Pyridine 5j was prepared via GP1 using 4f (77.0 mg, 0.25 mmol),
iPrMgCl·LiCl (0.32 mL, 0.50 mmol) and propane-2-thiol (0.04 mL,
0.50 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 5j.
Yield: 50.0 mg (0.21 mmol, 71%); colorless oil.
Yield: 35.0 mg (0.16 mmol, 64%); colorless oil.
IR (Diamond-ATR, neat): 2927, 2851, 1639, 1577, 1558, 1447, 1400,
1263, 1171, 1134, 1099, 1070, 997, 916, 785, 752 cm–1
.
IR (Diamond-ATR, neat): 3012, 2929, 2247, 1574, 1446, 1403, 1177,
1079, 904, 726 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.33 (dd, J = 4.8, 1.8 Hz, 1 H), 7.39–7.33
(m, 1 H), 6.95 (dd, J = 7.5, 4.8 Hz, 1 H), 6.06–5.87 (m, 1 H), 5.23–5.07
(m, 2 H), 4.00 (dd, J = 10.2, 4.2 Hz, 1 H), 3.39 (dd, J = 6.6, 1.5 Hz, 2 H),
2.16–2.07 (m, 2 H), 1.83–1.75 (m, 2 H), 1.70–1.62 (m, 1 H), 1.56–1.46
(m, 4 H), 1.40–1.29 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 157.9, 147.0, 135.6, 134.8, 133.3,
119.1, 117.1, 42.6, 36.4, 33.4, 26.1, 25.9.
1H NMR (400 MHz, CDCl3):  = 8.30 (dd, J = 4.8, 1.8 Hz, 1 H), 7.38 (dd,
J = 7.6, 1.8 Hz, 1 H), 6.96 (dd, J = 7.6, 4.8 Hz, 1 H), 6.02–5.92 (m, 1 H),
5.66–5.57 (m, 1 H), 3.73–3.63 (m, 1 H), 3.22 (qd, J = 7.4, 4.0 Hz, 2 H),
2.14–2.01 (m, 3 H), 1.68–1.59 (m, 2 H), 1.55–1.45 (m, 1 H), 1.37 (t, J =
7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 157.4, 146.7, 138.9, 134.5, 129.6,
128.6, 119.1, 37.0, 29.3, 25.0, 24.3, 20.6, 14.6.
MS (EI, 70 eV): m/z (%) = 200 (24), 150 (56), 136 (100), 118 (15).
HRMS (EI): m/z calcd. for C14H19NS: 233.1238; found: 233.1231.
MS (EI, 70 eV): m/z (%) = 190 (77), 186 (36), 162 (98), 148 (59), 144
(38), 136 (100), 130 (88), 124 (48), 117 (39), 41 (37).
HRMS (EI): m/z calcd. for C13H17NS: 219.1082; found: 219.1074.
Synthesis of 3-Allyl-2-(butylthio)pyridine (5h)
Pyridine 5h was prepared via GP1 using 4e (80.0 mg, 0.30 mmol),
iPrMgCl·LiCl (0.39 mL, 0.60 mmol) and butane-1-thiol (0.08 mL,
0.60 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 5h.
Synthesis of [2-(Cyclohexylthio)pyridin-3-yl](cyclopropyl) metha-
none (5k)
Pyridine 5k was prepared via GP1 using 4g (50.0 mg, 0.17 mmol),
iPrMgCl·LiCl (0.22 mL, 0.34 mmol) and cyclohexanethiol (0.05 mL,
0.34 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 5k.
Yield: 56.0 mg (0.27 mmol, 90%); colorless oil.
IR (Diamond-ATR, neat): 2958, 2930, 2872, 1640, 1578, 1560, 1400,
1291, 1173, 1135, 1101, 1070, 993, 916, 785, 752 cm–1
.
Yield: 36.0 mg (0.14 mmol, 81%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.31 (dd, J = 4.8, 1.8 Hz, 1 H), 7.38–7.29
(m, 1 H), 6.94 (dd, J = 7.5, 4.8 Hz, 1 H), 6.02–5.88 (m, 1 H), 5.19–5.06
(m, 2 H), 3.37 (dd, J = 6.6, 1.5 Hz, 2 H), 3.28–3.20 (m, 2 H), 1.74–1.63
(m, 2 H), 1.56–1.39 (m, 2 H), 0.95 (t, J = 7.3 Hz, 3 H).
IR (Diamond-ATR, neat): 2928, 2852, 2253, 1662, 1575, 1545, 1445,
1402, 1366, 1258, 1209, 1138, 1104, 1064, 980, 907, 755, 727,
696 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.51 (dd, J = 4.8, 1.8 Hz, 1 H), 8.03 (dd,
J = 7.7, 1.8 Hz, 1 H), 7.04 (dd, J = 7.7, 4.7 Hz, 1 H), 4.02–3.93 (m, 1 H),
2.51 (tt, J = 7.8, 4.5 Hz, 1 H), 2.11–2.03 (m, 2 H), 1.76 (dt, J = 9.8,
4.6 Hz, 2 H), 1.63 (dt, J = 12.5, 3.5 Hz, 1 H), 1.52–1.38 (m, 4 H), 1.33–
1.21 (m, J = 4.7 Hz, 3 H), 1.04 (dq, J = 7.4, 3.7 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 158.1, 146.9, 135.4, 134.7, 133.0,
119.0, 117.2, 36.3, 31.4, 29.6, 22.2, 13.8.
MS (EI, 70 eV): m/z (%) = 178 (119), 174 (13), 150 (100), 149 (12), 148
(16), 136 (68), 132 (14), 118 (28), 117 (18).
HRMS (EI): m/z calcd. for C12H17NS: 207.1082; found: 207.1076.
13C NMR (101 MHz, CDCl3):  = 200.9, 160.0, 151.1, 136.9, 131.9,
118.0, 42.1, 32.9, 26.2, 25.9, 19.3, 12.3.
MS (EI, 70 eV): m/z (%) = 261 (15), 260 (43), 228 (15), 151 (100), 148
(18), 138 (15), 136 (18), 67 (16).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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B. Heinz et al.
Paper
Synthesis
HRMS (EI): m/z [M – H]+ calcd. for C15H18ONS+: 260.1115; found:
260.1104.
1H NMR (400 MHz, CDCl3):  = 8.41 (dd, J = 4.8, 1.8 Hz, 1 H), 7.48–7.44
(m, 2 H), 7.40–7.36 (m, 3 H), 7.01 (dd, J = 7.5, 4.8 Hz, 1 H), 3.96–3.88
(m, 1 H), 2.08 (dt, J = 12.0, 3.4 Hz, 2 H), 1.75 (dd, J = 9.4, 4.7 Hz, 2 H),
1.67–1.59 (m, 1 H), 1.49–1.40 (m, 4 H), 1.38 (s, 9 H), 1.30–1.22 (m,
1 H).
13C NMR (101 MHz, CDCl3):  = 157.5, 150.8, 147.7, 136.6, 136.0,
135.5, 128.8, 125.3, 118.8, 42.7, 34.6, 33.2, 31.4, 26.3, 25.9.
Synthesis of [2-(Cyclohexylthio)pyridin-3-yl](thiophen-2-yl)
methanone (5l)
Pyridine 5l was prepared via GP1 using 4h (100 mg, 0.3 mmol),
iPrMgCl·LiCl (0.39 mL, 0.60 mmol) and cyclohexanethiol (0.08 mL,
0.60 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 9:1) to give 5l.
MS (EI, 70 eV): m/z (%) = 292 (22), 243 (23), 242 (100).
HRMS (EI): m/z calcd. for C21H27NS: 325.1864; found: 325.1857.
Yield: 71.0 mg (0.23 mmol, 78%); yellow solid; mp 89–90 °C.
IR (Diamond-ATR, neat): 3301, 2926, 2849, 1691, 1636, 1571, 1548,
Synthesis of Ethyl 4-[2-(Cyclohexylthio)pyridin-3-yl]benzoate (5o)
1410, 1387, 1352, 1292, 1062, 1044, 882, 847, 810, 759, 722 cm–1
.
Pyridine 5o was prepared via GP1 using 4k (93 mg, 0.25 mmol),
iPrMgCl·LiCl (0.32 mL, 0.50 mmol) and cyclohexanethiol (0.08 mL,
0.50 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.3) to give 5o.
1H NMR (400 MHz, CDCl3):  = 8.55 (dd, J = 4.9, 1.9 Hz, 1 H), 7.75 (dd,
J = 5.0, 1.2 Hz, 1 H), 7.68 (dd, J = 7.6, 1.8 Hz, 1 H), 7.46 (dd, J = 3.8,
1.2 Hz, 1 H), 7.13 (dd, J = 4.9, 3.8 Hz, 1 H), 7.06 (dd, J = 7.6, 4.9 Hz,
1 H), 3.96 (tt, J = 9.8, 4.0 Hz, 1 H), 2.08–2.00 (m, 2 H), 1.73 (h, J =
4.9 Hz, 2 H), 1.65–1.55 (m, 1 H), 1.49–1.35 (m, 4 H), 1.32–1.22 (m,
1 H).
Yield: 47.0 mg (0.14 mmol, 55%); yellow solid; mp 99–100 °C.
IR (Diamond-ATR, neat): 2929, 2850, 1716, 1609, 1574, 1447, 1383,
1367, 1272, 1178, 1100, 999, 858, 770, 706 cm–1
.
13C NMR (101 MHz, CDCl3):  = 187.1, 158.5, 150.7, 143.8, 135.9,
135.5, 135.4, 132.9, 128.2, 118.1, 43.1, 33.1, 26.1, 25.8.
1H NMR (400 MHz, CDCl3):  = 8.45 (dd, J = 4.9, 1.8 Hz, 1 H), 8.13–8.09
(m, 2 H), 7.52–7.49 (m, 2 H), 7.38 (dd, J = 7.5, 1.8 Hz, 1 H), 7.05 (dd, J =
7.5, 4.8 Hz, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 3.98–3.88 (m, 1 H), 2.08–2.01
(m, 2 H), 1.77–1.70 (m, 2 H), 1.62 (d, J = 12.7 Hz, 1 H), 1.49–1.33 (m,
7 H), 1.25 (q, J = 9.7, 6.5 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 270 (20), 220 (13), 206 (24), 193 (10), 192
(11), 192 (100), 188 (34), 165 (10), 148 (10), 138 (20).
HRMS (EI): m/z calcd. for C16H17ONS2: 303.0752; found: 303.0745.
13C NMR (101 MHz, CDCl3):  = 166.3, 157.5, 148.4, 143.0, 136.4,
135.2, 130.0, 129.6, 129.3, 118.8, 61.0, 42.9, 33.2, 26.1, 25.8, 14.3.
Synthesis of (4-Chlorophenyl)[2-(cyclohexylthio)pyridin-3-yl
]methanone (5m)
MS (EI, 70 eV): m/z (%) = 308 (27), 259 (25), 258 (100), 230 (43), 186
Pyridine 5m was prepared via GP1 using 4i (148 mg, 0.40 mmol),
iPrMgCl·LiCl (0.52 mL, 0.80 mmol) and cyclohexanethiol (0.10 mL,
0.80 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 5m.
(38), 185 (13), 153 (14).
HRMS (EI): m/z calcd. for C20H23O2NS: 341.1449; found: 341.1441.
Synthesis of 2,3-Bis(methylthio)pyridine (6a)
Yield: 114 mg (0.34 mmol, 86%); colorless solid; mp 88–89 °C.
Pyridine 6a was prepared via GP2 using 1 (57.0 mg, 250 mol),
TMPMgCl·LiCl (0.30 mL, 375 mol) and 1,2-dimethyl disulfide (0.04
mL, 375 mol). After workup, the crude product was purified via
flash chromatography (isohexane/EtOAc = 10:0.5) to give 6a.
IR (Diamond-ATR, neat): 3311, 2923, 2849, 1664, 1660, 1584, 1571,
1546, 1385, 1286, 1133, 1091, 1081, 1013, 921, 844, 757 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.56 (dd, J = 4.8, 1.8 Hz, 1 H), 7.74–7.70
(m, 2 H), 7.55 (dd, J = 7.6, 1.8 Hz, 1 H), 7.46–7.42 (m, 2 H), 7.06 (dd, J =
7.6, 4.8 Hz, 1 H), 3.97 (tt, J = 10.2, 4.1 Hz, 1 H), 2.08–1.98 (m, 2 H), 1.72
(dq, J = 9.5, 4.8 Hz, 2 H), 1.59 (d, J = 3.5 Hz, 1 H), 1.45–1.37 (m, 4 H),
1.30–1.21 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 194.2, 158.8, 150.9, 140.0, 136.7,
135.2, 132.4, 131.4, 129.0, 118.2, 43.2, 33.0, 26.1, 25.8.
Yield: 36 mg (0.21 mmol, 84%); yellow oil.
IR (Diamond-ATR, neat): 3035, 2988, 2920, 2848, 1557, 1542, 1431,
1371, 1312, 1145, 1123, 1067, 1047, 1034, 959, 780, 760 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.28 (dd, J = 4.8, 1.6 Hz, 1 H), 7.42 (dd,
J = 7.7, 1.6 Hz, 1 H), 6.97 (dd, J = 7.7, 4.8 Hz, 1 H), 2.58 (s, 3 H), 2.47 (s,
3 H).
13C NMR (101 MHz, CDCl3):  = 158.6, 145.9, 133.9, 132.4, 119.2, 16.0,
13.6.
MS (EI, 70 eV): m/z (%) = 331 (11), 298 (23), 234 (15), 222 (36), 221
(12), 220 (100), 192 (13), 185 (12), 138 (16).
HRMS (EI): m/z calcd. for C18H18ONClS: 331.0798; found: 331.0791.
MS (EI, 70 eV): m/z (%) = 171 (12), 156 (100), 154 (13), 124 (17).
HRMS (EI): m/z calcd. for C7H9NS2: 171.0176; found: 171.0167.
Synthesis of 3-[4-(tert-Butyl)phenyl]-2-(cyclohexylthio)pyridine
(5n)
Synthesis of 2,3-Bis(p-tolylthio)pyridine (6b)
Pyridine 5n was prepared via GP1 using 4j (89 mg, 0.25 mmol),
iPrMgCl·LiCl (0.32 mL, 0.50 mmol) and cyclohexanethiol (0.08 mL,
0.50 mmol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 5n.
Pyridine 6b was prepared via GP2 using 1 (57.0 mg, 250 mol),
TMPMgCl·LiCl (0.30 mL, 375 mol) and p-tolyl disulfide (93.0 mg,
375 mol). After workup, the crude product was purified via flash
chromatography (isohexane/EtOAc = 10:0.5) to give 6b.
Yield: 77.0 mg (0.24 mmol, 95%); colorless oil.
Yield: 40 mg (0.12 mmol, 50%); yellow solid; mp 112–113 °C.
IR (Diamond-ATR, neat): 3031, 2926, 2850, 1573, 1550, 1447, 1381,
1263, 1212, 1134, 1114, 1092, 1063, 999, 907, 835, 795, 752, 731,
IR (Diamond-ATR, neat): 3020, 2918, 2858, 1900, 1553, 1490, 1427,
1372, 1179, 1131, 1125, 1031, 1016, 805 cm–1
.
714 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.18 (dd, J = 4.7, 1.7 Hz, 1 H), 7.45–7.42
(m, 2 H), 7.35–7.32 (m, 2 H), 7.29–7.25 (m, 1 H), 7.23–7.17 (m, 4 H),
6.89 (dd, J = 7.8, 4.8 Hz, 1 H), 2.38 (d, J = 3.6 Hz, 6 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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B. Heinz et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3):  = 158.91, 147.52, 138.72, 138.43,
137.54, 134.83, 132.66, 132.15, 130.42, 129.96, 129.12, 127.36,
120.53, 21.39, 21.22.
1H NMR (400 MHz, CDCl3):  = 8.17 (dd, J = 4.7, 1.7 Hz, 1 H), 7.53 (dd,
J = 7.7, 1.7 Hz, 1 H), 7.46–7.41 (m, 2 H), 7.23–7.19 (m, 2 H), 6.96 (dd,
J = 7.7, 4.8 Hz, 1 H), 2.99–2.94 (m, 2 H), 2.38 (s, 3 H), 1.72–1.63 (m,
2 H), 1.53–1.46 (m, 2 H), 0.95 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.07, 147.09, 138.72, 137.11,
134.98, 130.98, 129.95, 127.37, 120.13, 33.38, 31.06, 21.99, 21.39,
13.67.
MS (EI, 70 eV): m/z (%) = 323 (20), 322 (100), 290 (11), 281 (12), 207
(45), 200 (10), 199 (15), 198 (20), 185 (11), 91 (11).
HRMS (EI): m/z [M – H]+ calcd. for C19H16NS2+: 322.0730; found:
322.0719.
MS (EI, 70 eV): m/z (%) = 289 (12), 234 (15), 233 (47), 232 (100), 200
(20), 199 (10), 198 (10).
Synthesis of 2,3-Bis(butylthio)pyridine (6c)
HRMS (EI): m/z calcd. for C16H19NS2: 289.0959; found: 289.0956.
Pyridine 6c was prepared via GP2 using 1 (57.0 mg, 250 mol),
TMPMgCl·LiCl (0.30 mL, 375 mol) and 1,2-dibutyl disulfane (0.07
mL, 375 mol). After workup, the crude product was purified via
flash chromatography (isohexane/EtOAc = 10:0.5) to give 6c.
Funding Information
Yield: 48 mg (0.19 mmol, 75%); colorless oil.
We thank the DFG (SFB749) for financial support.
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IR (Diamond-ATR, neat): 3038, 2955, 2926, 2870, 1557, 1464, 1429,
1372, 1273, 1221, 1128, 1066, 1048, 1033, 780 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.27 (s, 1 H), 7.47 (dd, J = 7.7, 1.6 Hz,
1 H), 6.93 (dd, J = 7.6, 4.7 Hz, 1 H), 3.23–3.17 (m, 2 H), 2.93–2.86 (m,
2 H), 1.70 (tt, J = 8.6, 6.9 Hz, 2 H), 1.66–1.58 (m, 2 H), 1.51–1.44 (m,
4 H), 0.93 (dt, J = 9.7, 7.3 Hz, 6 H).
Acknowledgment
We thank Albemarle (Hoechst, Germany) and BASF SE (Ludwigshafen,
Germany) for generous gifts of chemicals.
13C NMR (101 MHz, CDCl3):  = 160.06, 146.43, 136.48, 130.87,
118.98, 33.05, 31.22, 31.06, 30.25, 22.21, 21.96, 13.77, 13.64.
Supporting Information
MS (EI, 70 eV): m/z (%) = 198 (96), 166 (82), 157 (34), 156 (30), 154
Supporting information for this article is available online at
(42), 143 (100), 142 (60), 136 (35), 124 (22), 79 (20).
https://doi.org/10.1055/s-0039-1690199.
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HRMS (EI): m/z calcd. for C13H21NS2: 255.1115; found: 255.1111.
Synthesis of 1-Butyl-2-(p-tolyl)disulfane (8)
References
Adapted from a reported procedure.17 Dibutyl disulfide (0.1 mL,
0.50 mmol) was dissolved in THF (5 mL) and cooled to 0 °C. Sulfuryl
chloride (0.05 mL, 0.55 mmol) was added and the reaction was stirred
at 0 °C for 30 min. The reaction mixture was added to a mixture
of 4-methylbenzenethiol (124 mg, 1.00 mmol), water (0.20 mL,
10.0 mmol) and TEA (0.3 mL, 2.20 mmol) in THF (4 mL) at 25 °C. After
stirring for 1.5 h at 25 °C, the reaction was quenched with water, and
the mixture was extracted with EtOAc and dried over sodium sulfate.
After filtration, the solvent was removed in vacuo. The crude product
was purified by flash chromatography (pentane) to give 8.
(1) (a) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Curr. Top. Med. Chem.
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Yield: 133 mg (0.63 mmol, 63%); yellow oil.
IR (Diamond-ATR, neat): 2956, 2924, 2870, 1489, 1463, 1301, 1273,
1218, 1179, 1115, 1077, 1015, 802 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.46–7.41 (m, 2 H), 7.16–7.12 (m, 2 H),
2.76–2.71 (m, 2 H), 2.34 (s, 3 H), 1.70–1.62 (m, 2 H), 1.40 (dt, J = 14.8,
7.4 Hz, 2 H), 0.89 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 136.95, 134.22, 129.73, 128.33, 38.59,
30.85, 21.64, 21.05, 13.65.
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S.; Oae, S. Phosphorus Sulfur Relat. Elem. 1983, 16, 167.
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1983, 39, 4153. (c) Niazi, M.; Shahsavari, H. R.; Haghighi, M. G.;
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MS (EI, 70 eV): m/z (%) = 212 (71), 156 (46), 123 (21), 92 (100), 91
(65).
HRMS (EI): m/z calcd. for C11H16S2: 212.0693; found: 212.0687.
Synthesis of 3-(Butylthio)-2-(p-tolylthio)pyridine (6d)
Pyridine 6d was prepared via GP2 using 1 (57.0 mg, 0.25 mmol),
TMPMgCl·LiCl (0.30 mL, 0.38 mmol) and 8 (79.0 mg, 0.38 mmol). Af-
ter workup, the crude product was purified via flash chromatography
(isohexane/EtOAc = 10:0.3) to give 6d.
(7) Under similar basic conditions, double bond isomerization of
the allylic moiety can take place, see: Liu, X.; Li, B.; Liu, Q. Syn-
thesis 2019, 51, 1293.
Yield: 36 mg (0.12 mmol, 50%); colorless oil.
IR (Diamond-ATR, neat): 3031, 2955, 2925, 2870, 1552, 1492, 1429,
1371, 1129, 1032, 1018, 806 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

K
B. Heinz et al.
Paper
Synthesis
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K