Palladium-Catalyzed Direct α-Arylation of p -Methoxybenzyl-Protected S, S -Dimethylsulfoximine

Article abstract of DOI:10.1055/s-0036-1588894

Sulfoximines have recently gained considerable recognition as an important structural motif in the life sciences. This is especially true for (hetero)aryl-substituted S,S-dimethylsulfoximine derivatives, such as the marketed insecticide sulfoxaflor, as well as the clinical candidates PTEFb inhibitor BAY 1143572 and ATR inhibitor AZD 6738 for the treatment of cancer. Herein, the first palladium-catalyzed direct α-arylation of p-methoxybenzyl-protected S,S-dimethylsulfoximine using readily available (hetero)aryl bromides is reported. This new method provides a safe, short, and efficient approach to (hetero)aryl-substituted S,S-dimethylsulfoximine derivatives, an important class of bioactive compounds, demonstrated by application of this methodology to an improved synthesis of PTEFb inhibitor BAY 1143572.

Full text of DOI:10.1055/s-0036-1588894

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–M
paper
A
J. A. Sirvent et al.
Paper
Synthesis
Palladium-Catalyzed Direct α-Arylation of p-Methoxybenzyl-
Protected S,S-Dimethylsulfoximine
Juan A. Sirventa
O
N
Donald Biererb
Robert Websterb
Ulrich Lücking*a
S
Me
Me
(3 equiv)
OMe
XantPhos Pd G3 (3 mol%)
Xantphos (3 mol%)
Y
O
N
a Bayer Pharma AG, Drug Discovery, Müllerstr. 178,
13353 Berlin, Germany
ulrich.luecking@bayer.com
b Bayer Pharma AG, Drug Discovery, Aprather Weg 18a,
42113 Wuppertal, Germany
X
S
LiOt-Bu (3 equiv)
CPME, 110 °C
Me
OMe
17 examples
up to 75% yield
X
X = H, Me, F, Cl, OMe, CN,
CF3, CH=CH2, N=CH−Ph
Y = CH, N
Br
Y
Received: 28.07.2016
Accepted after revision: 12.09.2016
Published online: 12.10.2016
rarely seen use in life science applications, even though it
offers a unique combination of interesting properties,
namely high stability, favorable physicochemical proper-
ties, hydrogen-bond acceptor/donor functionalities, and
structural diversity.5 Possibly the very limited commercial
availability and few available synthetic methods with asso-
ciated safety concerns6 have hampered the use of the sulf-
oximine group, especially in industry. Over the last decade,
however, interest in sulfoximine chemistry has increased
substantially, paving the way to new and safe synthetic
methods.7 Very recent developments include, for instance,
the use of flow chemistry techniques, which mitigate the
safety risks associated with the classical direct imination of
sulfoxides to sulfoximines using azides,8 and photochemical
approaches to sulfoximines.9 This progress in synthetic
methodology goes hand in hand with the rapidly increasing
interest in sulfoximines as pharmacophores in the life sci-
ences.10 In particular, (hetero)aryl-substituted S,S-dimeth-
ylsulfoximine derivatives such as the commercial insecti-
cide sulfoxaflor10a,11 and the clinical kinase inhibitors BAY
114357212 and AZD 673813 have drawn considerable atten-
tion recently (Figure 1).
DOI: 10.1055/s-0036-1588894; Art ID: ss-2016-t0534-op
Abstract Sulfoximines have recently gained considerable recognition
as an important structural motif in the life sciences. This is especially
true for (hetero)aryl-substituted S,S-dimethylsulfoximine derivatives,
such as the marketed insecticide sulfoxaflor, as well as the clinical
candidates PTEFb inhibitor BAY 1143572 and ATR inhibitor AZD 6738
for the treatment of cancer. Herein, the first palladium-catalyzed direct
α-arylation of p-methoxybenzyl-protected S,S-dimethylsulfoximine us-
ing readily available (hetero)aryl bromides is reported. This new meth-
od provides a safe, short, and efficient approach to (hetero)aryl-
substituted S,S-dimethylsulfoximine derivatives, an important class of
bioactive compounds, demonstrated by application of this methodolo-
gy to an improved synthesis of PTEFb inhibitor BAY 1143572.
Key words sulfoximines, palladium, cross-coupling, drug design, crop
protecting agents
Since the late discovery of the sulfoximine group in
1949,1 sulfoximine chemistry2 has been rather a niche dis-
cipline. Applications have mainly focused on the use of sulf-
oximines as either chiral auxiliaries3 or ligands in asymmet-
ric catalysis.4 Until very recently, the sulfoximine group has
O
N
N
N
O
N
HN
O
O
S
HN
NH
S
S
O
N
F
F
N
N
N
N
H
N
F
N
F
Sulfoxaflor
BAY 1143572
PTEFb Inhibitor
(Phase I)
AZD 6738
ATR Inhibitor
(Phase I)
Figure 1 Structures of the commercial insecticide sulfoxaflor, and phase I kinase inhibitors BAY 1143572 and AZD 6738 for the treatment of cancer
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

B
J. A. Sirvent et al.
Paper
Synthesis
sulfide
oxidation
sulfoxide
imination
O
S
R1
R2
(+ deprotection)
Route A
HN
R1
O
S
R1
R2
S
sulfilimine
oxidation
R2
Route B
R3
R1
N
S
sulfide
imination
(+ deprotection)
R2
Scheme 1 Preparation of sulfoximines via oxidation/imination or imination/oxidation procedures (scheme adapted from Loso and co-workers10a
)
Whilst significant progress has been made, methods for
sulfoximine synthesis remain rather limited. In general,
most synthetic methods rely on sequential oxidation/
imination (Route A) or imination/oxidation (Route B) proce-
dures starting from thioethers (Scheme 1).
poor yields involving difficult purification procedures, or
even that they failed completely, depending on the chemi-
cal structure of the starting thioether. This can be particu-
larly problematic when attempting to construct the sulfoxi-
mine group via such sequential routes for more complex
thioethers containing several heteroatoms.
Our long-standing interest in sulfoximines as an under-
represented pharmacophore in drug discovery14 has often
been met with challenges in the syntheses of the desired
sulfoximine targets. For instance, during the lead optimiza-
tion program that led to the discovery of the potent and se-
lective PTEFb inhibitor BAY 1143572 for the treatment of
cancer, synthesis of the required sulfoximine building block
8 generally relied on the initial formation of a thioether 4,
for example, from a commercial acid or ester 1 via reduc-
tion and subsequent chlorination (Scheme 2). Thioether 4
was then converted into the unprotected sulfoximine build-
ing block 6 via sequential oxidation (4 → 5) and imina-
tion/deprotection (5 → 6) reactions.15 Finally, introduction
of a protecting group that is stable under both basic condi-
tions and elevated temperatures, followed by reduction of
the nitro group, gave the desired aniline building block 8. In
principle, however, this sequential approach has two major
drawbacks: first of all, the syntheses are quite long, requir-
ing seven steps to transform a commercial ester or acid 1 to
the desired aniline building block 8 with a protected S-ben-
zyl-S-methylsulfoximine group. Secondly, we often found
that the sequential oxidation/imination or imination/oxida-
tion procedures resulted in complex product mixtures in
We addressed this limitation by searching for methods
that would allow the synthesis of (hetero)aryl-substituted
S,S-dimethylsulfoximine derivatives via an intermolecular
cross-coupling reaction utilizing a readily available, pre-
formed sulfoximine building block.16 Whilst the synthesis
of functionalized benzylic sulfones using the palladium-
catalyzed Negishi coupling reaction with various alkyl sul-
fones and aryl halides was reported by Zhou and co-work-
ers in 2010,17 in the present context two more recent publi-
cations on palladium-catalyzed α-arylations of sulfones
were pivotal. In 2013, Walsh and co-workers reported the
first deprotonative cross-coupling process for the direct
α-arylation of aryl methyl and alkyl methyl sulfones 9 with
aryl bromides 10 using Kwong’s ligand (Scheme 3).18 Even
weakly acidic alkyl methyl sulfones 9 with pKa values as
high as 31 (in DMSO) were good substrates in this
palladium-catalyzed cross-coupling process.
More recently, Nambo and Crudden utilized a related
palladium-catalyzed C–H arylation of methyl phenyl sul-
fone (9a) to prepare complex triarylmethanes 12 via se-
quential α-arylations (Scheme 4).19
R1
R1
R1
R1
OR2
S
OH
Cl
O2N
O2N
O2N
O2N
O
1
2
3
4
R2 = H, alkyl
R1
R1
O
O
N
R1
R1
O
S
O
O
O
NH
O
N
O
S
O2N
O2N
S
S
O2N
H2N
7
8
6
5
Scheme 2 General synthetic route to aniline building blocks 8 with a protected sulfoximine group in the lead optimization project that led to the
identification of phase I PTEFb inhibitor BAY 1143572
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

C
J. A. Sirvent et al.
Paper
Synthesis
tives 15, since the substituent on the nitrogen atom signifi-
cantly influences the acidity of the hydrogens at the α-posi-
tion. Thus, pKa values in the range of 23–32 (in DMSO) have
been reported for various N-substituents.2b,21 To obtain a
first impression of the influence of the pKa on cross-
coupling reactivity, four N-protected DMSI compounds
15a–d were prepared with protecting groups that differ
significantly in their electron-donating/-withdrawing prop-
erties. Looking ahead, cleavage of the protecting groups
used in 15b–d to give the corresponding free sulfoximines
has, in principle, been demonstrated previously.22 While
the p-methoxybenzyl (PMB) group (as in 15a) is ubiquitous
in organic synthesis, it has not been previously employed as
a protecting group for sulfoximines.23
O
O
O
O
a)
S
Ar
+
Ar Br
S
R1
R1
N
P
9
11
10
Cy
Cy
R1 = alkyl, aryl
Kwong´s ligand
Scheme 3 Palladium-catalyzed direct α-arylation of methyl sulfones 9
with aryl bromides 10. Reagents and conditions: a) Pd(OAc)2 (10 mol%),
Kwong’s ligand (20 mol%), LiOt-Bu (3 equiv), toluene, 110 °C, 12 h; 18
examples, up to 90% yield.18
B(OR)2
Br
I
Ar3
Ar2
Ar1
Ar2
O
O
First, the protected DMSI compounds 15a–d were sub-
jected to reaction conditions adapted from the method of
Walsh and co-workers (Scheme 5).18 When Pd(OAc)2 and
Kwong’s ligand with LiOt-Bu in toluene at 110 °C were used,
all four cross-coupling reactions with bromobenzene failed
to provide the desired product. However, when conditions
modified from the method of Nambo and Crudden were
utilized [Pd(OAc)2, XPhos, LiOt-Bu, cyclopentyl methyl
ether (CPME), 110 °C],19 the corresponding cross-coupling
product 16a was formed in 25% yield, whereas the α-aryla-
tions with protected sulfoximines 15b–d failed, with most-
ly starting material remaining. These results were rather
surprising as electron-withdrawing substituents at the
sulfoximine nitrogen that increase the C–H acidity at the α-
position, such as in protected sulfoximines 15c and 15d,
were expected to be beneficial for cross-coupling reactivi-
ty.16b Instead, sulfoximine 15a with an electron-donating
PMB group gave the best result. Since the PMB group should
also enable easy deprotection under mild conditions, the
palladium-catalyzed direct α-arylation of PMB-protected
DMSI 15a was further explored.
S
Ar1
Ar3
9a
12
Scheme 4 Synthesis of triarylmethanes 12 via palladium-catalyzed se-
quential arylation reactions19
As sulfoximines are isoelectronic with sulfones, we en-
visaged developing a direct α-arylation of the structurally
simplest sulfoximine, commercial S,S-dimethylsulfoximine
(DMSI, 13) (Scheme 5). However, in contrast to sulfones,
sulfoximines offer an additional point for substitution,
namely the weakly nucleophilic nitrogen atom. To avoid the
well-established palladium-catalyzed N-arylation process
which yields 14,20 the sulfoximine nitrogen would have to
be protected (as 15) for the desired C–H arylation reaction
to obtain 16. Moreover, simple and efficient deprotection of
the cross-coupling products 16 should also be feasible, giv-
ing easy access to the free (hetero)aryl-substituted DMSI
derivatives 17. Assuming that the acidity of the S-methyl
protons would be important for the intended α-aryla-
tion,16b we envisaged utilizing the mandatory N-protecting
group to tune the reactivity of the protected DMSI deriva-
As our preliminary results had also indicated the impor-
tance of the ligand, a number of ligands structurally related
to XPhos were initially evaluated under comparable
reaction conditions (Table 1). t-BuXPhos did not efficiently
Ar Br
HN
O
R1
N O
a
c
Ar
N O
[Pd/L]
b
HN
O
R1
N O
S
Ar
S
S
S
Ar
S
14
13
15
16
17
17a: Ar = Ph
15a: R1 = PMB
15b: R1 = TBDPS
15c: R1 = Bz
16a: R1 = PMB;
Ar = Ph
15d: R1 = Ts
Scheme 5 Approach for the palladium-catalyzed direct α-arylation of protected DMSI compounds 15 with (hetero)aryl bromides. Reagents and condi-
tions: a) For 15a: 13 (1 equiv), 4-methoxybenzaldehyde (1 equiv), NaBH(OAc)3 (1.5 equiv), DCE, r.t., 16 h, 82%; For 15b: 13 (1 equiv), TBDPSCl (1.2
equiv), imidazole (3 equiv), DMF, 60 °C, 2 h, 63%; For 15c: 13 (1 equiv), BzCl (1.1 equiv), DMAP (0.1 equiv), Et3N (1.2 equiv), CH2Cl2, r.t., 3 h, 97%; For
15d: 13 (1 equiv), TsCl (1.05 equiv), pyridine, r.t., 12 h, 60%; b) Method A (based on that of Walsh and co-workers18): 15a–d (2 equiv), PhBr (10a, 1
equiv), Pd(OAc)2 (10 mol%), Kwong’s ligand (20 mol%), LiOt-Bu (3 equiv), toluene, 110 °C, 16 h; Method B (based on that of Nambo and Crudden19):
15a–d (2 equiv), PhBr (10a, 1 equiv), Pd(OAc)2 (10 mol%), XPhos (20 mol%), LiOt-Bu (3 equiv), CPME, 110 °C, 16 h; c) 16a (1 equiv), CAN (2 equiv),
MeCN/H2O (3:1), r.t., 15 min, 80%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

D
J. A. Sirvent et al.
Paper
Synthesis
16a
promote the α-arylation of 15a, whereas SPhos and Dave-
Phos resulted in slightly improved yield of 30% and 33%, re-
spectively (Table 1, entries 2–4). Next, a number of biden-
tate phosphine ligands were evaluated. With BINAP, a li-
gand that was successfully used by Bolm and co-workers in
an early intramolecular α-arylation reaction of a methyl-
sulfoximine compound,16a the desired cross-coupling reac-
tion to 16a failed (entry 5). The ferrocenyl ligand DTBPF
gave little improvement over XPhos; however, with Xant-
phos the yield jumped to 74% (entries 6, 7). A decreased
yield of 55% was obtained with the structurally related N-
Xantphos, while t-BuXantphos failed to promote the de-
sired cross-coupling (entries 8, 9).
traces of product were observed, but the use of Cs2CO3
resulted in a 44% yield (entries 7, 8). After establishing
LiOt-Bu as the best base for this coupling, a reduced amount
of base was also evaluated; however, 1 or 2 equivalents of
LiOt-Bu resulted in a decreased yield of 28% and 63%, re-
spectively (entries 9, 10).
Table 2 Optimization of the Solvent and Base for the α-Arylation of
PMB-Protected DMSI 15a with 10aa
Br
Pd(OAc)2/Xantphos
PMB N
O
PMB N
O
+
S
S
base
solvent, 110 °C
16a
15a
10a
Table 1 Optimization of the Ligand for the α-Arylation of PMB-
Protected DMSI 15a with Bromobenzene (10a)a
Entry
Solvent
Base
Base
(equiv)
Yield
(%)b
1
2
toluene
1,4-dioxane
DMF
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
NaOt-Bu
KOt-Bu
LiHMDS
Cs2CO3
LiOt-Bu
LiOt-Bu
3
3
3
3
3
3
3
3
1
2
64
71
24
<10
51
–
O
O
3
4
CPME + H2Oc
CPME
Br
Pd(OAc)2/L
N
O
N
O
+
5
S
S
LiOt-Bu
CPME, 110 °C
6
CPME
15a
10a
16a
Yield (%)b
7
CPME
<10
44
28
63
8
CPME
Entry
Ligand
XPhos
9
CPME
1
2
3
4
5
6
7
8
9
25
<10
33
30
–
10
CPME
t-BuXPhos
DavePhos
SPhos
a Reaction conditions: 10a (0.15 mmol, 1 equiv), 15a (0.30 mmol, 2 equiv),
Pd(OAc)2 (10 mol%), Xantphos (20 mol%), base (3 equiv), solvent (1 mL),
110 °C, 16 h, under argon.
b Reactions were performed in the presence of 4,4′-di-tert-butylbiphenyl
(0.025 mmol, 0.167 equiv) as an internal standard. Yields were calculated
from the 1H NMR spectra of the reaction crude, by comparison of the methyl
signal of product 16a (δ = 2.71) and the tert-butyl signal of the internal stan-
dard (δ = 1.37).
rac-BINAP
DTBPF
29
74
55
–
Xantphos
c Addition of 0.02 mL of H2O.
N-Xantphos
t-BuXantphos
Employing an excess of PMB-protected DMSI 15a is
beneficial: when the reaction was conducted with a 3:1 ra-
tio of 15a/10a instead of 1:1, the yield of product 16a in-
creased from 50% to 80% (Table 3, entries 1, 2). An excess of
15a probably minimizes the formation of diarylation prod-
ucts.24 As PMB-protected DMSI 15a is easily prepared in
only one step from commercial DMSI (13), the subsequent
cross-coupling reactions were performed with a 3:1 ratio of
15a/10a. Altering the Pd(OAc)2/Xantphos ratio from 1:2 to
1:1 resulted in a lower yield of 16a (58%; entry 3). Use of a
1:2 ratio of PdCl2/Xantphos provided a yield of 79%, where-
as Pd2(dba)3/Xantphos (1:2) gave product 16a in only 51%
yield (entries 4, 5). Pd(OAc)2/Xantphos (1:2) and a reduced
5 mol% palladium loading still resulted in 76% yield; how-
ever, upon further reduction to 2 mol% there was incom-
plete reaction and only a 43% yield of 16a (entries 6, 7).
Conducting the reaction with a 5 mol% palladium loading at
only 90 °C was not beneficial, but a good yield of 16a (78%)
a Reaction conditions: 10a (0.15 mmol, 1 equiv), 15a (0.30 mmol, 2 equiv),
Pd(OAc)2 (10 mol%), ligand (20 mol%), LiOt-Bu (3 equiv), CPME (1 mL),
110 °C, 16 h, under argon.
b Reactions were performed in the presence of 4,4′-di-tert-butylbiphenyl
(0.025 mmol, 0.167 equiv) as an internal standard. Yields were calculated
from the 1H NMR spectra of the reaction crude, by comparison of the
methyl signal of product 16a (δ = 2.71) and the tert-butyl signal of the in-
ternal standard (δ = 1.37).
Next, three alternative solvents were evaluated using
Xantphos as the ligand and LiOt-Bu as the base, resulting in
yield of 64% and 71% in toluene and 1,4-dioxane, respec-
tively (Table 2, entries 1, 2). In DMF, the coupling product
16a was obtained in a significantly lower 24% yield (entry
3). The reaction process was also sensitive to water, with
the yield of 16a sharply decreasing when a small quantity
of water was added to CPME (Table 1, entry 7 vs Table 2, en-
try 4). In a screen of four alternative bases, a 51% yield of
16a was obtained with NaOt-Bu, whereas the reaction with
KOt-Bu failed to proceed (entries 5, 6). With LiHMDS only
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

E
J. A. Sirvent et al.
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Synthesis
Table 3 Optimization of the Reaction Stoichiometry, Catalyst Parameters, and Reaction Conditions for the α-Arylation of PMB-Protected DMSI 15a
with 10aa
Br
[Pd]/Xantphos
PMB N
O
PMB N
O
+
S
S
LiOt-Bu
CPME
15a
10a
16a
Entry
Ratio 15a/10a
Ratio Pd/Xantphos
Pd source
Pd load (mol%)
Temp (°C)
[10a] (mmol/mL)
Yield (%)b
1
2
3
4
5
6
7
8
9
1:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
1:2
1:2
1:1
1:2
1:2
1:2
1:2
1:2
1:2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
10
10
10
10
5
110
110
110
110
110
110
110
90
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.25
50
80
58
79
51
76
43
31
78
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
5
2
5
5
110
a Reaction conditions: 10a (0.15 mmol), 15a, Pd source, Xantphos, LiOt-Bu (3 equiv), CPME, temperature as given, 16 h, under argon.
b Reactions were performed in the presence of 4,4′-di-tert-butylbiphenyl (0.025 mmol, 0.167 equiv) as an internal standard. Yields were calculated from the
1H NMR spectra of the reaction crude, by comparison of the methyl signal of product 16a (δ = 2.71) and the tert-butyl signal of the internal standard (δ = 1.37).
was observed when employing 5 mol% of Pd(OAc)2 and in-
creasing the concentration of 10a from 0.15 M to 0.25 M
(entries 8, 9).
Deprotection of the cross-coupling products 16 to yield
the unprotected (hetero)aryl-substituted DMSI derivatives
17 (Scheme 5) was envisaged as being crucial for the appli-
cability of this new α-arylation process. Gratifyingly, cleav-
age of the PMB group in 16a using 2 equivalents of ammo-
nium cerium(IV) nitrate (CAN) in acetonitrile and water
(3:1) at room temperature gave the desired free sulfoxi-
mine product 17a in 80% isolated yield. To our knowledge,
the PMB group has not been previously utilized as a pro-
tecting group in sulfoximine chemistry, but our results
clearly demonstrate its effectiveness: the PMB moiety can
be easily introduced, has high stability under basic condi-
With the optimized conditions in hand, the scalability
of the direct α-arylation of 15a was evaluated by perform-
ing the cross-coupling reaction with bromobenzene (10a)
on a 5.3 mmol scale (0.84 g). With 5 mol% Pd(OAc)2, 10
mol% Xantphos, 3 equivalents of 15a, and 3 equivalents of
LiOt-Bu in a 0.25 M solution of 10a in CPME at 110 °C for 7
hours, the desired α-arylation product 16a was isolated in
76% yield (NMR yield: 75%). Furthermore, 8.1 mmol of 15a
was recovered with a purity of 97% and used in additional
reactions.
PMB
a,b
PMB
c
N
N
O
O
N
N
S
S
Br
N
Ph
NH2
N
N
Cl
H
21
16q
(0.84 g)
10q
(6 mmol)
d
PMB
N
N
N
O
O
N
N
O
e
O
HN
S
S
N
N
N
H
N
H
F
F
22
BAY 1143572 (racemate)
Scheme 6 Synthesis of PTEFb inhibitor BAY 1143572 in racemic form based on the direct α-arylation of PMB-protected DMSI 15a. Reagents and condi-
tions: a) 15a (3 equiv), XantPhos Pd G3 (3 mol%), Xantphos (3 mol%), LiOt-Bu (3 equiv), CPME (0.25 M), 110 °C, 3 h; b) 0.5 M HCl, r.t., 45 min, 46% over
two steps; c) 2,4-dichloro-1,3,5-triazine (1.1 equiv), DIPEA (2 equiv), THF/i-PrOH (1:1), 0 °C, 30 min, 97%; d) 4-fluoro-2-methoxyphenylboronic acid
(1.5 equiv), Pd(PPh3)4 (5 mol%), aq 2 M K2CO3 (2 equiv), DME, 85 °C, MW, 5 h, 40%; e) CAN (2.5 equiv), MeCN/H2O (3:1), r.t., 1 h, 95%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

F
J. A. Sirvent et al.
Paper
Synthesis
tions and elevated temperatures, and can be simply and ef-
ficiently removed.
Suzuki reaction to yield 22 (Scheme 6). Finally, removal of
the PMB group using CAN cleanly afforded the desired
PTEFb inhibitor BAY 1143572 in racemic form.27
After these successes with both scalability and depro-
tection, the scope of the (hetero)aryl substrates in the α-
arylation of 15a was explored (Table 4), employing the con-
ditions from our scale-up experiment. With iodobenzene
(18) and phenyl triflate (19), product 16a was obtained in
59% and 23% yield, respectively, whereas the cross-coupling
reaction with chlorobenzene (20) failed (Table 4, entries 1–
3). Then, a broad range of (hetero)aryl bromides was evalu-
ated, which disappointingly resulted in unsatisfactory
yields for a number of substrates. Therefore, we opted to
evaluate the use of XantPhos Pd G3 precatalyst instead of
Pd(OAc)2 to ensure efficient generation of the active cata-
lyst species, which is often pivotal to the success of a cross-
coupling reaction.25 Although this switch to the precatalyst
gave a comparable yield for our model reaction to product
16a (entry 4), superior yields were indeed mostly obtained
for other substrates. XantPhos Pd G3 precatalyst was there-
fore used to explore the scope of the α-arylation reaction,
usually affording good to moderate yields of products 16a–
p (entries 4–19). The addition of an extra 3 mol% of Xant-
phos was necessary to obtain full conversion, although in a
few cases it was not essential (entries 9, 11, 19). In general,
electron-donating and electron-withdrawing substituents
are compatible with the reaction, but para- and meta-sub-
stituted bromobenzenes resulted in better yields than the
corresponding ortho-substrates (entries 4–16). The use of
an increased palladium loading (10 mol%) was beneficial for
formation of the ortho-fluoro derivative 16d, but not for the
more sterically hindered ortho-methyl compound 16g (en-
tries 7, 10). Interestingly, even a vinyl substituent is tolerat-
ed (entry 16). Moreover, 3-bromopyridine, 3-bromoquino-
line, and 2-bromonaphthalene are compatible in this pro-
cess, yielding the corresponding α-arylation products 16n–
p (entries 17–19). In some reactions, the formation of a side
product in various amounts was observed, which was final-
ly isolated and, to our surprise, identified as α-phenyl-sub-
stituted sulfoximine 16a. After ruling out contamination,
the only rational explanation for the formation of 16a in
these reactions is that a phenyl group from the phosphine
ligand Xantphos is incorporated into the coupling prod-
uct.26
Table 4 Substrate Scope of the α-Arylation of 15a with (Hetero)aryl
Halides 10a–p, 18, 20, and Triflate 19a
catalytic system
(conditions A–D)
PMB N
O
PMB N
O
Ar
X
+
S
Ar
S
LiOt-Bu (3 equiv)
CPME (0.25 M)
110 °C
15a
18–20
10a–p
16a–p
Entry ArX
Conditionsb Product Time Yield
(h)
(%)c
1
2
3
4
PhI (18)
A
A
A
16a
16a
16a
8
(59)
PhOTf (19)
PhCl (20)
8
8
(23)
n.r.
PhBr (10a)
A
B
16a
16a
16
6
78
75
5
6
7
4-FC6H4Br (10b)
3-FC6H4Br (10c)
2-FC6H4Br (10d)
B
B
16b
16c
16
4
69
62
B
D
16d
16d
24
24
9
34
8
9
4-MeC6H4Br (10e)
3-MeC6H4Br (10f)
2-MeC6H4Br (10g)
B
C
16e
16f
4
3
54
67
10
B
D
16g
16g
24
24
7
8
11
12
13
14
15
16
17
18
19
3,5-Me2C6H3Br (10h)
3-MeOC6H4Br (10i)
C
B
B
B
B
B
B
B
C
16h
16i
5
5
73
49
62
38
37
39
44
48
54
3-ClC6H4Br (10j)
16j
10
24
6
3-NCC6H4Br (10k)
16k
16l
4-F3CC6H4Br (10l)
3-(H2C=CH)C6H4Br (10m)
3-bromopyridine (10n)
3-bromoquinoline (10o)
2-bromonaphthalene (10p)
16m
16n
16o
16p
12
4
5
6
a Reaction conditions: ArX (0.25 mmol, 1 equiv), 15a (3 equiv), Pd source,
ligand, LiOt-Bu (3 equiv), CPME (1.0 mL), 110 °C, under argon. Reactions
were performed in the presence of 4,4′-di-tert-butylbiphenyl (0.042 mmol,
0.167 equiv) as an internal standard.
b Conditions A: Pd(OAc)2 (5 mol%), Xantphos (10 mol%); Conditions B: Xant-
Phos Pd G3 (3 mol%), Xantphos (3 mol%); Conditions C: XantPhos Pd G3 (3
mol%); Conditions D: XantPhos Pd G3 (10 mol%), Xantphos (10 mol%).
c Isolated yields. For entries 1 and 2, calculated yields in parentheses. n.r. =
No reaction.
Our new methodology was then successfully applied to
an improved synthesis of PTEFb inhibitor BAY 1143572. Di-
rect α-arylation of 15a with 3-bromo-N-[(E)-phenylmeth-
ylidene]aniline (10q) on a 6 mmol scale, followed by hydro-
lysis of the imine moiety by addition of HCl to the crude
coupling product, yielded the desired aniline 16q in 46%
isolated yield and only two steps, which compares favorably
to the previous route (Scheme 2).15 Aniline 16q was then
coupled with the commercial 2,4-dichloro-1,3,5-triazine to
give chloride 21, which was employed in a subsequent
In summary, we have developed the first intermolecular
direct α-arylation of PMB-protected DMSI 15a with
(hetero)aryl bromides. This palladium-catalyzed process
provides
a
safe, short, and efficient approach to
(hetero)aryl-substituted DMSI derivatives, which have re-
cently drawn considerable attention in the life sciences due
to their successful application as pharmacophores in bio-
logically active molecules. With this new method, the often
tedious, traditional sequential oxidation/imination or imi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

G
J. A. Sirvent et al.
Paper
Synthesis
nation/oxidation procedures starting from thioethers can
be avoided. A broad range of substrates and functional
groups common in the life sciences were tolerated under
the optimized conditions, which provided the target prod-
ucts in moderate to good yields. Very high selectivity for
the desired monoarylation products was observed. Further-
more, the PMB group proved to be a versatile protecting
group in sulfoximine chemistry that can be easily intro-
duced, has high stability under basic conditions and elevat-
ed temperatures, and can be conveniently removed with
CAN. We are currently investigating the regioselectivity of
the palladium-catalyzed α-arylation of unsymmetrical S,S-
dialkylsulfoximines as well as the stereoselectivity of this
new process in the presence of chiral ligands or chiral ben-
zyl protecting groups.
sure. The crude was purified by flash chromatography (Cartridge: KP-
Sil 100 g; eluent: EtOAc, then EtOH) to afford 15a (5.27 g, 82%) as a
white solid; mp 78–79 °C; Rf = 0.06 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.27–7.33 (m, 2 H), 6.81–6.90 (m, 2 H),
4.24 (s, 2 H), 3.79 (s, 3 H), 2.98 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 158.5, 133.4, 128.9, 113.9, 55.3, 46.5,
42.6.
MS (ES+): m/z (%) = 214 (100, [M+ + 1]), 121 (96), 215 (36), 216 (18),
122 (16).
HRMS (ES+): m/z [M + H+] calcd for C10H16NO2S: 214.0902; found:
214.0899.
N-(tert-Butyldiphenylsilyl)-S,S-dimethylsulfoximine (15b)
To a solution of S,S-dimethylsulfoximine (13; 512 mg, 5.5 mmol) and
imidazole (1.12 g, 16.5 mmol) in anhyd DMF (2.5 mL), cooled to 0 °C,
was added TBDPSCl (1.71 mL, 6.6 mmol) dropwise. Then, the reaction
mixture was stirred at 60 °C. After 2 h, the batch was cooled to r.t.,
hydrolyzed with brine (10 mL), and extracted with EtOAc (2 × 20 mL).
The combined organic phases were dried (Na2SO4), filtered, and con-
centrated under reduced pressure. The crude was purified by flash
chromatography (Cartridge: KP-Sil 50 g; eluent: n-hexane/EtOAc,
60:40) to afford 15b (1.14 g, 63%) as a white solid; mp 52–53 °C; Rf =
0.10 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.72–7.76 (m, 4 H), 7.33–7.42 (m, 6 H),
2.82 (s, 6 H), 1.06 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 136.4, 135.7, 129.3, 127.7, 47.2, 27.2,
19.3.
Commercially available reagents and anhyd solvents were purchased
from Alfa Aesar, abcr, Acros Organics, Merck, and Sigma-Aldrich, and
were used without further purification. Reactions were carried out
under argon in microwave reaction vials (Biotage®) placed in a steel
heating block. Reactions were monitored by UPLC analysis with a Wa-
ters Acquity UPLC MS Single Quad system; column: Acquity UPLC BEH
C18 1.7 μm, 50 × 2.1 mm; eluent A: H2O + 0.2 vol% aq NH3 (32%), elu-
ent B: MeCN; gradient: 0–1.6 min 1–99% B, 1.6–2.0 min 99% B; flow:
0.8 mL/min; temperature: 60 °C; DAD scan: 210–400 nm. Flash chro-
matography was carried out using a Biotage® Isolera™ One system
with 200–400 nm variable detector, using Biotage® SNAP KP-Sil car-
tridges. Preparative HPLC was carried out with a Waters AutoPurifica-
tion MS Single Quad system; column: Waters XBridge C18 5 μm,
100 × 30 mm; eluent A: H2O + 0.2 vol% aq NH3 (32%), eluent B: MeCN;
gradient: 0–5.5 min 5–100% B; flow: 70 mL/min; temperature: 25 °C;
DAD scan: 210–400 nm. Analytical TLC was carried out on aluminum-
backed plates coated with Merck Kieselgel 60 F254, with visualization
under UV light at 254 nm. All NMR spectra were recorded on Bruker
Avance III HD spectrometers. 1H NMR spectra were obtained at 400
MHz and referenced to the residual solvent signal (7.26 ppm for CD-
Cl3). 13C NMR spectra were obtained at 101 MHz and also referenced
to the residual solvent signal (77.16 ppm for CDCl3). All spectra were
obtained at ambient temperature (22 ± 1 °C). Data are reported as fol-
lows: chemical shift (δ) in ppm, multiplicity (standard abbreviations),
coupling constant(s) (Hz), and integration. Mass spectra were record-
ed on LC-MS instruments: (i) Waters Acquity UPLC MS Single Quad
system; column: Kinetex 2.6 μm, 50 × 2.1 mm, or (ii) Agilent 1290
UPLC MS 6230 TOF system; column: BEH C18 1.7 μm, 50 × 2.1 mm;
eluent A: H2O + 0.05% formic acid (99%), eluent B: MeCN + 0.05% for-
mic acid (99%). Fragment ions are reported as m/z values with relative
intensities (%) in parentheses. High-resolution mass spectra were re-
corded on a Xevo® G2-XS QTof (Waters) instrument. Melting points
were determined with a Büchi B-540 melting point apparatus.
MS (ES+): m/z (%) = 332 (100, [M+ + 1]), 333 (29), 334 (12).
HRMS (ES+): m/z [M + H+] calcd for C18H26NOSSi: 332.1504; found:
332.1506.
N-Benzoyl-S,S-dimethylsulfoximine (15c)28
A solution of S,S-dimethylsulfoximine (13; 240 mg, 2.6 mmol), benzo-
yl chloride (0.33 mL, 2.8 mmol), DMAP (31 mg, 0.26 mmol), and Et3N
(0.43 mL, 3.1 mmol) in CH2Cl2 (20 mL) was stirred at r.t. for 3 h. The
reaction was hydrolyzed with H2O (10 mL) and the organic phase was
separated. The aqueous phase was extracted with CH2Cl2 (2 × 20 mL).
The organic phases were combined, dried (Na2SO4), filtered, and con-
centrated at 1 mbar. The crude was obtained as a white crystalline
solid and was used without further purification (492 mg, 97%); mp
99–102 °C (Lit.28 mp 106–108 °C); Rf = 0.43 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.10–8.16 (m, 2 H), 7.47–7.54 (m, 1 H),
7.38–7.44 (m, 2 H), 3.39 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 174.3, 135.5, 132.3, 129.4, 128.2, 41.9.
MS (ES+): m/z (%) = 198 (100, [M+ + 1]), 199 (12).
HRMS (ES+): m/z [M + H+] calcd for C9H12NO2S: 198.0589; found:
198.0590.
N-(p-Tolylsulfonyl)-S,S-dimethylsulfoximine (15d)
N-(4-Methoxybenzyl)-S,S-dimethylsulfoximine (15a)
TsCl (859 mg, 4.5 mmol) was added to a solution of S,S-dimethylsulf-
oximine (13; 400 mg, 4.3 mmol) in pyridine (4 mL). The resulting sus-
pension was stirred at r.t. for 12 h. Then, the mixture was poured into
H2O and extracted with CHCl3 (3 × 15 mL). The combined organic
phases were washed with H2O, dried (Na2SO4), filtered, and concen-
trated under reduced pressure, affording 15d (640 mg, 60%) as a
white crystalline solid; mp 169–170 °C; Rf = 0.49 (EtOAc).
A solution containing S,S-dimethylsulfoximine (13; 2.79 g, 30 mmol)
and 4-methoxybenzaldehyde (3.64 mL, 30 mmol) in DCE (20 mL) was
stirred at r.t. for 2 h. Then, NaBH(OAc)3 (9.54 g, 45 mmol) was added
in one portion and the resulting suspension was stirred at r.t. for 16 h.
The reaction mixture was hydrolyzed with sat. aq NaHCO3 (60 mL)
and extracted with EtOAc (2 × 50 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated under reduced pres-
1H NMR (400 MHz, CDCl3): δ = 7.83–7.89 (m, 2 H), 7.27–7.31 (m, 2 H),
3.36 (s, 6 H), 2.41 (s, 3 H).
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J. A. Sirvent et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 143.1, 140.5, 129.5, 126.7, 44.3, 21.7.
MS (ES+): m/z (%) = 248 (100, [M+ + 1]), 249 (12), 407 (10).
HRMS (ES+): m/z [M + H+] calcd for C9H14NO3S2: 248.0415; found:
1H NMR (400 MHz, CDCl3): δ = 7.31–7.38 (m, 2 H), 7.24–7.31 (m, 2 H),
7.03–7.11 (m, 2 H), 6.82–6.89 (m, 2 H), 4.19–4.30 (m, 4 H), 3.79 (s, 3
H), 2.71 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 163.1 (d, J = 248.8 Hz), 158.6, 133.5,
132.6 (d, J = 8.5 Hz), 129.0, 125.5 (d, J = 3.4 Hz), 116.1 (d, J = 21.6 Hz),
113.9, 60.5, 55.4, 46.5, 39.3.
248.0419.
(Hetero)arylation of N-(4-Methoxybenzyl)-S,S-dimethylsulfoxi-
mine (15a); General Procedures for the Synthesis of Compounds
16
MS (ES+): m/z (%) = 308 (100, [M+ + 1]), 309 (24), 121 (13).
HRMS (ES+): m/z [M + H+] calcd for C16H19FNO2S: 308.1121; found:
308.1126.
Conditions A: A stirred suspension containing N-(4-methoxybenzyl)-
S,S-dimethylsulfoximine (15a; 160 mg, 0.75 mmol), Pd(OAc)2 (2.8 mg,
0.0125 mmol), Xantphos (14.5 mg, 0.025 mmol), LiOt-Bu (60 mg, 0.75
mmol), 4,4′-di-tert-butylbiphenyl as an internal standard (11.1 mg,
0.042 mmol), and the corresponding aryl bromide 10 (0.25 mmol) in
anhyd cyclopentyl methyl ether (CPME, 1 mL) was heated under ar-
gon at 110 °C until reaction completion. Then, the reaction mixture
was cooled to r.t., hydrolyzed with brine (5 mL), and extracted with
EtOAc (2 × 10 mL). The combined organic phases were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue was
purified by preparative HPLC using MeCN/H2O mixtures as the mobile
phase (see general information for details).
1-Fluoro-3-{[N-(4-methoxybenzyl)-S-methylsulfonimidoyl]meth-
yl}benzene (16c)
The general procedure was followed (Conditions B) using 1-bromo-3-
fluorobenzene (10c; 27 μL); reaction time: 4 h; white solid (48 mg,
62%); mp 51–53 °C; Rf = 0.45 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.35 (td, J = 7.8, 6.0 Hz, 1 H), 7.29 (d,
J = 8.6 Hz, 2 H), 7.14 (d, J = 7.6 Hz, 1 H), 7.03–7.12 (m, 2 H), 6.84–6.88
(m, 2 H), 4.18–4.33 (m, 4 H), 3.79 (s, 3 H), 2.73 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 162.9 (d, J = 247.5 Hz), 158.6, 133.5,
132.2 (d, J = 7.6 Hz), 130.6 (d, J = 8.5 Hz), 129.0, 126.5 (d, J = 3.4 Hz),
117.8 (d, J = 22.0 Hz), 115.9 (d, J = 21.2 Hz), 114.0, 60.8 (d, J = 1.7 Hz),
55.4, 46.5, 39.6.
Conditions B: As for Conditions A, but Pd(OAc)2 was replaced by Xant-
Phos Pd G3 (7.8 mg, 0.008 mmol, 3 mol%), and Xantphos (4.3 mg,
0.008 mmol, 3 mol%) was used.
MS (ES+): m/z (%) = 308 (100, [M+ + 1]), 309 (27), 121 (22).
HRMS (ES+): m/z [M + H+] calcd for C16H19FNO2S: 308.1121; found:
Conditions C: As for Conditions B, without the addition of Xantphos.
Conditions D: As for Conditions B, but XantPhos Pd G3 (25.8 mg, 0.025
mmol, 10 mol%) and Xantphos (14.4 mg, 0.025 mmol, 10 mol%) were
used. For Conditions B–D, strict argon control is necessary.
308.1123.
1-Fluoro-2-{[N-(4-methoxybenzyl)-S-methylsulfonimidoyl]meth-
yl}benzene (16d)
{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}benzene
The general procedure was followed (Conditions D) using 1-bromo-2-
fluorobenzene (10d; 27 μL); reaction time: 24 h; colorless oil (26 mg,
34%); Rf = 0.53 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.42 (m, 2 H), 7.27–7.32 (m, 2 H),
7.15–7.21 (m, 1 H), 7.08–7.14 (m, 1 H), 6.83–6.89 (m, 2 H), 4.24–4.39
(m, 4 H), 3.79 (s, 3 H), 2.79 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 161.0 (d, J = 248.0 Hz), 158.6, 133.6,
133.1 (d, J = 3.0 Hz), 130.9 (d, J = 8.5 Hz), 129.0, 124.9 (d, J = 3.8 Hz),
117.6 (d, J = 14.8 Hz), 115.8 (d, J = 21.6 Hz), 113.9, 55.4, 53.9 (d, J = 3.0
Hz), 46.5, 39.6 (d, J = 3.0 Hz).
(16a)
The general procedure was followed (Conditions B) using bromoben-
zene (10a, 26 μL); reaction time: 6 h; white solid (54 mg, 75%).
Gram-Scale Reaction: A stirred suspension containing N-(4-methoxy-
benzyl)-S,S-dimethylsulfoximine (15a; 3.41 g, 16.0 mmol), Pd(OAc)2
(60 mg, 0.27 mmol), Xantphos (308 mg, 0.53 mmol), LiOt-Bu (1.28 g,
16.0 mmol), 4,4′-di-tert-butylbiphenyl as an internal standard (237
mg, 0.89 mmol), and bromobenzene (10a; 0.56 mL, 5.3 mmol) in an-
hyd CPME (21 mL) was heated at 110 °C for 7 h. Then, the reaction
mixture was cooled to r.t., hydrolyzed with brine, and extracted with
EtOAc (2 × 30 mL). The combined organic phases were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude was pu-
rified by flash chromatography (Cartridge: KP-Sil 100 g; eluent: n-
hexane/EtOAc, 12% → 100% EtOAc) to afford 16a (1.18 g, 76%) as a
white solid; mp 77–79 °C; Rf = 0.41 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.42 (m, 5 H), 7.28–7.33 (m, 2 H),
6.84–6.88 (m, 2 H), 4.23–4.32 (m, 4 H), 3.79 (s, 3 H), 2.71 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.5, 133.6, 130.7, 129.8, 129.0,
128.9, 128.8, 113.9, 61.1, 55.3, 46.5, 39.2.
MS (ES+): m/z (%) = 290 (100, [M+ + 1]), 291 (20).
HRMS (ES+): m/z [M + H+] calcd for C16H20NO2S: 290.1215; found:
MS (ES+): m/z (%) = 308 (100, [M+ + 1]), 309 (20).
HRMS (ES+): m/z [M + H+] calcd for C16H19FNO2S: 308.1121; found:
308.1119.
1-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}-4-
methylbenzene (16e)
The general procedure was followed (Conditions B) using 4-bromo-
toluene (10e; 43 mg); reaction time: 4 h; white solid (41 mg, 54%);
mp 81–83 °C; Rf = 0.45 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 8.9 Hz, 2 H), 7.22–7.27 (m, 2
H), 7.16–7.21 (m, 2 H), 6.83–6.88 (m, 2 H), 4.21–4.32 (m, 4 H), 3.79 (s,
3 H), 2.69 (s, 3 H), 2.36 (s, 3 H).
290.1215.
13C NMR (101 MHz, CDCl3): δ = 158.6, 138.9, 133.8, 130.7, 129.8,
129.0, 126.8, 113.9, 61.0, 55.4, 46.6, 39.1, 21.4.
1-Fluoro-4-{[N-(4-methoxybenzyl)-S-methylsulfonimidoyl]meth-
yl}benzene (16b)
MS (ES+): m/z (%) = 304 (100, [M+ + 1]), 121 (52), 305 (45), 306 (17).
The general procedure was followed (Conditions B) using 1-bromo-4-
fluorobenzene (10b; 27 μL); reaction time: 16 h; white solid (53 mg,
69%); mp 74–76 °C; Rf = 0.40 (EtOAc).
HRMS (ES+): m/z [M + H+] calcd for C17H22NO2S: 304.1371; found:
304.1373.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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J. A. Sirvent et al.
Paper
Synthesis
1-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}-3-
1-Chloro-3-{[N-(4-methoxybenzyl)-S-methylsulfonimidoyl]meth-
methylbenzene (16f)
yl}benzene (16j)
The general procedure was followed (Conditions C) using 3-bromo-
toluene (10f; 30 μL); reaction time: 3 h; white solid (51 mg, 67%); mp
63–65 °C; Rf = 0.45 (EtOAc).
The general procedure was followed (Conditions B) using 1-bromo-3-
chlorobenzene (10j; 29 μL); reaction time: 10 h; white solid (50 mg,
62%); mp 68–70 °C; Rf = 0.43 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.23–7.33 (m, 3 H), 7.13–7.20 (m, 3 H),
6.83–6.89 (m, 2 H), 4.23–4.32 (m, 4 H), 3.79 (s, 3 H), 2.71 (s, 3 H), 2.35
(s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.23–7.38 (m, 6 H), 6.83–6.89 (m, 2 H),
4.24–4.31 (m, 2 H), 4.17–4.24 (m, 2 H), 3.79 (s, 3 H), 2.74 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.6, 134.9, 133.5, 131.8, 130.8,
130.3, 129.1, 129.0, 128.9, 114.0, 60.7, 55.4, 46.6, 39.6.
13C NMR (101 MHz, CDCl3): δ = 158.6, 138.9, 133.8, 131.5, 129.8,
129.6, 129.0, 128.9, 127.8, 113.9, 61.2, 55.4, 46.6, 39.3, 21.5.
MS (ES+): m/z (%) = 304 (100, [M+ + 1]), 305 (36), 306 (11).
HRMS (ES+): m/z [M + H+] calcd for C17H22NO2S: 304.1371; found:
MS (ES+): m/z (%) = 324 (100, [M+ + 1]), 326 (49), 325 (25), 121 (21).
HRMS (ES+): m/z [M + H+] calcd for C16H19ClNO2S: 324.0825; found:
324.0821.
304.1371.
3-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}benzo-
1-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}-2-
nitrile (16k)
methylbenzene (16g)
The general procedure was followed (Conditions B) using 3-bromo-
benzonitrile (10k; 46 mg); reaction time: 24 h; white solid (30 mg,
38%); mp 104–106 °C; Rf = 0.33 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.64–7.68 (m, 1 H), 7.57–7.63 (m, 2 H),
7.46–7.53 (m, 1 H), 7.27 (d, J = 8.1 Hz, 2 H), 6.82–6.90 (m, 2 H), 4.18–
4.33 (m, 4 H), 3.79 (s, 3 H), 2.75 (s, 3 H).
The general procedure was followed (Conditions D) using 2-bromo-
toluene (10g; 30 μL); reaction time: 24 h; white solid (6 mg, 8%); mp
70–73 °C; Rf = 0.42 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.17–7.38 (m, 6 H), 6.84–6.88 (m, 2 H),
4.41 (d, J = 13.9 Hz, 1 H), 4.23–4.32 (m, 3 H), 3.79 (s, 3 H), 2.75 (s, 3 H),
2.45 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.7, 135.1, 134.2, 133.3, 132.4,
131.5, 129.8, 128.9, 118.2, 114.0, 113.3, 60.6, 55.4, 46.5, 39.9.
13C NMR (101 MHz, CDCl3): δ = 158.6, 138.2, 133.9, 131.8, 131.2,
129.1, 128.9, 128.2, 126.5, 113.9, 59.0, 55.4, 46.6, 39.5, 20.2.
MS (ES+): m/z (%) = 304 (100, [M+ + 1]), 305 (26), 121 (9).
MS (ES+): m/z (%) = 315 (100, [M+ + 1]), 121 (93), 316 (42), 317 (16),
290 (14), 122 (11).
HRMS (ES+): m/z [M + H+] calcd for C17H22NO2S: 304.1371; found:
HRMS (ES+): m/z [M + H+] calcd for C17H19N2O2S: 315.1167; found:
304.1371.
315.1163.
1-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}-3,5-di-
1-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}-4-(tri-
methylbenzene (16h)
fluoromethyl)benzene (16l)
The general procedure was followed (Conditions C) using 5-bromo-
m-xylene (10h; 34 μL); reaction time: 5 h; colorless oil (58 mg, 73%);
Rf = 0.48 (EtOAc).
The general procedure was followed (Conditions B) using 4-bromo-
benzotrifluoride (10l; 35 μL); reaction time: 6 h; white solid (33 mg,
37%); mp 83–85 °C; Rf = 0.44 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 8.6 Hz, 2 H), 6.92–7.02 (m, 3
H), 6.86 (d, J = 8.6 Hz, 2 H), 4.16–4.34 (m, 4 H), 3.79 (s, 3 H), 2.71 (s, 3
H), 2.30 (s, 2 × 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.1 Hz, 2 H), 7.49 (d, J = 8.1
Hz, 2 H), 7.24–7.32 (m, 2 H), 6.82–6.89 (m, 2 H), 4.21–4.37 (m, 4 H),
3.79 (s, 3 H), 2.74 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.5, 138.6, 133.8, 130.5, 129.6,
128.9, 128.5, 113.9, 61.0, 55.4, 46.5, 39.2, 21.3.
MS (ES+): m/z (%) = 318 (100, [M+ + 1]), 320 (29), 294 (23), 293 (20).
HRMS (ES+): m/z [M + H+] calcd for C18H24NO2S: 318.1522; found:
13C NMR (101 MHz, CDCl3): δ = 158.7, 133.9 (d, J = 1.3 Hz), 133.4,
131.1, 131.1 (q, J = 32.6 Hz), 128.9, 125.9 (q, J = 3.5 Hz), 124.0 (q,
J = 272.1 Hz), 113.9, 60.8, 55.4, 46.5, 39.7.
MS (ES+): m/z (%) = 358 (100, [M+ + 1]), 121 (23), 359 (23).
HRMS (ES+): m/z [M + H+] calcd for C17H19F3NO2S: 358.1089; found:
318.1527.
358.1084.
1-Methoxy-3-{[N-(4-methoxybenzyl)-S-methylsulfonimi-
doyl]methyl}benzene (16i)
1-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}-3-
vinylbenzene (16m)
The general procedure was followed (Conditions B) using 3-bromoan-
isole (10i; 32 μL); reaction time: 5 h; colorless oil (39 mg, 49%); Rf =
0.45 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.26–7.33 (m, 3 H), 6.88–6.96 (m, 3 H),
The general procedure was followed (Conditions B) using 3-bromo-
styrene (10m; 33 μL); reaction time: 12 h; white solid (31 mg, 39%);
mp 56–58 °C; Rf = 0.41 (EtOAc).
6.83–6.88 (m, 2 H), 4.21–4.35 (m, 4 H), 3.79 (s, 2 × 3 H), 2.72 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.0, 158.6, 133.7, 131.3, 130.0,
129.0, 123.0, 116.2, 114.5, 113.9, 61.2, 55.4 (2 ×), 46.6, 39.3.
MS (ES+): m/z (%) = 320 (100, [M+ + 1]), 321 (46), 322 (16).
HRMS (ES+): m/z [M + H+] calcd for C17H22NO3S: 320.1320; found:
320.1317.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.44 (m, 2 H), 7.34 (t, J = 7.6 Hz, 1
H), 7.28–7.32 (m, 2 H), 7.23–7.28 (m, 1 H), 6.83–6.88 (m, 2 H), 6.69
(dd, J = 17.7, 10.9 Hz, 1 H), 5.76 (d, J = 17.7 Hz, 1 H), 5.29 (d, J = 10.9
Hz, 1 H), 4.23–4.33 (m, 4 H), 3.79 (s, 3 H), 2.72 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.6, 138.4, 136.2, 133.7, 130.2,
130.0, 129.2, 128.9, 128.7, 126.6, 115.0, 113.9, 61.1, 55.4, 46.5, 39.3.
MS (ES+): m/z (%) = 316 (100, [M+ + 1]), 317 (24).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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J. A. Sirvent et al.
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HRMS (ES+): m/z [M + H+] calcd for C18H22NO2S: 316.1371; found:
316.1368.
[(S-Methylsulfonimidoyl)methyl]benzene (17a);29 Typical Proce-
dure for the Deprotection of N-(4-Methoxybenzyl)-Protected Sulf-
oximines 16
3-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}pyri-
dine (16n)
CAN (1.1 g, 2 mmol) was added to a solution of 16a (289 mg, 1 mmol)
in MeCN/H2O (3:1, 4 mL). The resulting yellow solution was stirred at
r.t. for 15 min. Then, sat. aq NaHCO3 (5 mL) was added and the mix-
ture was extracted with EtOAc (4 × 15 mL). The combined organic
phases were dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude was purified by flash chromatography (Cartridge:
KP-Sil 10 g; eluent: EtOAc/EtOH, 0 → 100% EtOH) to afford 17a (135
mg, 80%) as a white solid; mp 80–84 °C; Rf = 0.10 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.46 (m, 5 H), 4.39 (d, J = 12.9 Hz,
1 H), 4.25 (d, J = 13.7 Hz, 1 H), 2.92 (s, 3 H), 2.60 (br s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 130.9, 129.2, 129.1, 128.6, 64.1, 41.5.
MS (ES+): m/z (%) = 170 (100, [M+ + 1]), 106 (13), 171 (10).
The general procedure was followed (Conditions B) using 3-bromopy-
ridine (10n; 24 μL); reaction time: 4 h; colorless oil (32 mg, 44%); Rf =
0.50 (CH2Cl2/MeOH, 90:10).
1H NMR (400 MHz, CDCl3): δ = 8.61 (dd, J = 4.8, 1.3 Hz, 1 H), 8.57 (d,
J = 1.5 Hz, 1 H), 7.74 (d, J = 7.9 Hz, 1 H), 7.32 (dd, J = 7.9, 4.8 Hz, 1 H),
7.24–7.29 (m, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 4.19–4.31 (m, 4 H), 3.78 (s,
3 H), 2.74 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.6, 151.3, 150.1, 138.2, 133.4,
128.9, 126.1, 123.8, 114.0, 58.5, 55.4, 46.5, 39.6.
MS (ES+): m/z (%) = 291 (100, [M+ + 1]), 121 (60), 171 (42), 292 (33),
293 (12).
HRMS (ES+): m/z [M + H+] calcd for C8H12NOS: 170.0640; found:
HRMS (ES+): m/z [M + H+] calcd for C15H19N2O2S: 291.1167; found:
170.0638.
291.1168.
Synthesis of BAY 1143572
3-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}quino-
line (16o)
3-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}aniline
(16q)
The general procedure was followed (Conditions B) using 3-bromo-
quinoline (10o; 34 μL), reaction time: 5 h; yellow oil (41 mg, 48%);
Rf = 0.31 (CH2Cl2/MeOH, 95:5).
A stirred suspension containing N-(4-methoxybenzyl)-S,S-dimethyl-
sulfoximine (15a; 3.84 g, 18 mmol), XantPhos Pd G3 (186 mg, 0.18
mmol), Xantphos (104 mg, 0.18 mmol), LiOt-Bu (1.44 g, 18 mmol),
4,4′-di-tert-butylbiphenyl as an internal standard (267 mg, 1.0
mmol), and 3-bromo-N-[(E)-phenylmethylidene]aniline (10q; 1.56 g,
6 mmol) in anhyd CPME (24 mL) was heated at 110 °C for 3 h in a 100
mL round-bottom flask equipped with a reflux condenser. Then, the
reaction mixture was cooled to r.t., hydrolyzed with brine (30 mL),
and extracted with EtOAc (2 × 60 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The crude was dissolved in EtOAc (30 mL), HCl (0.5 M, 24 mL)
was added, and the biphasic mixture was vigorously stirred for 45
min. The aqueous phase was separated, basified with sat. aq NaHCO3,
and then extracted with EtOAc (2 × 20 mL). These new organic ex-
tracts were combined, dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. Purification of the crude by column chromatog-
raphy (Cartridge: KP-NH 55 g; eluent: EtOAc) afforded 16q (840 mg,
46%) as a colorless oil; Rf = 0.19 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.88 (d, J = 2.3 Hz, 1 H), 8.08–8.17 (m, 2
H), 7.79 (d, J = 8.1 Hz, 1 H), 7.75 (ddd, J = 8.4, 7.0, 1.5 Hz, 1 H), 7.55–
7.62 (m, 1 H), 7.24–7.32 (m, 2 H), 6.80–6.88 (m, 2 H), 4.46 (d, J = 13.7
Hz, 1 H), 4.40 (d, J = 13.9 Hz, 1 H), 4.28 (s, 2 H), 3.78 (s, 3 H), 2.73–2.81
(m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.6, 151.7, 148.0, 138.1, 133.4,
130.4, 129.4, 128.9, 128.0, 127.7, 127.4, 123.0, 114.0, 58.7, 55.4, 46.6,
39.8.
MS (ES+): m/z (%) = 341 (100, [M+ + 1]), 221 (31), 121 (25), 342 (23),
158 (22).
HRMS (ES+): m/z [M + H+] calcd for C19H21N2O2S: 341.1318; found:
341.1290.
2-{[N-(4-Methoxybenzyl)-S-methylsulfonimidoyl]methyl}naph-
thalene (16p)
1H NMR (400 MHz, CDCl3): δ = 7.28–7.32 (m, 2 H), 7.10–7.14 (m, 1 H),
6.83–6.87 (m, 2 H), 6.71 (d, J = 7.4 Hz, 1 H), 6.63–6.69 (m, 2 H), 4.30
(d, J = 13.9 Hz, 1 H), 4.26 (d, J = 13.9 Hz, 1 H), 4.17 (s, 2 H), 3.77 (s, 3
H), 3.67 (br s, 2 H), 2.70 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.4, 147.1, 133.7, 130.7, 129.8,
128.9, 120.5, 117.0, 115.3, 113.8, 61.0, 55.3, 46.4, 39.1.
The general procedure was followed (Conditions C) using 2-bromo-
naphthalene (10p; 52 mg); reaction time: 6 h; white solid (34 mg,
54%); mp 94–96 °C; Rf = 0.40 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.78–7.89 (m, 4 H), 7.47–7.55 (m, 3 H),
7.32 (d, J = 8.6 Hz, 2 H), 6.82–6.90 (m, 2 H), 4.41–4.48 (m, 2 H), 4.28–
4.36 (m, 2 H), 3.79 (s, 3 H), 2.73 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.6, 133.7, 133.3, 133.2, 130.3,
129.0, 128.8, 128.0, 127.9, 127.9, 127.3, 126.8, 126.7, 113.9, 61.4, 55.4,
46.6, 39.3.
MS (ES+): m/z (%) = 305 (100, [M+ + 1]), 306 (28), 121 (11), 307 (10).
HRMS (ES+): m/z [M + H+] calcd for C16H21N2O2S: 305.1324; found:
305.1326.
MS (ES+): m/z (%) = 340 (100, [M+ + 1]), 121 (76), 341 (61), 141 (33),
342 (27), 680 (22), 276 (13).
4-Chloro-N-(3-{[N-(4-methoxybenzyl)-S-methylsulfonimi-
doyl]methyl}phenyl)-1,3,5-triazin-2-amine (21)
HRMS (ES+): m/z [M + H+] calcd for C20H22NO2S: 340.1371; found:
2,4-Dichloro-1,3,5-triazine (69 mg, 0.46 mmol) was dissolved in
THF/i-PrOH (1:1, 2 mL) and the solution was cooled to 0 °C. Then,
DIPEA (0.14 mL, 0.84 mmol) and a solution containing 16q (128 mg,
0.42 mmol) in THF/i-PrOH (1:1, 2 mL) were added sequentially. The
resulting solution was stirred at 0 °C for 30 min. Volatiles were re-
340.1371.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

K
J. A. Sirvent et al.
Paper
Synthesis
moved under reduced pressure and the crude was purified by column
chromatography (EtOAc) to give 21 (170 mg, 97%) as a colorless oil;
Rf = 0.27 (EtOAc).
HRMS (ES+): m/z [M + H+] calcd for C18H19FN5O2S: 388.1243; found:
388.1240.
1H NMR (400 MHz, CDCl3): δ = 8.48 (s, 1 H), 8.15 (br d, J = 22.8 Hz, 1
H), 7.58 (br d, J = 8.1 Hz, 1 H), 7.56 (s, 1 H), 7.30–7.40 (m, 1 H), 7.27 (d,
J = 8.6 Hz, 2 H), 7.14 (d, J = 7.6 Hz, 1 H), 6.79–6.86 (m, 2 H), 4.25–4.36
(m, 4 H), 3.77 (s, 3 H), 2.85 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 167.3, 163.9, 158.6, 137.3,
133.5, 130.8, 129.6, 128.9, 127.1, 123.4, 121.3, 113.9, 60.9, 55.4, 46.5,
39.5.
Acknowledgment
We thank Richard Menssen and René Loechtefeld for high-throughput
experimentation (screening) assistance and Kay Greenfield for valu-
able technical support with the manuscript.
MS (ES+): m/z (%) = 418 (100, [M+ + 1]), 420 (72).
HRMS (ES+): m/z [M + H+] calcd for C19H21ClN5O2S: 418.1104; found:
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588894.
418.1101.
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4-(4-Fluoro-2-methoxyphenyl)-N-(3-{[N-(4-methoxybenzyl)-S-
methylsulfonimidoyl]methyl}phenyl)-1,3,5-triazin-2-amine (22)
Primary Data
A mixture containing chloride 21 (167 mg, 0.40 mmol), 4-fluoro-2-
methoxyphenylboronic acid (102 mg, 0.6 mmol), Pd(PPh3)4 (23 mg,
0.02 mmol), and aq 2 M K2CO3 (0.4 mL) in DME (2 mL) was heated un-
der microwave irradiation (Biotage® Initiator Classic, 60 W, 85 °C) for
5 h. The resulting solution was poured into sat. aq NaHCO3 (10 mL)
and the mixture was extracted with EtOAc (2 × 20 mL). The combined
organic phases were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude was purified by column chromatography
(Cartridge: KP-Sil 10 g; eluent: CH2Cl2/MeOH, 95:5) to afford 22 (82
mg, 40%) as a colorless oil; Rf = 0.31 (CH2Cl2/MeOH, 95:5).
1H NMR (400 MHz, CDCl3): δ = 8.80 (s, 1 H), 7.93 (br s, 1 H), 7.65 (br s,
1 H), 7.60 (s, 1 H), 7.37 (t, J = 7.9 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 2 H), 7.11
(d, J = 7.4 Hz, 1 H), 6.81–6.88 (m, 2 H), 6.70–6.80 (m, 2 H), 4.23–4.33
(m, 4 H), 3.92 (s, 3 H), 3.77 (s, 3 H), 2.75 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 172.1, 166.4, 165.7 (d, J = 252.2 Hz),
163.6, 160.4, 158.6, 138.5, 133.6, 130.8, 129.7, 128.9, 126.2, 122.6,
122.1 (d, J = 3.4 Hz), 120.7, 113.9, 107.7 (d, J = 21.6 Hz), 100.3 (d,
J = 25.9 Hz), 61.1, 56.4, 55.4, 46.6, 39.5.
MS (ES+): m/z (%) = 508 (16, [M+ + 1]), 388 (100), 121 (38), 389 (24).
HRMS (ES+): m/z [M + H+] calcd for C26H27FN5O3S: 508.1819; found:
Primary data for this article are available online at http://www.thieme-
connect.com/products/ejournals/journal/10.1055/s-00000084 and can
be cited using the following DOI: 10.4125/pd0084th.
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References
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4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimi-
doyl)methyl]phenyl}-1,3,5-triazin-2-amine (BAY 1143572)15
CAN (206 mg, 0.375 mmol) was added to a solution of 22 (76 mg, 0.15
mmol) in MeCN/H2O (3:1, 4 mL) and the mixture was stirred at r.t. for
1 h. Then, sat. aq NaHCO3 (5 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 15 mL). The combined organic phases were
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude was purified by column chromatography (Cartridge: KP-Sil
10 g; eluent: CH2Cl2/MeOH, 95:5) to afford BAY 1143572 (55 mg, 95%)
as a white solid; mp 166–168 °C; Rf = 0.27 (CH2Cl2/MeOH, 95:5).
1H NMR (400 MHz, CDCl3): δ = 8.79 (br s, 1 H), 7.51–8.19 (m, 4 H),
7.38 (t, J = 7.9 Hz, 1 H), 7.13 (br d, J = 7.5 Hz, 1 H), 6.67–6.79 (m, 2 H),
4.39 (br d, J = 12.8 Hz, 1 H), 4.25 (br d, J = 13.2 Hz, 1 H), 3.91 (br s, 3 H),
2.97 (s, 3 H), 2.82 (s, 1 H).
(5) Lücking, U. Angew. Chem. Int. Ed. 2013, 52, 9399.
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(7) See, for example: (a) Okamura, H.; Bolm, C. Org. Lett. 2004, 6,
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13C NMR (101 MHz, CDCl3): δ = 172.1, 166.4, 165.7 (d, J = 251.1 Hz),
163.7, 160.4, 138.6, 133.9, 129.7, 129.4, 126.3, 122.7, 122.1 (d, J = 3.2
Hz), 121.1, 107.7 (d, J = 21.6 Hz), 100.3 (d, J = 26.1 Hz), 64.1, 56.4,
41.7.
MS (ES+): m/z (%) = 388 (10, [M+ + 1]), 195 (100).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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J. A. Sirvent et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M