N-Arylated Sulfoximines as Cross-Coupling Building Blocks

Article abstract of DOI:10.1002/adsc.201701394

The application of borylated N-aryl sulfoximines as newly designed synthetic building blocks in Suzuki-type cross coupling reactions offers rapid access to a wide range of N-biaryl derivatives with potential relevance for medicinal chemistry and crop protection in good to excellent yields (up to 98%). (Figure presented.).

Full text of DOI:10.1002/adsc.201701394

Title: N-Arylated Sulfoximines as Cross-Coupling Building Blocks
Authors: Anne-Katrin Bachon, Anne-Dorothee Steinkamp, and Carsten
Bolm
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701394
Link to VoR: http://dx.doi.org/10.1002/adsc.201701394

10.1002/adsc.201701394
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
N-Arylated Sulfoximines as Cross-Coupling Building Blocks
Anne-Katrin Bachon,a, Anne-Dorothee Steinkamp,a and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany; Fax: (+49) 241
809 2391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Me
Abstract. The application of borylated N-aryl sulfoximines
N
as newly designed synthetic building blocks in Suzuki-type
O
O
cross coupling reactions offers rapid access to a wide range
of N-biaryl derivatives with potential relevance for
medicinal chemistry and crop protection in good to
excellent yields (up to 98%).
B
Me
biaryl
biaryl
Me
S
Me
S
O
O
S
O
NH
O
O
O
NC(O)CF3
1
methyl sulfone
replacement
(previously reported)
Me
N
Keywords: building block; MIDA boronate; Miyaura
borylation; sulfoximine; Suzuki cross-coupling
O
O
O
O
O
R
R
O
B
R
S
biaryl
S
biaryl
S
O
O
R’
N
N
H
R’
N
2
sulfone amide
replacement
(described here)
In 2011 Roughley and Jordan reported the results of
"An Analysis of Reactions Used in the Pursuit of
Drug Candidates", and they found that the Suzuki
cross-coupling reaction accounted for 40% of all C–C
bond forming reactions, thereby being the single most
often applied transformation within this category.[1,2]
As highlighted by others, Suzuki's method - in
conjunction with other metal-catalyzed sp2-sp2
couplings - has become so powerful that the number
of published "flatland"[3] molecules with relevance for
medicinal chemistry has consistently increased during
the past decades.[4] In addition to chemical advances,
technological progress has also contributed to this
development because many of such cross-coupling
reactions are amenable to automated parallel
synthesis[5] and continuous flow.[6] In all of those
processes, "ready-to-couple" molecular building
blocks play a central role because they provide rapid
access to a large number of derivatives in a most
efficient manner. A particularly elegant study along
these lines was reported by Burke and co-workers,[7]
who demonstrated the use of N-methyliminodiacetic
acid (MIDA) boronates[8] for the automated synthesis
of a large variety of structurally diverse organic small
molecules. The high synthetic value of such MIDA
boronates and their advantage compared to other
boronate esters is a result of their high chemical
stability and chemoselectivity[8g], which allow for
both an extensive modification of MIDA boronates
while leaving the boron-containing site intact as well
as boron-selective transformations of polyboron
compounds.[8a,9]
Figure 1. MIDA boronates with sulfoximidoyl
substituents.
containing MIDA boronates 1 and demonstrated their
cross-coupling potential for providing biaryl
sulfoximines with free NH groups.[10-12] The latter
products were regarded as analogs of methyl
sulfones. Noting the importance of compounds with
N-bound polar substituents, we identified MIDA
boronates 2 as interesting building blocks.[12] Cross-
couplings of such molecules would allow accessing
compounds with N-sulfoximidoyl groups, which
could prove useful as sulfone amide replacements.[14-
16]
Considering the pronounced functional group
tolerance in Suzuki cross-couplings with MIDA
boronates,[17] a late-stage functionalization[18] of
promising drug candidates could be envisaged with
compounds of type 2. Our approach towards a range
of such building blocks and a summary of their cross-
coupling behavior is presented here.
As first specific target, MIDA boronate 2a
having a para-connected N-bound S-methyl S-phenyl
sulfoximidoyl unit was selected. Initial attempts to
use standard N-arylation protocols[16] starting from
halo-substituted analogs 3 and NH-sulfoximine 4a
failed [Scheme 1, (a)]. Neither palladium nor copper
or iron catalysis proved effective. Also the second
approach, trying to use bisboronic acid ester 5 in
combination with 4a under Chan-Lam coupling
conditions[16e,19] remained unsuccessful [Scheme 1,
(b)]. Finally, an N-arylation/Miyaura borylation
strategy proved applicable [Scheme 1, (c)]. It
In the context of our research program on sulfur
chemistry we recently introduced sulfoximidoyl-
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701394
Advanced Synthesis & Catalysis
proceeded via N-aryl sulfoximine 6a and involved
two sequential metal-catalyzed cross-coupling
reactions starting from NH-sulfoximine 4a and 4-
bromophenyl boronic acid (7a) (for details, see
below).[20]
acid (7b) and 2-bromophenyl boronic acid (7c) gave
6g and 6h in 93% and 66% yield, respectively.
Next, borylations of aryl bromides 6 were
studied. Readily available 6a was used as
representative substrate. Under the classical Miyaura
conditions with B2Pin2 as borylating agent and a
palladium catalyst,[21] 8a was obtained in 70% yield
(Scheme 3).
Me
O
N
O
O
B
O
(a)
Me
Pd(dppf)Cl2 (5.0 mol %)
KOAc (3.0 equiv.)
B2Pin2 (1.5 equiv.)
O
N
Br
BPin
O
O
O
O
X
3 (X = Br, I)
Me
Me
B
O
S
O
S
S
O
S
Me
Ph
N
N
DMSO, 90 °C, 22 h
Me
Ph
H
Ph
Ph
N
70%
N
6a
8a
4a
2a
Me
O
N
O
O
(b)
Scheme 3. Palladium-catalyzed borylation of 6a with
B2Pin2.
(c)
B
O
O
Me
Me
Br
B
O
S
An apparently rapid product degradation and the
fact that the conversion of 8a into 2a required
additional deprotection/protection steps, stimulated
the search for alternative pathways. Molander's
method with tetrahydroxydiboron [B2(OH)4] as
borylating agent appeared particularly attractive
because it directly led to boronic acids, which could
further be converted to boronates and related products
by reactions with diacids and diols (Table 1).[22]
Already the first attempts were successful. Under
nickel catalysis and with N-methylimidodiacetic acid
(10, MIDA) as capping agent in the second step, 6a
reacted via boronic acid 9a to give 2a in 86% yield
(Table 1, entry 1). Lowering the originally used 5
mol % of NiCl2(dppp) (combined with 10 mol % of
PPh3) to 1 mol % of catalyst (with 3 mol % of PPh3)
led to incomplete conversion of 6a, even after
extending the initial reaction time of 3 h to 9 h (Table
1, entry 2). A screening of various palladium
catalysts (Table 1, entries 3-8) showed that a
combination of Pd(dppf)Cl2 and XPhos was optimal
in terms of catalyst performance and efficiency. Thus,
with only 1 mol % of palladium and 3 mol % of
ligand, MIDA boronate 2a was obtained with high
purity in 80% yield (Table 1, entry 7).[23] Reacting in-
situ formed 9a with pinacol (11) and neopentyl glycol
(12) afforded the respective boron reagents in yields
of 75% and 78%, respectively (Table 1, entries 9 and
10). In particular the former product proved difficult
to purify. The attempt to directly prepare the
respective BF3K salt of 9a was unsuccessful (Table 1,
entry 11).
Me
Ph
O
Me
N
Me
6a
5
Scheme 1. Strategies for synthesizing MIDA
boronate 2a.
After having established a reaction path towards
MIDA boronate 2a, each synthetic step was
reevaluated and generalized by applying substrate
variants. First, N-arylations of NH-sulfoximines with
bromophenyl boronic acids (7) were investigated
(Scheme 2). Under copper catalysis [with 10 mol %
of Cu(OAc)2], the cross coupling of sulfoximine 4a
and 7a provided 6a in 90% yield. Also S,S-dimethyl
sulfoximine (4b) and 7a reacted well, leading to 6b in
94% yield. The analogous coupling of S,S-diphenyl
sulfoximine (4c) with 7a proved challenging, and
even with 20 mol % of Cu(OAc)2 and after extending
the original 24 h reaction time to 48 h, product 6c
was obtained in only 26% yield. Substituted S-alkyl
S-aryl sulfoximines afforded the corresponding N-
arylated products 6d-f in yields ranging from 42% to
77%. Couplings of 4a with 3-bromophenyl boronic
Cu(OAc)2
(10 mol %)
O
NH
O
R1
Br
+
Br
S
S
MeOH (0.3 M)
r.t., 24 h
R1
R2
(HO)2B
7 (2.3 equiv.)
N
R2
4
6
Br
O
O
R1
R1
S
S
N
N
Br
R2
R2
Having established the optimal conditions for
the conversion of 6a into 2a (Table 1, entry 7), the
substrate scope with respect to the substituents on
sulfur and the position of the bromo group on the
arene was examined. In general, the transformations
were smooth, and the corresponding MIDA boronates
2 were obtained in good yields (Scheme 4). The only
exception was the reaction sequence starting from
S,S-dimethyl sulfoximine 6b, which appeared to be
hampered by the instability of the respective boronic
acid under the conditions of the second step.
Consequently, pinacol (12) was used instead of
1 = Me, R2 = Ph, 90%
1 = R2 = Me, 94%
6g: R1 = Me, R2 = Ph, 93%
6a:
R
R
R
R
R
6b:
6c:
6d:
6e:
6f:
1 = R2 = Ph, 26%*
O
1 = CF3, R2 = Ph, 42%*
1 = cyclopropyl, R2 = Ph, 77%
R1
S
N
R1 = Me, R2 = 4-CF3-Ph, 76%
R1 = Me, R2 = pyridin-2-yl, 66%*
R1 = Me, R2 = thiophen-2-yl, 79%*
R2
Br
6i:
6j:
6h: R1 = Me, R2 = Ph, 66%
* use of 20 mol % of Cu(OAc)2;
reaction time of 48 h.
Scheme 2. Copper-catalyzed N-arylations of NH-
sulfoximines 4 with bromophenyl boronic acids 7a-c.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701394
Advanced Synthesis & Catalysis
Table 1. Optimization of the conversion of 6a into 2a via boronic acid 9a.
OH
O
B
Br
B
[M], ligand, base
B2(OH)4 (1.7 equiv.)
capping
agent
OH
O
O
O
O
Me
Me
Me
S
S
S
N
N
N
EtOH
Ph
Ph
Ph
6a
9a
2a (and analogs)
Me
Me
Me Me
Me
Me
HO2C
N
CO2H
HO
OH
Me
HO
OH
MIDA (10)
Nep (11)
Pin (12)
Entry
[M] (mol %)
Ligand (mol %)
Base (equiv.)
T [°C]
t [h] Caping
Yield [%]
86
agent
1
2
3
4
5
6
7
8
NiCl2(dppp) (5.0)
NiCl2(dppp) (1.0)
Pd(OAc)2 (5.0)
Pd2(dba)3 (2.5)
Pd(OAc)2 (2.5)
Pd(dppf)Cl2 (2.5)
Pd(dppf)Cl2 (1.0)
Pd2(dba)3 (0.5)
Pd(dppf)Cl2 (1.0)
Pd(dppf)Cl2 (1.0)
Pd(dppf)Cl2 (1.0)
PPh3 (10)
PPh3 (3.0)
DIPEA (3.0)
DIPEA (3.0)
KOAc (3.0)
KOAc (3.0)
KOAc (3.0)
KOAc (3.0)
KOAc (3.0)
KOAc (3.0)
KOAc (3.0)
KOAc (3.0)
KOAc (3.0)
50
50
80
80
80
80
80
80
80
80
80
3
9
MIDA[a]
MIDA[a]
MIDA[a]
MIDA[a]
MIDA[a]
MIDA[a]
[b]
-
XPhos (15)
XPhos (15)
XPhos (7.5)
XPhos (7.5)
XPhos (3.0)
XPhos (3.0)
XPhos (3.0)
XPhos (3.0)
XPhos (3.0)
16
14
18
18
18
18
18
18
18
89
83
[b]
-
64
MIDA[a] 80
MIDA[a]
Nep[c,d]
Pin[c,f]
-
[b]
9
75[e]
78
10
11
[g]
[e]
KHF2
-
[a] Reaction conditions: MIDA (1.5 equiv.), DMSO, toluene, dean-stark trap, 135 °C, 8 h.
[b] Incomplete conversion.
[c] Reaction conditions: Diol (2.0 equiv.), DCM, r.t.
[d] Nep = neopentyl glycol (11).
[e] Difficult purification.
[f] Pin = pinacol (12).
[g] Reaction conditions: KHF2 (3.5 equiv., 4.5 M in H2O), MeOH, 0 °C.
Me
catalyst system consisted of Pd(OAc)2 (5 mol %),
XPhos (10 mol %), K2CO3 (5 equiv. as degassed 2 M
aq. solution), and 1,4-dioxane, which was kept at 60
°C for 24 h. In general, the yields of the resulting
arylated products 14 were high (>90%). Neither steric
nor electronic effects were noticable. 2-Bromothio-
phene (13o), 7-bromoindole (13p), and 2-bromo-
pyridine (13q) were chosen as representative
heteroaryl bromides. Whereas in couplings with 2a
the first two compounds provided the corresponding
products in high yields (14ao: 92% and 14ap: 84%),
the latter afforded 14ap in only 25% yield.
Concomitant, the last reaction led to significant
amounts of protodeboronated 2a, which presumably
resulted from an interference of the coupling by
coordination of the pyridine nitrogen to the metal
catalyst.[8c]
N
O
O
R1
Br
R1
B
S
S
O
conditions, see:
Table 1, entry 7
N
N
O
O
R2
R2
O
2a, 2c-j or 8b
6a-j
BMIDA
O
O
O
R1
Me
Me
S
N
S
S
N
BMIDA
N
R2
Ph
Ph
BMIDA
2g, 83%
1
R = Me, R2 = Ph, 80%
2h, 63%
BPin
2a:
2c:
2d:
2e:
2f:
R
R
R
1 = R2 = Ph, 70%
1 = CF3, R2 = Ph, 70%
O
1 = cyclopropyl, R2 = Ph, 78%
Me
S
R1 = Me, R2 = 4-CF3-Ph, 66%
R1 = Me, R2 = pyridin-2-yl, 59%
N
Me
2i:
2j:
8b, 60%
R1 = Me, R2 = thiophen-2-yl, 76%
For 8b: Use of 1.5 equiv. of 12 (instead of MIDA) in DCM at r.t. overnight
Scheme 4. Conversions of N-aryl sulfoximines 6 into
MIDA boronates
2
by palladium-catalyzed
borylations with B2(OH)4 and subsequent ligand
exchange with MIDA [or pinacol (12) for 8b].
MIDA providing aryl boronic acid pinacol ester 8b in
60% yield.[13]
The cross-coupling potential of MIDA boronates
2 was investigated next.[17] Scheme 5 summarizes the
results obtained by combining 2a, 2g, and 2h with a
series of aryl bromides 13 on a 0.2 mmol scale. The
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701394
Advanced Synthesis & Catalysis
Me
O
B
ArBr (13)
Pd(OAc)2, XPhos
K2CO3 (2 M, aq.)
PhBr (13a)
Pd(OAc)2, XPhos
K2CO3 (2 M, aq.)
N
Ph
Ph
O
O
O
O
O
Me
Me
B
Ar
R1
R1
S
S
O
S
S
N
N
O
O
1,4-dioxane, 60 °C
N
N
Ph
Ph
R2
1,4-dioxane, 60 °C
R2
O
14
2a, 2g, 2h
2c-f, 2i, 2j, 8b
14
14aa: p-Ph, 96%
14ga: m-Ph, 99%
14ha: o-Ph, 82%
O
Ph
Ph
Me
Ph
R
O
O
O
S
Ph
F3C
N
S
O
S
S
Ph
Me
N
N
N
Ph
S
Ph
Ph
N
14ca, 98%
14da, 80%
14ea, 89%
Me
Me
Ph
14ab: R = p-OMe, 94%
14ac: R = m-OMe, 96%
Ph
O
Ph
Me
O
Me
14ad:
S
R = o-OMe, 92%
O
S
Me
Me
N
14ae: R = p-Me, 96%
14af: R = m-Me, 97%
14ag: R = o-Me, 93%
N
S
Ph
N
Me
14an, >98%
14ia, 83%
(from 8b and 13a at 80 °C)
S
14ah:
R = p-Ph, 94%
14ai: R = p-NO2, >98%
14aj: R = p-F, 86%
14ak: R = p-2-naphthyl, 98%
14al: R = p-SMe, 95%
14am:R = p-COMe, 96%
F3C
14fa, >98%
O
R
Ph
Me
O
O
S
S
Me
N
Me
N
S
S
Ph
N
N
14ao, 92%
S
14ja (R = Ph), 46% (calc.)
[as 52:48 mixture with
protodeboronation product 15 (R = H)]
14ka, 93%
O
N
O
Me
Ph
Me
HN
S
N
N
Ph
14ap, 84%
14aq, 25%
Scheme 6. Cross couplings of MIDA boronates 2c-f,
2i, 2j and boronic acid pinacol ester 8b with phenyl
bromide (13a).
Scheme 5. Cross couplings of MIDA boronates 2a,
2g, and 2h with aryl bromides 13.
In summary, we prepared shelf-stable MIDA
boronates with N-bound sulfoximidoyl groups, which
can be applied as building blocks in Suzuki-type
cross-coupling reactions.[24] We envisage their use in
automated parallel synthesis and continuous flow
leading to libraries of molecules for high-throughput
screenings.
Next, MIDA boronates 2c-f, 2i and 2j were
applied in Suzuki cross-couplings with boronic acid
pinacol ester 8b aiming to evaluate the effect of the
S-substituents on the catalyst efficiency (Scheme 6).
Phenyl bromide (13a) was selected as representative
coupling partner, and the catalyst system was kept
identical to the one utilized before (Scheme 5). Also
with those boron reagents the transformations
proceeded well affording the corresponding products
in high yields. Compared to the reactivity of the
MIDA boronates, pinacol ester 8b was less reactive
as indicated by the reaction temperature, which
needed to be raised from 60 °C to 80 °C for achieving
reactivity. Then, however, the yield of the resulting
product (14ia) was high (83%) as well. Pyridyl-
containing MIDA boronate 2i did not react under the
standard conditions. However, by applying a protocol
of Burke for the coupling of pyridyl-containing
MIDA boronates,[8c] product 14ja was obtained,
albeit only in an amount corresponding to a 46%
yield as calculated from the 52:48 mixture with the
protodeboronation product N-phenyl-S-methyl-S-
(pyridin-2-yl)sulfoximine (15).
Experimental Section
General method for the synthesis of MIDA boronates 2
N-(Bromophenyl)sulfoximine 6 (1.00 mmol), Pd(dppf)Cl2
(7.32 mg, 0.01 mmol, 1.0 mol %), XPhos (14.3 mg, 0.03
mmol, 3.0 mol %), B2(OH)4 (152.00 mg, 1.70 mmol, 1.7
equiv.) and KOAc (294.00 mg, 3.00 mmol, 3.0 equiv.)
were placed in a dry Schlenk tube equipped with a
magnetic stirring bar and dissolved in absolute EtOH
(6.6 mL). The reaction mixture was purged with argon for
10 min. before the tube was sealed and heated at 80 °C for
18 h. After this time, full conversion of the starting
material was observed (as monitored by TLC). The
reaction mixture was cooled to r.t., filtered over a plug of
celite (eluting with 100 mL of EtOAc), and the filtrate was
evaporated under reduced pressure. The residues were
suspended in EtOAc (25 mL) and 1 M aqueous HCl
(25 mL). The organic layer was separated and washed with
brine. The aqueous layers were extracted with EtOAc (3 x
25 mL each). The combined organic extracts were dried
over Na2SO4, and the solvent was removed under reduced
pressure. The resulting boronic acid 9 was suspended in
toluene (42 mL) and DMSO (8.4 mL) and MIDA (10, 221
mg, 1.50 mmol, 1.5 equiv.) was added. The resulting
mixture was fitted to a dean-stark trap and refluxed at
135 °C for 8 h. Removal of the solvents under reduced
pressure afforded MIDA boronate 2, which was purified by
FCC.
General Method for the synthesis of N-arylated
sulfoximines 14
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701394
Advanced Synthesis & Catalysis
In a Schlenk tube equipped with a magnetic stirring bar
boronate 2 (0.220 mmol, 1.1 equiv.), Pd(OAc)2 (2.25 mg,
10.0 mol, 5.0 mol %) XPhos (9.53 mg, 20.0 μmol,
Lücking, Angew. Chem., Int. Ed. 2013, 52, 9399–9408;
b) M. Frings, C. Bolm, A. Blum, C. Gnamm, Eur. J.
Med. Chem. 2017, 126, 225–245; c) J. A. Bull, L.
Degennaro, R. Luisi, Synlett online, DOI: 10.1055/s-
0036-1590874; d) K. E. Arndt, D. C. Bland, N. M.
Irvine, S. L. Powers, T. P. Martin, J. R. McConnell, D.
E. Podhorez, J. M. Renga, R. Ross, G. A. Roth, B. D.
Scherzer, T. W. Toyzan, Org. Process Res. Dev. 2015,
19, 454–462 and references therein.
10 mol %) and the
- if solid - aryl bromide 13
(0.200 mmol) were suspended in 1,4-dioxane (2.4 mL). (A
liquid aryl bromide 13 was added by using a syringe after
the tube was sealed.) The tube was placed under argon and
sealed with a rubber septum. The mixture was stirred at r.t.
for 10 min., and then a 2 M aqueous degassed K2CO3
solution (0.500 mL, 1.00 mmol, 5.0 equiv.) was added by
syringe, and the mixture was heated at 60 °C for 24 h.
After cooling to r.t., the solvents were removed under
reduced pressure and the residue was directly subjected to
purification by FCC affording N-arylated sulfoximine 14.
[12] For a review on sulfur imidations providing NH- and
N-functionalized sulfoximines, see: V. Bizet, C. M. M.
Hendriks, C. Bolm, Chem. Soc. Rev. 2015, 44, 3378–
3390.
Acknowledgements
[13] In the recent patent literature, palladium-catalyzed
cross-couplings with 4,4,5,5-tetramethyl-2-aryl-1,3,2-
dioxaborolanes bearing N-bound S,S-dimethylsulfox-
imidoylic substituents can be found. For examples, see:
a) F. Himmelsbach, E. Langkopf, H. Wagner, Patent
Appl. WO 2015007669 A1, 2015; b) Y. Tamura, Y.
Hinata, E. Kojima, H. Ozasa, Patent Appl. WO
2016031842 A1, 2016; c) F. Himmelsbach, E.
Langkopf, WO 2016113299 A1, 2016.
This work was supported by the Deutsche Forschungsgemein-
schaft through the International Research Training Group
SeleCa (IGRK 1628).
References
[1] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54,
3451–3479.
[2] For the "Nobel Review", see: A. Suzuki, Angew. Chem.
2011, 123, 6854-6869; Angew. Chem. Int. Ed. 2011, 50,
6723–6737.
[14] For recent examples of molecules with N-bound
methyl sulfonamidoyl groups, where this concept could
be applied, see: a) J. Kankanala, C. Marchand, M.
Abdelmalak, H. Aihara, Y. Pommier, Z. Wang, J. Med.
Chem. 2016, 59, 2734–2746; b) J. Schmidt, M. Rotter,
T. Weiser, S. Wittmann, L. Weizel, A. Kaiser, J.
Heering, T. Goebel, C. Angioni, M. Wurglics, A.
Paulke, G. Geisslinger, A. Kahnt, D. Steinhilber, E.
Proschak, D. Merk, J. Med. Chem. 2017, 60, 7703–
7724.
[3] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem.
2009, 52, 6752–6756.
[4] W. P. Walters, J. Green, J. R. Weiss, M. A. Murcko, J.
Med. Chem. 2011, 54, 6405–6416.
[5] B. J. Reizman, Y.-M. Wang, S. L. Buchwald, K. F.
Jensen, React. Chem. Eng. 2016, 1, 658–666.
[6] C. Len, S. Bruniaux, F. Delbecq, V. S. Parmar,
[15] An analogy can be seen in the research performed by
AstraZeneca, who described transformations of
"dimethylsulfoximine as a versatile precursor". For
details, see: F. W. Goldberg, J. G. Kettle, J. Xiong, D.
Lin, Tetrahedron 2014, 70, 6613–6622.
Catalysts 2017, 7, 146.
[7] J. Li, S. G. Ballmer, E. P. Gillis, S. Fujii, M. J. Schmidt,
A. M. E. Palazzolo, J. W. Lehmann, G. F. Morehouse,
M. D. Burke, Science 2015, 347, 1221–1226.
[16] The state-of-the art approach towards biaryls with N-
bound sulfoximidoyl groups makes use of Buchwald-
Hartwig type cross couplings starting from biaryl
halides and NH-sulfoximines. It is a well established
route, but requires multi-step syntheses of individual
starting materials. For representative examples, see: a)
C. Bolm, J. P. Hildebrand, Tetrahedron Lett. 1998, 37,
5731–5734; b) M. Harmata, N. Pavri, Angew. Chem.
1999, 111, 2577–2579; Angew. Chem. Int. Ed. 1999, 38,
2419–2421; c) C. Bolm, J. P. Hildebrand, J. Org. Chem.
2000, 65, 169–175; d) J. Sedelmeier, C. Bolm, J. Org.
Chem. 2005, 70, 6904–6906; e) C. Moessner, C. Bolm,
Org. Lett. 2005, 7, 2667–2669; f) A. Correa, C. Bolm,
Adv. Synth. Catal. 2008, 350, 391–394; g) M. Harmata,
X. Hong, Synthesis 2007, 969–973; h) M. Yongpruksa,
N. L. Calkins, M. Harmata, Chem. Commun. 2011, 47,
7665–7667.
[8] a) J. Li, A. S. Grillo, M. D. Burke, Acc. Chem. Res.
2015, 48, 2297–2307; b) E. M. Woerly, J. E. Miller, M.
D. Burke, Tetrahedron 2013, 69, 7732–7740; c) G. R.
Dick, E. M. Woerly, M. D. Burke, Angew. Chem. Int.
Ed. 2012, 51, 2667–2672; d) J. Li, M. D. Burke, J. Am.
Chem. Soc. 2011, 133, 13774–13777; e) J. R. Struble, S.
J. Lee, M. D. Burke, Tetrahedron 2010, 66, 4710–
4718; f) G. R. Dick, D. M. Knapp, E. P. Gillis, M. D.
Burke, Org. Lett. 2010, 12, 2314–2317; g) D. M.
Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem. Soc.
2009, 131, 6961–6963.
[9] a) Q. I. Churches, J. F. Hooper, C. A. Hutton, J. Org.
Chem. 2015, 80, 5428–5435; b) L. Xu, S. Zhang, P. Li,
Chem. Soc. Rev. 2015, 44, 8848–8858; c) L. Xu, S.
Ding, P. Li, Angew. Chem., Int. Ed. 2014, 53, 1822–
1826; d) A. J. J. Lennox, G. C. Lloyd-Jones, Chem.
Soc. Rev. 2014, 43, 412–443.
[17] For detailed insight into Suzuki cross-couplings, see:
a) J. A. Gonzalez, O. M. Ogba, G. F. Morehouse, N.
Rosson, K. N. Houk, A. G. Leach, P. H. Y. Cheong, M.
D. Burke, G. C. Lloyd-Jones, Nat. Chem. 2016, 8,
1067–1075; b) A. J. J. Lennox, G. C. Lloyd-Jones,
[10] A.-D. Steinkamp, S. Wiezorek, F. Brosge, C. Bolm,
Org. Lett. 2016, 18, 5348–5351.
[11] For the relevance of sulfoximines in medicinal
chemistry and crop protection, see, for example: a) U.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701394
Advanced Synthesis & Catalysis
Chem. Soc. Rev. 2014, 43, 412–443; c) P. A. Cox, A. G. [22] a) G. A. Molander, S. L. J. Trice, S. M. Kennedy, J.
Leach, A. D. Campbell, G. C. Lloyd-Jones, J. Am.
Chem. Soc. 2016, 138, 9145–9157; d) A. J. J. Lennox,
G. C. Lloyd-Jones, J. Am. Chem. Soc. 2012, 134, 7431–
7441; e) A. J. J. Lennox, G. C. Lloyd-Jones, Angew.
Chem. Int. Ed. 2013, 52, 7362–7370
Org. Chem. 2012, 77, 8678–8688; b) G. A. Molander,
S. L. J. Trice, S. M. Kennedy, S. D. Dreher, M. T.
Tudge, J. Am. Chem. Soc. 2012, 134, 11667–11673; c)
G. A. Molander, S. L. J. Trice, S. D. Dreher, J. Am.
Chem. Soc. 2010, 132, 17701–17703.
[18] T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S.
[23] Under these conditions, the use of the analogous aryl
iodide of 6a (with I instead of Br; compound 6i) led to
2a in a yield of 60%. Applying the corresponding aryl
chloride (6a with Cl instead of Br; compound 6j)
resulted in incomplete conversion.
W. Krska, Chem. Soc. Rev. 2016, 45, 546–576.
[19] For reviews, see: a) J. X. Qiao, P. Y. S. Lam.
Synthesis 2011, 829–856; b) K. S. Rao, T.-S. Wu,
Tetrahedron 2012, 68, 7735–7754.
[24] Here, all applied chiral sulfoximines were racemic.
For well-established synthetic routes towards enantio-
pure substrates, which should lead to optically active
products, see: S. Dong, M. Frings, H. Cheng, J. Wen, D.
Zhang, G. Raabe, C. Bolm, J. Am. Chem. Soc. 2016,
138, 2166–2169 and references therein.
[20] We also attempted photochemical borylations of 6a
using B2Pin2 and B2(OH)4 under irradiation with UV
light. However, only decomposition of the sulfoximine
was observed. For examples on photochemical
borylations, see: a) K. Chen, S. Zhang, P. He, P. Li,
Chem. Sci. 2016, 7, 3676–3680; b) A. M. Mfuh, J. D.
Doyle, B. Chhetri, H. D. Arman, O. V. Larionov, J.
Am. Chem. Soc. 2016, 138, 2985–2988; c) K. Chen, M.
S. Cheung, Z. Lin, P. Li, Org. Chem. Front. 2016, 3,
875–879.
[21] T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem.
1995, 60, 7508–7510.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701394
Advanced Synthesis & Catalysis
COMMUNICATION
N-Arylated Sulfoximines as Cross-Coupling
Building Blocks
Me
N
Aryl-/heteroaryl
O
R1
Ar
O
Adv. Synth. Catal. Year, Volume, Page – Page
bromide
R1
B
S
S
N
O
Suzuki cross-
coupling
R2
N
O
O
R2
O
Anne-Katrin Bachon, Anne-Dorothee Steinkamp,
Carsten Bolm*
7
This article is protected by copyright. All rights reserved.