Photoredox mediated C[sbnd]N cross coupling of sulfoximines with aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2019.151100

A new photoredox-catalyzed C[sbnd]N coupling reaction of sulfoximines with aryl halides has been developed for a general N-arylation of sulfoximines. The reactions proceed in the presence of visible light with high levels of chemoselectivity and a wide ra

Full text of DOI:10.1016/j.tetlet.2019.151100

Tetrahedron Letters 60 (2019) 151100
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photoredox mediated CAN cross coupling of sulfoximines with aryl
iodides
⇑
Sudhir Hande , Adelphe Mfuh, Scott Throner, Ye Wu, Qing Ye, XiaoLan Zheng
Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Boston, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2019
Revised 28 August 2019
Accepted 30 August 2019
Available online 10 September 2019
A new photoredox-catalyzed CAN coupling reaction of sulfoximines with aryl halides has been developed
for a general N-arylation of sulfoximines. The reactions proceed in the presence of visible light with high
levels of chemoselectivity and a wide range of functionality is tolerated. There is a rapidly increasing
interest in sulfoximines as pharmacophores in drug discovery and this new method offers potential in
terms of high functional group tolerance and late-stage functionalization of compounds.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Sulfoximine
Photo redox
CAN coupling
Ni-catalyst
Introduction
In 1998, Bolm reported the first CAN cross coupling of sulfox-
imines with aryl halides using Pd catalyst. However, the scope of
In recent years, sulfoximines have appeared as key structural
motifs in a number of drug molecules that have progressed into
the clinic. Sulfoximines are chemically stable, weakly basic and rel-
atively polar functional groups which often afford favourable drug-
like properties such as high microsomal stability, hydrogen-bond
acceptor/donor functionalities, and favorable physicochemical
properties such as decreased lipophilicity, improved aqueous solu-
bility, and permeability [1]. It has been demonstrated that the sul-
foximine derivatives of marketed drugs like vardenafil and
fulvestrant possesses equipotent activity as of parent drugs [1b].
To date there are at least three sulfoximinecontaining kinase inhi-
bitors (roniciclib (BAY1000394), BAY1143572 and AZD6738)) that
were progressed into the clinical studies. In addition, chiral sulfox-
imines have been also recognized as an interesting new class of
ligands which are successfully used in asymmetric synthesis of
various chiral organic molecules [2]. Although there is increasing
interest in sulfoximines, their routine use in drug discovery is still
limited because of their synthetic tractability. Therefore, further
advances in synthetic methodology would allow the use of sulfox-
imines as a pharmacophore in medicinal chemistry as well as their
other catalytic applications. As a result, significant efforts have
been devoted to the development of effective strategies towards
the N-functionalization of sulfoximines [3].
this N-arylation reaction was limited to electron-deficient bro-
mides [4]. Shortly thereafter, a number of groups introduced other
transition-metal catalysts such as Cu, Fe, Ni, Ru, etc. to achieve this
trasformation [5]. Nonetheless, these methods are not efficient in
terms of functional group tolerance and suitability for late-stage
functionalization because they require relatively harsh conditions
such as high reaction temperatures, strong bases such as Cs2CO3,
K2CO3, etc. and long reaction times (8–24 h) (Scheme 1). As a result
of our continued interest in sulfoximines for internal medicinal
chemistry programs at AstraZeneca [6], we were looking for milder
coupling conditions which would allow broader functional group
tolerance and late stage functionalization .
The immense impact of the photoredox catalysis in the CAN
cross coupling of anilines and amines has been well documented.
N-arylation of sulfonamides reported by McMillan was of particu-
lar interest to us [7]. Visible-light mediated metallaphotocatalysis
for sulfoximine CAN coupling was not explored until recently
[8]. Based on the photoredox catalyzed CAN cross coupling of ani-
lines with aryl halides reported in the literature, we anticipated
that development of single-electron transfer (SET) chemistry
would constitute a more efficient strategy for the N-arylation of
sulfoximines [9].
Results and discussion
⇑
Considering the broader interest of the medicinal chemistry
community and inspired by the literature precedent on related
Corresponding author.
E-mail address: sudhir.hande@astrazeneca.com (S. Hande).
https://doi.org/10.1016/j.tetlet.2019.151100
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
S. Hande et al. / Tetrahedron Letters 60 (2019) 151100
Table 2
Substrate scope of aryl halides.
Scheme 1. Transition metal catalyzed C-N cross couplings of NH-sulfoximines.
compounds, we commenced our study by the reaction of 4-iodo
toluene 1a (1 mmol) with S,S-dimethyl sulfoximine (1.1 mmol)
using 2 mol% of ([Ir(ppy)2(dtbbpy)]PF6) as a photocatalyst, 10 mol
% of NiCl2ꢀglyme and 15 mol% of 4,40-di-tert-butyl-2,20-bipyridine
in presence of 2 eq of triethylamine (TEA) as base in dry acetoni-
trile (CH3CN) (0.17 M) under inert atmosphere. To our delight,
the desired product 3a was obtained in 88% yield after irradiation
of the above reaction mixture with blue light for 5 h at 25 °C
(Table 1, entry 1). Encouraged by these results, we next performed
a series of control experiments to establish the importance of pho-
toredox catalysis for this transformation. In the absence of visible
light irradiation, none of the desired product was formed after
24 h (entry 2). Similarly, in the absence of nickel or iridium catalyst
we did not observe any product formation (entries 3 and 4). We
also found that the absence of the base gave only trace of the
desired product (entry 5). As shown in entry 6, further optimiza-
tion significantly decreased the catalyst loading. Only 1 mol% of
[Ir]-catalyst and 5 mol% of [Ni]-catalyst was found to be sufficient
to yield the desired product 3a in 82% isolated yield after irradia-
tion for 16 h (entry 6).
With these optimal dual catalysis conditions in hand, we next
sought to explore the scope of aryl halides amenable to reaction
with S,S-dimethyl sulfoximine. As shown in Table 2, the reaction
takes place efficiently using substrates that contain a variety of
arene ring substituents or heterocycles and tolerates broad range
of functional groups. For example, reactions of aryl iodide contain-
ing an unprotected phenol gave the coupled product 3b in excel-
lent yield. Other substrates containing electron donating groups
such as 3-iodoanisole and 4-iodophenylsulfur pentafluoride under-
went the reaction efficiently to give the corresponding products in
[a]
[c]
ꢁ6% aniline coupling observed. [b]No reaction with corresponding bromide.
-
Only mono coupled product 3f was obtained when 2 equivalent of S,S-dimethyl
sulfoximine was used. General procedure: Ir[dF(CF3)ppy]2(dtbpy))PF6 (5.6 mg,
4.99 mmol) was added to
a stirred solution of aryl iodide (1.00 mmol), imin-
Table 1
odimethyl-lambda6-sulfanone (102 mg, 1.10 mmol), 4,40-di-tert-butyl-2,20-bipyr-
idine (20 mg, 0.07 mmol), TEA (0.279 mL, 2.00 mmol) and NiCl2(glyme) (11 mg,
0.05 mmol) in acetonitrile (5.6 mL). The resulting mixture was irradiated with a
blue LED (450 nm, Penn Optical Photoreactor m1) and stirred at 29 °C for 16 h. The
reaction mixture was quenched with saturated aqueous NaHCO3 (2 mL) and
extracted with EtOAc. The organic layer was dried over MgSO4, filtered and con-
centrated under reduced pressure and the resulting residue was purified by flash
silica chromatography, to afford the corresponding products.
Optimization of reaction conditions and controlled experiments.
Entry
Variation from standard conditions
Time (h)
Yield (%)[b]
good yields (Table 2, 3c-d). Interestingly, the reaction of 3-iodo
aniline gave desired sulfoximine coupling as a major product with
reasonable yield and selectivity (3e). The reaction of 4-chloro
iodobenzene gave the corresponding monosulfoxime derivative
3f with complete regioselectivity. Substrates containing orthogo-
nal functional groups useful for further chemical transformations
such as nitro (3g), ester (3h), ketone (3i), aldehyde (3j) and nitrile
(3l) reacted efficiently and with complete chemoselectivity to give
the corresponding products in good yields. The reaction also toler-
ated electron deficient aryl rings bearing substituents such as tri-
fluoromethyl (3k). Iodo heterocycles such thiophene and
1
2
3
4
5
6
none
no irradiation
no NiCl2.glyme
No Ir[dF(CF3)ppy]2dtbbpy)PF6
No TEA
NiCl2.dtbbpy (5 mol%),
Ir[dF(CF3)ppy]2dtbbpy)PF6 (1 mol%),
4,40-di-tert-butyl-2,20-bipyridine
(0.075 mol%)
5
88
0
0
0
<6
82
24
24
24
24
16
[a]No reaction with corresponding bromide.
[b]
Isolated yield.

S. Hande et al. / Tetrahedron Letters 60 (2019) 151100
3
used as a synthetic handles for further chemical transformation.
Reaction conditions were also compatible with labile functional
groups such as boronate, aldehyde and terminal acetylene, and
afforded the corresponding sulfoximine coupled products in excel-
lent yields. We also demonstrated that this catalytic system works
well with other sulfoximine derivatives with diverse electronic
demand. Moreover, this methodology offers excellent selectivity
for aryl iodides over aryl chlorides and bromides which would ulti-
mately allow further late stage functionalization via cross cou-
plings and it would be of interest to medicinal chemists.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151100.
Scheme 2. Scope of other NH-sulfoximines[a]
.
References
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