Palladium catalyzed aroylation of NH-sulfoximines with aryl halides using chloroform as the CO precursor

Article abstract of DOI:10.1016/j.tetlet.2017.05.088

A palladium-catalyzed aroylation of NH-sulfoximines for the efficient synthesis of N-aroyl sulfoximines from aryl halides and chloroform has been developed. The mild reaction conditions (temperature, catalyst loading) and the use of a CO surrogate render this transformation a useful method for the synthesis of N-aroyl sulfoximines from available feedstock.

Full text of DOI:10.1016/j.tetlet.2017.05.088

Accepted Manuscript
Palladium Catalyzed Aroylation of NH-sulfoximines with Aryl Halides Using
Chloroform as the CO Precursor
Sheng-rong Guo, Pailla Santhosh Kumar, Yan-qin Yuan, Ming-hua Yang
PII:
S0040-4039(17)30690-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.088
TETL 48981
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 April 2017
24 May 2017
27 May 2017
Please cite this article as: Guo, S-r., Santhosh Kumar, P., Yuan, Y-q., Yang, M-h., Palladium Catalyzed Aroylation
of NH-sulfoximines with Aryl Halides Using Chloroform as the CO Precursor, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.05.088
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Palladium Catalyzed Aroylation of NH-sulfoximines with
Aryl Halides Using Chloroform as the CO Precursor
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Sheng-rong Guo a, Pailla Santhosh Kumar a * Ming-hua Yang a and Yan-qin Yuan a *

1
Tetrahedron Letters
journal homepage: www.els evier.com
Palladium Catalyzed Aroylation of NH-sulfoximines with Aryl Halides Using
Chloroform as the CO Precursor
Sheng-rong Guo a, Pailla Santhosh Kumar a * Yan-qin Yuan a * and Ming-hua Yang a
a Department of Chemistry, Lishui University, 323000, Lishui, P.R. China, E-mail: paillasanthosh@gmail.com; yuanyq5474@lsu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
A palladium-catalyzed Aroylation of NH-sulfoximines for the efficient synthesis of N-aroyl
sulfoximines from aryl halides and chloroform has been developed. The mild reaction conditions
(temperature, catalyst loading) and the use of a CO surrogate render this transformation a useful
method for the synthesis of N-aroyl sulfoximines from available feedstock.
2009 Elsevier Ltd. All rights reserved.
Received in revised form
Accepted
Available online
Keywords:
Aroylation
sulfoximines
Chloroform
Pd(OAc)2
CO Precursor
Transition-metal catalyzed carbonylation reaction using carbon
monoxide as C=O source has evolved as one of the most
powerful protocol to introduce C1 building block into an organic
molecule.1 While the intrinsic odorless toxic and high pressure
make it difficult to using normal flask in the application of CO
gas. Aiming at this issue, some “CO-free” carbonylation methods
have been devised to avoid CO gas directly by using such as
Mo(CO)6, formic acid, acid chloride or aryl formate.2 Recently,
the chloroform (CHCl3) serves as a highly practical CO precursor
for transition-metal-mediated carbonylation reactions attracted
chemists attention.3 In 2015, Hull reported Pd-catalyzed
aminocarbonylation of aryl halides with amines by using
biological and medicinal molecules or as exciting species for
drug discovery programs.4 Some typical examples are
exemplified by Figure 1.5 the compound AZD6738 from
AstraZeneca is a novel and potent inhibitor of ATR kinase
activity;5a the heterocyclic sulfoximine Go 4962 is known as a
partial benzodiazepine receptor agonist.5b However, the more
general use of the sulfoximine group in medicinal chemistry
follows the development of BAY 1000394, a pan-CDK inhibitor
for cancer in patients with advanced solid tumors.5c In
comparison to sulfones, the inherent nucleophilicity of N-H
group allows sulfoximines for more valuable building blocks in
organic synthesis.6 In the past decade, Bolm and others have
developed many NH group functionalizations methods such as
3a
chloroform as CO source. The metal-catalyzed carbonylative
Suzuki and Sonogashira coupling reaction using CHCl3 as the
CO source were also described in 2016 by the Jain, Lei and Han
groups. 3c-3e This “CO-free” carbonylation shows some superior
performance such as readily available and strong practical
compared to direct use of CO gas, although remarkable advances
have been achieved using CO gas as carbonyl surrogates.
Undoubtedly, exploration of “CO-free” strategies to construct the
carbonyl scaffold through a low cost and highly efficient process
will be highly valuable.
N-arylations,7
N-alkynylation,8
N-silylation,9
N-
12
trifluoromethylation,10 N-thioetherification,11 N-acylation and
so on.13 In the case of direct N-aroylation of sulfoximines, Bolm
reported some elegant work relative to transition-metal catalyzed
oxidative N-acylation of sulfoximine using aldehyde, and methyl
arenes as coupling partner.12e-12h Very recently, Sekar disclosed a
three-component strategy for the synthesis of N-aroyl
sulfoximines skeleton, direct using CO gas as a carbonyl
source.14 Stimulated by those pioneering works and continue to
our ongoing project on the synthesis of functionalized sulfides,
we herein demonstrate a simple and efficient aroylation of NH-
sulfoximines using CHCl3 as in situ CO source.
At the beginning of the reaction, the model substrate S-methyl-
S-phenylsulfoximine (1a 1.0 equiv) was treated with
iodobenzene (2a 1.2 equiv.), and CHCl3 (10.0 equiv). To our
delight, the desired aroylation product 3aa was obtained in 79%
yield using Pd(OAc)2 (2 mol%) as catalyst, PPh3 (20 mol %) as
ligand and KOH (6.0 equiv) as base in toluene after 12 h at 80 oC
(table 1, entry 1). The reported relative reaction mechanism
suggested that the Pd-catalyst serves two purposes: to catalyze
the hydrolysis of CHCl3 and to catalyze the subsequent formation
Fig. 1 Examples of biologically relevant sulfoximines.
Sulfoximines are mono-aza analogues of sulfones with an
additional NH group which appear as a valuable structural unit in

2
of aroyl intermediate, and it is obvious that the CO group is from
chloroform. Screening of other catalyst revealed that no
aroylation was observed when using FeCl2, Cu(OAc)2,
Ru3(CO)12, AgOAc as catalyst (entries 2-5). Other palladium
catalysts such as PdCl2 and Pd(dba)2 were also examined, and
both were found to be active and yielded 3aa in 36 and 58 %
yields, respectively (entries 6 and 7). Since Pd(OAc)2 was found
to have the highest activity, it was used for further optimizations.
Next, the effect on selected ligands toward the process was
examined. It turned out that the reaction failed with 1,10-
phenanthroline and BINAP as the ligand (entries 8 and 9), In
contrast, other ligands such as DBU, DMAP, and 2,6-lutidine led
to the formation of the desired product 3aa (entries 10-12), DBU
was found to be the best ligand giving 3aa in 85% yield, albeit
with lower efficiency lowering or raising the amount of DBU to
10 or 40 mol %. Following the above investigation, the screening
of base was conducted. A low yield was observed with NaOH
and LiOH (entries 13 and 14), while CsOH·H2O resulted in an
88% yield. However, taking into account the higher cost as well
as hygroscopic nature of CsOH·H2O, we used KOH as base.
After a brief solvent screening, we found out that toluene was the
best solvent under our optimized reaction parameters (entries 15-
18). Therefore, optimal reaction conditions involved heating 1
equiv of 1a, 1.2 equiv of 2a, 2 mol % of Pd(OAc)2, 20 mol % of
DBU as ligand, 6 equiv of KOH and 10 equiv of CHCl3 at 80 °C
for 12 h in the toluene solvent. It is noteworthy that no desired
product 3aa was obtained in the absence of palladium or base
(entries 19 and 20).
substituents on the benzene ring, including 4-F and 4-Cl, were
compatible for this kind of coupling reaction (entries 4-5). The
electron-withdrawing functional group, such as 4-CF3 and 4-CN
were well tolerated to give the desired product in 90% and 82%
yield (entries 6-7). In addition, a slight steric effect was observed
since the substrates bearing
−OCH −SCH
a
3, -F, Br, -NO2 and
meta-substituent such as
−CF
led to relatively
3
−CH3 ,
,
3
lower yields compared to para-substituted variant (entries 8-14).
Heterocyclic compounds such as thiophenes are also readily
functionalized (entries 15-16). Unfortunally, the ortho-substituted
aryl iodides failed to afford the desired products. These results
obviously suggested that the steric hindrance of aryl iodides has
significant effect on this carbonylative coupling reaction. The
reaction was also applied for gram-scale synthesis starting from
1g of S-methyl-S-phenylsulfoximine 1a and 1579 mg of
iodobenzene to yield 3aa in a 70 % yield (1169 mg).
Table 2. Pd(OAc)2 catalyzed N-aroylation of 1a with aryl iodides a,b
O
Pd(OAc)2 (2 mol%)
C
R
I
O
NH
DBU (20 mol%)
O
N
+
S
R
S
CH3
CHCl3 (10 equiv)
KOH (6 equiv)
toluene
CH3
1a
2a-2p
3aa-3ap
80 oC, 12 h
Table 1. Optimization of the Reaction Conditions [a]
entry 1, 3aa (85%)
entry 3, 3ac (82%)
entry 5, 3ae (81%)
entry 2, 3ab (89%)
entry 4, 3ad (86%)
entry 6, 3af (90%)
Entry
Cat.
Ligand/Base
Solvent
Yield (%) [b]
1
2
3
4
5
6
7
Pd(OAc)2
FeCl2,
Cu(OAc)2,
Ru3(CO)12
AgOAc
PPh3/KOH
PPh3/KOH
PPh3/KOH
PPh3/KOH
PPh3/KOH
PPh3/KOH
PPh3/KOH
1,10-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
79
0
0
0
,
0
36
58
PdCl2 and
Pd(dba)2
8
Pd(OAc)2
toluene
0
phenanthroline/KOH
BINAP/KOH
DBU/KOH
DMAP/KOH
2,6-lutidine/KOH
DBU/NaOH
DBU/LiOH
DBU/CsOH·H2O
DBU/KOH
DBU/KOH
DBU/KOH
-
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMF
0
10
11
12
13
14
15
16
17
18
19
20
85
80
82
75
70
88
20
0
entry 7, 3ag (82 %)
entry 8, 3ah (80%)
DCE
toluene
toluene
50
0
entry 9, 3ai (82%)
entry 10, 3aj (78%)
DBU/KOH
0
[a] Reaction conditions: S-methyl-S-phenylsulfoximine (0.5 mmol),
iodobenzene (0.6 mmol), chloroform (5 mmol, 10 equiv.), Ligand (20 mol%)
and base (3 mmol, 6 equiv.) and solvent (2 mL) heated at 80 oC for 12 h. [b]
Isolated yield.
entry 11, 3ak (80%)
entry 12, 3al (80%)
With the optimized reaction conditions, scope of this
transformation was investigated. The reactivity of S-methyl-S-
phenylsulfoximine 1a toward different substituted aryl iodides
was seen. As shown in table 2, the electron-withdrawing as well
as electron-donating functional groups in aromatic ring of aryl
iodides were well tolerated. Aryl iodides bearing alkyl or alkoxyl
entry 13, 3am (75%)
entry 14, 3an (77%)
−CH3 −OCH
3, coupled
group at the para position, such as
,
smoothly with 1a to give the corresponding products in 89%
(3ab) and 82% (3ac) yields, respectively (entries 2-3). Halogen

3
entry 11, 3bk (91%)
entry 12, 3bl (80%)
entry 15, 3ao (80%)
entry 16, 3ap (76%)
[a] Reaction conditions: S-methyl-S-arylsulfoximine (0.5 mmol), ArI (0.6
mmol), chloroform (5 mmol), KOH ( 3 mmol), Pd(OAc)2 (2 mol%) and
DBU (20 mol%), toluene (2 mL), heated at 80 oC for 12 h. [b] Isolated
yield. [c] ArBr (1.5 equiv.) used.
[a]
Reaction conditions: sulfoximines 1a (0.5 mmol), ArI (2a-2p, 0.6
mmol), chloroform (5 mmol, 10 equiv.), KOH (3 mmol, 6 equiv.),
Pd(OAc)2 (2 mol%) and DBU (20 mol%), toluene (2 mL), heated at
80 oC for 12 h. [b] Isolated yield.
With respect to the reaction mechanism, this transformation
would be a typical carbonylation reaction.3 Initially, chloroform
decomposed to generate CO in situ, which undergoes the
insertion process to generate the acyl palladium complex. Then
this key intermediate is attacked by N-H nucleophiles to give the
products.
In summary, we have developed a convenient and efficient
palladium-catalyzed aroylation process of aryl halides with
sulfoximines to construct N-aroyl sulfoximines derivatives using
CHCl3 as CO precursor. A wide range of aryl halides and
sulfoximines reacted smoothly under the optimized reaction
conditions to give the corresponding products in moderate to
good yields. Further this work will provide an alternate pathway
for the construction of various N-aroylation reactions in the use
of CO releasing molecules for the transition metal mediated
carbonylation reactions.
Subsequently, the reaction scope with respect to NH-
sulfoximine substrates is presented in Table 3. They proved to
efficiently couple with meta- and para-substituted aryl iodides
under the optimize conditions and no significant electronic
effects were observed to sulfoximine (entries 1-7). A slight
decline of yields was observed using ortho-substituted NH-
sulfoximine comparable with meta- and para-substituted NH-
sulfoximines (entries 8-9). The S-ethyl-S-arylsulfoximine
coupled well with aryl iodides to provide 3aj and 3ak in 89% and
91% yields respectively (entries 10-11). Even the sterically
diphenylsulfoximine also smoothly reacted with iodobenzene to
provide the product 3al in 80% yield (entry 12). Further, the
reaction is not limited to aryl iodides, the aromatic bromides also
afford the desired product, but aryl bromides were proved to be a
less efficient coupling partner, resulted in the desired product in
low yields (entries 1-3).
Table 3. Pd(OAc)2 catalyzed N-aroylation of sulfoximines with aryl halides
a,b
Acknowledgments
This work was supported by the Natural Science Foundation
of Zhejiang Province P.R. China (No. Y16B020018) and
Public Welfare Technology Application Foundation of Lishui
(2014JYZB49).
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35%c
entry 2, 3bb (93%)
30%c
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22%c
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3.
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entry 10, 3bj (89%) c

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Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/ xxxxxxxxxxxx.
Highlights:
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
“CO-free” carbonylation shows readily available and
easy to handle.
Palladium-catalyzed aroylation of sulfoximines using
CHCl3 as CO precursor.
Various aryl halides and sulfoximines reacted
smoothly in moderate to good yields.
Providing an alternative carbonylation in the use of
CO releasing molecules.
Mild reaction condition and avoids harsh reaction
conditions.