Palladium-Catalyzed N-Arylation of Sulfoximines with Aryl Sulfonates

Article abstract of DOI:10.1021/acs.joc.8b01599

Palladium-catalyzed C-N bond coupling reaction between NH-sulfoximines and aryl halides (e.g., -Br, -I, and -Cl and pseudohalides -OTf and -ONf) was successfully achieved. Nevertheless, aryl tosylates/mesylates left much to be achieved. In this report, a general N-arylation of sulfoximines with aryl sulfonates is described. Using Pd(OAc)₂/MeO-CM-phos complex, the N-aryl sulfoximine products can be obtained in good-to-excellent yields (up to 99%) with good common functional group compatibility. In addition to arene moieties, alkenyl tosylates are shown to be successful coupling partners.

Full text of DOI:10.1021/acs.joc.8b01599

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Note
Palladium-Catalyzed N-Arylation of Sulfoximines with Aryl Sulfonates
Qingjing Yang, Pui Ying Choy, Qingyang Zhao, Man Pan Leung, Hoi
Shan Chan, Chau Ming So, Wing-Tak Wong, and Fuk Yee Kwong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01599 • Publication Date (Web): 31 Jul 2018
Downloaded from http://pubs.acs.org on July 31, 2018
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PalladiumꢀCatalyzed NꢀArylation of Sulfoximines with Aryl Sulfonates
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Qingjing Yang,a Pui Ying Choy,b Qingyang Zhao,b Man Pan Leung,b Hoi Shan Chan,b
Chau Ming So,a WingꢀTak Wonga and Fuk Yee Kwonga,b,
*
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aThe Hong Kong Polytechnic University Shenzhen Research Institute (SZRI), Shenzhen,
P. R. of China
bDepartment of Chemistry, The Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong
Email: fykwong@cuhk.edu.hk
Abstract:
Palladiumꢀcatalyzed C−N bond coupling reaction between NHꢀsulfoximines and aryl
halides (e.g. −Br, −I, −Cl and pseudohalides, −OTf, −ONf) has been successfully
achieved. Nevertheless, aryl tosylates/mesylates left much to be succeeded. In this
report, a general Nꢀarylation of sulfoximines with aryl sulfonates is described. Using
Pd(OAc)2/MeOꢀCMꢀphos complex, the Nꢀaryl sulfoximine products can be obtained in
goodꢀtoꢀexcellent yields (up to 99%) with good common functional group compatibility.
In addition to arene moieties, alkenyl tosylates are shown to be successful coupling
partners.
Keywords: sulfoximines, palladium, arylation, sulfonates, phosphine
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Sulfoximines, the monoaza analogues of sulfones, have received continuous
attention over the past decades because of their unique and valuable structures.1 This
privileged scaffold offers distinctive physicochemical and biologically properties2 that are
favourable to medicinal chemistry (Figure 1).3 In view of synthetic chemistry, they serve
as important chiral auxiliaries in resolution steps, 4 useful ligands in asymmetric
catalysis,5 and building blocks in assembling pseudopeptides.6 Recently, they were
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even employed as directing groups for catalytic orthoꢀCꢀH functionalizations.
Considering their importance and versatility, the development of a complementary
synthetic method which allows other commonly available arene reagents to be used, is
thus highly desirable.
Figure 1. Examples of useful bioactive molecules with sulfoximine scaffold
Palladiumꢀcatalyzed Nꢀarylation of sulfoximines has been successful since the
pioneering work of Bolm in 1998 (Figure 2).8 Aryl bromides were wellꢀcoupled with NHꢀ
sulfoximines in the presence of Pd(OAc)2/racꢀBINAP complex.8,9 The same catalyst
system was further extended to the corresponding aryl triflates and nonaflates in this
C−N coupling process.10 Since then, chemists have been actively searching other
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arene sources for this reaction, for instance, nucleophilic aryl siloxanes
and
arylboronic acids,12 hypervalent diaryliodonium salts,13 arylsulfinates,14 azoles15 and
acyl peroxides.16 Recently, a transition metalꢀfree Nꢀarylation of sulfoximine using nonꢀ
regioselective aryne was also reported.17 In fact, aryl halides are attractive and more
readily available coupling partners. Bolm showed that, apart from palladium catalyst
system, copper and iron salts were able to catalyze this sulfoximination process (Figure
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2).18,19,20 In 2004, Harmata showed the crossꢀcoupling of activated aryl chlorides with
NHꢀsulfoximines under microwave reaction conditions.21 The same group later reported
a more efficient system (Pd2dba3/RuPhos) which allowed the nonꢀactivated aryl
chlorides to be coupled smoothly (Figure 2).22 Even though most of the aryl halides are
commonly available, some of their arene substitution patterns may not be
straightforwardly accessed from electrophilic halogenation. Indeed, it would be
desirable having opportunity of using other complementary arene sources for expanding
the scope of such coupling reactions. Rich feedstock phenolꢀderived coupling partners
are thus complementary entities.23 Herein we report the first examples of Pdꢀcatalyzed
Nꢀarylation of sulfoximines with aryl tosylates and mesylates.
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Figure 2. Recent development for preparation of N-aryl sulfoximine using crossꢀ
coupling protocol
We commenced the investigation using sulfoximine 1a and electronically neutral
aryl tosylate 2a as the model substrates (Scheme 1). A number of previously found
remarkable ancillary ligands were examined for their efficacy towards this Nꢀarylation
process. Poor conversions were observed with XPhos24 and MorꢀDalPhos,25 whereas
CataCXium PCy, 26 and Xantphos 27 were found to be ineffective. RuPhos24 and
BrettPhos24 gave moderate product yield. CMꢀphos28 which formerly reported by our
group, gave 89% product yield. Yet, a small amount of phenol side product (~3ꢀ4%
from GC analysis) was observed due to possible competitive alkaline hydrolysis under
alcoholic medium. In order to further facilitate the rate of oxidative addition of Ar−OTs
bond, a more electronꢀrich MeOꢀCMꢀphos was employed (Xꢀray crystal structure, CCDC
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1851614). To our delight, no competitive phenolic side products was detected and the
desired product yield was afforded in 94%.
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Scheme 1. An evaluation of ligand efficacy in Pdꢀcatalyzed sulfoximinationa
tꢀBu
NH
tꢀBu
1.5 mol% Pd(OAc)2
3.0 mol% Ligand
Me
S
O
Me
O
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N
N
S
+
K2CO3, tꢀBuOH
110 °C, 18 h
1a
2a
3aa
OTs
Me
Ligands:
SPhos, 0%
XPhos, 5%
RuPhos, 63%
MorꢀDalPhos, 31%
Xantphos, 0%
CataCXium PCy, 0%
BrettPhos, 70% DPPF, 0%
Cy2P
CMꢀphos, 89%
Me
N
OMe
Cy2P
MeOꢀCMꢀphos, 94%
aReaction conditions: 1a (0.4 mmol), 2a (0.48 mmol), Pd(OAc)2 (1.5 mol%), Ligand (3.0 mol%; Pd/L = 1:2),
K2CO3 (0.8 mmol) and tꢀBuOH (1 mL) were stirred at 110 °C under nitrogen for 18 h. GC yields with
dodecane as the internal standard.
We then carried out a series of investigations to optimize the reaction conditions
(Table 1). Pd(OAc)2 showed the best performance among palladium sources examined
(entries 1ꢀ4). After screening of several common inorganic bases, we identified K2CO3
as the most effective base (entry 1 vs entries 5ꢀ10). When tꢀBuOH was replaced by
CH3CN, the yield of 3aa sharply decreased to 20% (entry 13). Other commonly used
solvents such as DMF and dioxane did not work well (entries 11ꢀ12, 14). Further
reducing the Pd catalyst loading or Pdꢀtoꢀligand ratio (e.g. 1:1) resulted a slightly drop of
product yield (entry 1 vs entries 16ꢀ17).
Table 1. Initial conditions screening of Pdꢀcatalyzed Nꢀarylation of sulfoximine with 2aa
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catalyst
(mol%)
entry
1
solvent
base
% yieldb
94
(93)
Pd(OAc)2 (1.5)
tꢀBuOH
K2CO3
2
3
4
5
6
Pd2(dba)3 (1.5)
Pd(TFA)2 (1.5)
PdCl2 (1.5)
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
NR
91
86
55
80
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Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
K3PO4ꢀH2
7
Pd(OAc)2 (1.5)
tꢀBuOH
90
O
8
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (2.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (1.5)
tꢀBuOH
tꢀBuOH
tꢀBuOH
toluene
DMF
Na3PO4
KOtꢀBu
KF
33
NR
NR
NR
NR
20
NR
94
77
79
93
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17c
18d
19
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH3CN
dioxane
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
iꢀPrOH
aReaction conditions: 1a (0.4 mmol), 2a (0.48 mmol), Pd source (as indicated), MeOꢀCMꢀphos (2.0ꢀ4.0
mol%, Pd/Ligand = 1:2), base (0.8 mmol) and solvent (1.0 mL) were stirred at 110 °C under nitrogen for
18 h. bYields were determined by GCꢀFID with dodecane as the internal standard. Isolated yield was
shown in parentheses. Pd/Ligand = 1:1. dPd/Ligand = 1:3.
c
We next explored the substrate scope by first examining a series of aryl
sulfonates (Scheme 2). In general, Nꢀarylation of sulfoximine proceeded smoothly to
give the desired product in goodꢀtoꢀexcellent yields. Common functional groups such
as methoxy, methyl ester, nitrile and enolizable ketone were wellꢀtolerated under these
reaction conditions (compounds 3af, 3ag, 3ai, 3aj, and 3am). To the best of our
knowledge, there has been no successful example of aryl mesylates reported toꢀdate in
the Nꢀarylation of sulfoximine derivatives. When 1a was treated with aryl mesylates, the
Nꢀarylation proceeded smoothly to afford the desired products. A range of functional
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groups were tolerated (compounds 3aaꢀ3ag and 3al). Heteroaryl tosylates/mesylates
could also be used as the coupling partners to give excellent product yields (compounds
3ac, 3al, 3an). Nevertheless, the oꢀtolyl and pꢀhydroxylphenyl tosylates were found not
applicable.
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Scheme 2. Palladiumꢀcatalyzed Nꢀarylation of sulfoximine 1a with aryl sulfonatesa
NH
1.5 mol% Pd(OAc)2
3.0 mol% MeOꢀCMꢀphos
Me
S O
Me
O
R
N
R
S
+
K2CO3, tꢀBuOH
110 °C, 18 h
OTs/OMs
3
1a
2
N
tꢀBu
Me
Me
O
Me
O
N
N
N
S
S
S
O
3aa
3ab
3ac
98% (OTs)
90% (OMs)
97% (OTs)
80% (OMs)
91% (OTs)
82% (OMs)
Me
Me
O
Me
O
Me
O
Me
N
S
N
N
S
S
Me
O
3af
3ae
3ad
87% (OTs)
84% (OMs)
80% (OTs)
61% (OMs)
71% (OTs)
60% (OMs)
O
S
O
Ph
Me
S
N
N
N
S
Me
Me
O
O
Me
3ag
98% (OMs)
3ah
92% (OTs)
Me
S
CN
Me
O
N
R
N
Me
O
N
S
S
S
O
3ai, 3aj, 3ak
3al
3am
R = COPh, 72% (OTs)
R = COOMe, 85% (OTs)
R = OMe, 85% (OTs)
62% (OTs)
84% (OMs)
89% (OTs)
Me
NO2
Me
Me
O
N
N
N
Me
S
N
Me
S
O
S
O
3an
91% (OTs)
3ao
70% (OTs)
3ap
52% (OTs)b
aReaction conditions: 1a (0.4 mmol), 2 (0.48 mmol), Pd(OAc)2 (1.5 mol%), MeOꢀCMꢀphos (3.0 mol%;
Pd/L = 1:2), K2CO3 (0.8 mmol) and tꢀBuOH (1 mL) were stirred at 110 °C under nitrogen for 18 h.
Isolated yields were reported. Reaction times were not optimized for each substrate. b3.0 mol% of
Pd(OAc)2 and 6.0 mol% of MeOꢀCMꢀphos were used.
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When 4ꢀchloroꢀ3,5ꢀdimethylphenyl tosylate (2q) was used as the substrate, the
Nꢀarylation appeared at the chloroꢀposition instead of the tosylꢀposition even there is a
higher steric hindrance alongside the chloro group (Scheme 3).
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Scheme 3. Palladiumꢀcatalyzed Nꢀarylation of sulfoximine 1a with 2qa
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aReaction conditions: 1a (0.4 mmol), 2q (0.48 mmol), Pd(OAc)2 (1.5 mol%), MeOꢀCMꢀphos (3.0 mol%),
K2CO3 (0.8 mmol) and tꢀBuOH (1 mL) were stirred at 110 °C under nitrogen for 18 h. Isolated yield.
The Pd/MeOꢀCMꢀphos catalytic system was also found to be effective in
promoting the sulfoximination of alkenyl tosylate (Scheme 4). Goodꢀtoꢀexcellent product
yields were obtained (compounds 5aa, 5ab and 5ac).
Scheme 4. Palladiumꢀcatalyzed Nꢀarylation of sulfoximine 1a with alkenyl tosylatesa
aReaction conditions: 1a (0.4 mmol), alkenyl tosylate 4 (0.48 mmol), Pd(OAc)2 (1.5 mol%), MeOꢀCMꢀphos
(3.0 mol%; Pd/L = 1:2), K2CO3 (0.8 mmol) and tꢀBuOH (1 mL) were stirred at 110 °C under nitrogen for 18
h. Isolated yields were reported. Reaction times were not optimized for each substrate.
The scope of the N-arylation reaction with respect to other substituted
sulfoximines 1 and aryl tosylate 2 were next investigated (Scheme 5). An array of
sulfoximines bearing different electron–donating (compounds 3ba, 3dc, 3de, and 3ee)
and –withdrawing substituents (compounds 3ca and 3bc) were tested, and the
corresponding Nꢀarylated sulfoximines were furnished in excellent yields. Notably, S,Sꢀ
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dimethylsulfoximine was also found to be a feasible substrate, affording the product 3gc
in 93% yield. When S,Sꢀtetramethylenesulfoximine was treated with 2a, 70% of the
product 3ha was obtained.
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Scheme 5. Pdꢀcatalyzed Nꢀarylation of substituted sulfoximine 1 with 2a
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aReaction conditions: 1 (0.4 mmol), 2 (0.48 mmol), Pd(OAc)2 (1.5 mol%), MeOꢀCMꢀphos (3.0 mol%; Pd/L
= 1:2), K2CO3 (0.8 mmol) and tꢀBuOH (1 mL) were stirred at 110 °C under nitrogen for 18 h. Isolated
b
yields were reported. Reaction times were not optimized for each substrate. 2.5 mol% Pd(OAc)2 was
used.
In conclusion, we reported the first general examples of palladiumꢀcatalyzed Nꢀ
arylation of sulfoximines using aryl(alkenyl) tosylates or mesylates as the electrophilic
coupling partners. The structure of MeOꢀCMꢀphos ligand was characterized and its
efficacy was found more successful than the corresponding CMꢀphos in dealing with
sulfoximination process. The reaction conditions were compatible with methyl ester,
nitrile, enolizable ketone and etc, and goodꢀtoꢀexcellent product yields were afforded.
This catalyst system would be of interest to organic chemists, as the inherently inert
feature of the tosyloxy/mesyloxy group could offer its protecting characteristic in the
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early stage of synthetic scheme and ultimately allow postꢀfunctionalization via crossꢀ
coupling technology.
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Experimental Section
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General Information. Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without purification. All the reactions were performed in
Rotaflo®(England) reꢀsealable screwꢀcap Schlenk tube (approx. 20 mL volume) in the
presence of Teflon coated magnetic stirrer bar (4 mm × 10 mm). Dioxane and toluene
were freshly distilled over sodium under nitrogen.29 N,NꢀDimethylformamide (DMF) was
distilled from calcium hydride under reduced pressure. Acetonitrile was distilled over
calcium hydride under nitrogen. tꢀBuOH was first distilled over sodium and stored with
calcium hydride under nitrogen. Ligand SPhos, XPhos, RuPhos, BrettPhos, Morꢀ
DalPhos, Xantphos, CataCXium PCy and DPPF were purchased from commercial
suppliers. CMꢀphos ligand was developed by Kwong and prepared according to
literature.30 Thin layer chromatography was performed on precoated silica gel 60 F254
plates. Silica gel (230ꢀ400 mesh) was used for column chromatography. 1H NMR
spectra were recorded on a 400 or 500 MHz spectrometer. Spectra were referenced
internally to the residual proton resonance in CDCl3 (δ 7.26 ppm), or with TMS (δ 0.00
ppm) as the internal standard. Chemical shifts (δ) were reported as part per million
(ppm) in δ scale downfield from TMS. 13C NMR spectra were recorded on a 100 or 125
MHz spectrometer and the spectra were referenced to CDCl3 (δ 77.0 ppm, the middle
peak). Coupling constants (J) were reported in Hertz (Hz). Mass spectra (EIꢀMS and
ESꢀMS) were recorded on a Mass Spectrometer. Highꢀresolution mass spectra (HRMS)
were obtained on a ESIꢀQToF mass spectrometer which the ionization method is
electrospray ionization (ESI) and the mass analyzer is a quadrupole timeꢀofꢀflight mass
analyzer. GCꢀMS analysis was conducted on a GCD system. Products described in GC
yield were accorded to the authentic samples/dodecane calibration standard from GCꢀ
FID system.
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Preparation of 2ꢀ(2ꢀ(dicyclohexylphosphanyl)ꢀ5ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ1Hꢀ
indole (MeOꢀCMꢀphos)
An ovenꢀdried 500ꢀmL singleꢀnecked roundꢀbottomed flask equipped with a Teflonꢀ
coated magnetic stir bar is charged with 2ꢀbromoꢀ5ꢀmethoxyacetophenone (9.8 mL, 60
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mmol) and phenylhydrazine (7.1 mL, 72 mmol) via syringe. Phosphoric acid (30 mL) is
added slowly and the mixture is stirred for 30 min. Polyphosphoric acid (100 g) is
added to the reaction mixture slowly with continuous stirring, and is placed in a
preheated oil bath (80 °C) for 15 min. The bath temperature is raised to 100 °C for 30
min. After completion of the reaction, the resulting mixture is then poured into ice water
and extracted with water and dichloromethane for several times. The organic layer was
separated and the aqueous layer was washed with dichloromethane. The filtrate was
concentrated under rotary evaporation. The crude product was purified by flash column
chromatography on silica gel to afford 2ꢀ(2ꢀbromoꢀ5ꢀmethoxyphenyl)ꢀ1Hꢀindole31 ligand
precursor. Pale yellow powder, 41% yield (7.43 g), hexane:EtOAc=9:1, Rf=0.26. 1H
NMR (500 MHz, CDCl3): δ 8.68 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.5 H, 1H),
7.46 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0, 7.0 Hz, 1H), 7.19ꢀ7.16 (m, 2H), 6.85ꢀ6.80 (m,
2H), 3.86 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 159.0, 136.2 (overlapped), 134.6,
134.1, 128.1, 122.6, 120.8, 120.2, 116.6, 115.3, 111.7, 111.0, 103.6, 55.6.
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An ovenꢀdried 100ꢀmL threeꢀnecked roundꢀbottomed flask is equipped with a Teflonꢀ
coated magnetic stir bar, is charged with sodium hydride (63 % dispersion in mineral oil)
(0.46 g of NaH in oil, 12 mmol). The necks are fitted with pressureꢀequalizing dropping
funnel, is charged with 2ꢀ(2ꢀbromoꢀ5ꢀmethoxyphenyl)ꢀ1Hꢀindole (2.93 g, 9.7 mmol),
rubber septum and nitrogen stopcock inlet. The flask is evacuated and backfilled with
nitrogen three times. Anhydrous tetrahydrofuran (5 mL) is added to the reaction flask
via syringe to form a suspension of sodium hydride. The suspension is cooled to 0 °C
in iceꢀwater bath. The solution of 2ꢀ(2ꢀbromoꢀ5ꢀmethoxyphenyl)ꢀ1Hꢀindole is added
dropwise via dropping funnel to the reaction mixture. Upon completion of addition, the
reaction mixture is allowed to reach room temperature and stirred for 30 min. Dimethyl
sulfate (1.1 mL, 11.6 mmol) are added and the mixture is stirred for overnight. Methanol
is added to quench the reaction and the mixture is extracted with water and ethyl
acetate. The filtrate is concentrated and purified by column chromatography to afford
Nꢀmethylꢀ2ꢀ(2’ꢀbromoꢀ5’ꢀmethoxyphenyl)indole32 ligand precursor. Pale yellow solid,
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72% yield (2.18 g), hexane:EtOAc=9:1, Rf=0.47. H NMR (500 MHz, CDCl3): δ 7.70 (d,
J = 5.0 Hz, 1H), 7.61 (d, J = 8.5 H, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.5, 8.0 Hz,
1H), 7.19 (t, J = 7.5 Hz, 1H), 7.0 (s, 1H), 7.00ꢀ6.90 (m, 1H), 6.54 (s, 1H), 3.85 (s, 3H),
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3.62 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 158.6, 139.6, 137.2, 135.0, 133.3, 127.6,
121.8, 120.7, 119.58, 118.1, 116.2, 115.5, 109.5, 101.9, 55.6, 30.7.
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NꢀMethylꢀ2ꢀ(2’ꢀbromoꢀ5’ꢀmethoxyphenyl)indole (1.26 g, 4.0 mmol) is dissolved in freshly
distilled THF (10 mL) at room temperature under nitrogen atmosphere. The solution is
cooled to ꢀ78 °C in dry ice/acetone bath. Titrated nꢀBuLi (4.4 mmol) is added dropwise
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with
a
syringe.
After the reaction mixture is stirred for 30 min,
chlorodicyclohexylphosphine (1.02 mL, 4.4 mmol) in THF is added. The reaction is
allowed to warm to room temperature and stirred overnight. The solvent is removed
under reduced pressure. The product was recrystallized by cold ethanol and hexane to
afford 2ꢀ(2ꢀ(dicyclohexylphosphanyl)ꢀ5ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ1Hꢀindole (MeOꢀCMꢀ
phos). Offꢀwhite solid, 65% yield (1.73 g), m.p. 112.2ꢀ113.6. 1H NMR (400 MHz,
CDCl3): δ 7.60 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H),
7.21 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6, 7.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.88 (s,
1H), 6.38 (s, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 1.70ꢀ7.55 (m, 11H), 7.18ꢀ1.06 (m, 11H). 13C
NMR (100 MHz, CDCl3): δ 159.3, 142.6, 142.3, 141.3 (overlapped), 136.6, 133.9
(overlapped), 127.8, 127.7, 127.6, 121.1, 120.3, 119.4, 116.8, 116.7, 114.5, 109.5,
103.0, 55.2, 30.9, 30.8, 27.3, 26.4. 31P NMR (162 MHz, CDCl3): δ ꢀ12.36. HRMS: calcd.
for C28H37NOP [M + H]+: 434.2613 found 434.2625.
General Procedures for Ligand and Reaction Condition Screenings
Palladium source (1.5 mol%), ligand (3.0 mol%), 4ꢀtertꢀbutylphenyl tosylate (2a) (145.9
mg, 0.48 mmol), and base (0.8 mmol) were loaded into a Schlenk tube equipped with a
Teflonꢀcoated magnetic stir bar. The tube was evacuated and flushed with nitrogen for
three cycles. Solvent (1.0 mL) and SꢀmethylꢀSꢀphenylsulfoximine (1a) (54.5 ꢁL, 0.4
mmol) were then added with stirring at room temperature for several minutes. The tube
was then placed into a preheated oil bath (110 °C) and stirred for 18 hours. After
completion of reaction, the reaction tube was allowed to cool to room temperature.
Ethyl acetate (~10 mL), dodecane (90.8 ꢂL, internal standard) and water (~3 ml) were
added. The organic layer was subjected to GC analysis. The GC yield obtained was
previously calibrated by authentic sample/dodecane calibration curve.
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General Procedures for Nꢀarylation of Substituted Sulfoximine with Aryl Sulfonate
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Pd(OAc)2 (1.5 mol%, 1.4 mg, 0.006 mmol), MeOꢀCMꢀphos (3.0 mol%, 5.2 mg, 0.012
mmol), aryl sulfonate 2 or alkenyl tosylate 4 (0.48 mmol), and K2CO3 (110.5 mg, 0.8
mmol) were loaded into a Schlenk tube equipped with a Teflonꢀcoated magnetic stir bar.
The tube was evacuated and flushed with nitrogen for three cycles. tꢀBuOH (1.0 mL)
and substituted sulfoximine 1 (0.4 mmol) were then added with stirring at room
temperature for several minutes. The tube was then placed into a preheated oil bath
(110 °C) and stirred for 18 hours. After completion of reaction, the reaction tube was
allowed to cool to room temperature and quenched with water and diluted with ethyl
acetate. The organic layer was separated and the aqueous layer was washed with
ethyl acetate. The filtrate was concentrated under reduced pressure. The crude
product was purified by flash column chromatography on silica gel (230ꢀ400 mesh) to
afford the desired product.
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Nꢀ[(4ꢀ(tertꢀButyl)phenyl)]ꢀSꢀmethylꢀSꢀphenylsulfoximine
(Scheme 1 and 2,
product 3aa)9
Yellow oil, 93% yield (106 mg) for tosyl substrate; 80% yield (92 mg) for mesyl substrate,
hexane:EtOAc=2:1, Rf=0.4. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 7.2 Hz, 2H), 7.60ꢀ
7.53 (m, 3H), 7.16 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 3.23 (s, 3H), 1.25 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 144.3, 142.0, 139.9, 133.1, 129.5, 128.6, 125.8, 122.7,
46.0, 34.0, 31.4.
Nꢀ(2ꢀNaphthyl)ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product 3ab)17a
White solid, 98% yield (110 mg) for tosyl substrate, 92% yield (103 mg) for mesyl
1
substrate, m.p.=141ꢀ142°C, hexane:EtOAc=6:1, Rf=0.6. H NMR (400 MHz, CDCl3): δ
8.16ꢀ8.14 (m, 4H), 7.72 (t, J = 6.6 Hz, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.50ꢀ
7.46 (m, 7H), 7.38 (t, J = 7.1 Hz, 1H), 7.33ꢀ7.28 (m, 1H). 13C NMR (100 MHz, CDCl3): δ
142.6, 140.8, 134.5, 132.8, 129.6, 129.4, 128.7, 128.6, 127.5, 126.9, 125.9, 125.2,
123.8, 119.2. HRMS (ESI) m/z: calcd for C22H18NOS [M + H]+ 344.1109, found 344.1111.
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NꢀQuinolinꢀ6ꢀylꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product 3ac)
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Yellow oil, 97% yield (109 mg) for tosyl substrate, 80% yield (90 mg) for mesyl substrate,
hexane:EtOAc=1:3, Rf=0.3. 1H NMR (400 MHz, CDCl3): δ 8.65 (dd, J = 4.0, 1.2 Hz, 1H),
7.8 (d, J = 7.2 Hz, 2H), 7.87 (t, J = 9.0 Hz, 2H), 7.55ꢀ7.44 (m, 4H), 7.30 (d, J = 2.6 Hz,
1H), 7.20 (q, J = 4.2 Hz, 1H), 3.28 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 148.0, 144.7,
143.7, 138.9, 134.8, 133.4, 130.1, 129.6, 129.2, 128.5, 128.4, 121.0, 117.5, 46.2.
HRMS (ESI) m/z: calcd for C16H15N2OS [M + H]+ 283.0905, found 283.0904.
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Nꢀ[(3,4ꢀDimethyl)phenyl]ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product 3ad)
Yellow oil, 79% yield (81 mg) for tosyl substrate, 60% yield (62 mg) for mesyl substrate,
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hexane:EtOAc=2:1, Rf=0.33. H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 7.4 Hz, 2H),
7.59ꢀ7.52 (m, 3H), 6.90ꢀ6.87 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H) 3.23 (s, 3H), 2.15 (s, 3H),
2.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 142.5, 139.7, 137.1, 133.1, 130.0, 129.8,
129.5, 128.6, 124.8, 120.5, 45.8, 19.8, 19.0. HRMS (ESI) m/z: calcd for C15H18NOS [M +
H]+ 260.1109, found 260.1106.
Nꢀ(1ꢀNaphthyl)ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product 3ae)10
Yellow solid, 88% yield (99 mg) for tosyl substrate, 80% yield (90 mg) for mesyl
substrate, hexane:EtOAc=2:1, Rf=0.5. 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 8.1 Hz,
1H), 8.03 (d, J = 7.4 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.60ꢀ7.48 (m, 5H), 7.42 (d, J =
8.1 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 3.36 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 141.6, 139.4, 134.6, 133.3, 130.1, 129.5, 128.4, 127.8, 126.0,
125.9, 125.0, 124.0, 121.5, 116.5, 45.9.
Nꢀ[(3ꢀAcetyl)phenyl]ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product 3af)
Yellow oil, 82% yield (90 mg) for tosyl substrate, 60% yield (66 mg) for mesyl substrate,
hexane:EtOAc=1:1, Rf=0.4. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.2 Hz, 2H), 7.60ꢀ
7.56 (m, 2H), 7.53ꢀ7.50 (m, 2H), 7.46ꢀ7.43 (m, 1H), 7.20ꢀ7.15 (m, 2H), 3.26 (s, 3H),
2.48 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 198.2, 145.5, 138.9, 138.0, 133.5, 129.6,
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129.1, 128.5, 127.6, 123.3, 121.4, 46.0, 26.7. HRMS (ESI) m/z: calcd for C15H16NO2S
[M + H]+ 274.0902, found 274.0901.
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Nꢀ(6ꢀBenzoylnaphthalenꢀ2ꢀyl)ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product
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3ag)
Yellow solid, 92% yield (142mg), m.p.=104ꢀ105 °C, hexane:EtOAc=1:1, Rf=0.5. 1H NMR
(400 MHz, CDCl3): δ 8.13 (s, 1H), 8.04 (d, J = 7.4 Hz, 2H), 7.86ꢀ7.81 (m, 3H), 7.70 (q, J
= 8.8 Hz, 2H), 7.63ꢀ7.48 (m, 6H), 7.43 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.7, 2.1 Hz, 1H),
3.34 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.6, 146.0, 139.0, 138.3, 136.7, 133.5,
132.6, 132.1, 132.0, 130.4, 129.9, 129.7, 128.5, 128.3, 128.0, 127.0, 126.0, 125.6,
118.0, 46.3. HRMS (ESI) m/z: calcd for C24H20NO2S [M + H]+ 386.1215, found 386.1219.
N,N’ꢀ[Naphthalene]ꢀ2,7ꢀbisꢀ(SꢀmethylꢀSꢀphenylsulfoximine) (Scheme 2, product
3ah)
White soild, 90% yield (156 mg), m.p.=140ꢀ141 °C, hexane:EtOAc=1:3, Rf=0.4. 1H NMR
(400 MHz, CDCl3): δ 8.02ꢀ7.99 (m, 4H), 7.59ꢀ7.56 (m, 2H), 7.53ꢀ7.47 (m, 6H), 7.18 (dd,
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J = 4.7, 1.8 Hz, 2H), 7.08 (t, J = 2.4 Hz, 1H), 7.06 (t, J = 2.4 Hz, 1H), 3.29 (s, 6H). C
NMR (100 MHz, CDCl3): δ 142.9, 139.2 (d, J = 8.4 Hz), 135.4, 133.2, 129.5 (d, J = 2.0
Hz), 128.6 (d, J = 3.0 Hz), 128.2, 125.6, 122.5 (d, J = 11.3 Hz), 117.6 (d, J = 10.1 Hz),
45.9 (d, J = 17.6 Hz). HRMS (ESI) m/z: calcd for C24H23N2O2S2 [M + H]+ 435.1201,
found 435.1205.
Nꢀ[(4ꢀBenzoyl)phenyl]ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product 3ai)
White solid, 78% yield (105 mg), m.p.=177ꢀ178 °C, hexane:EtOAc=1:1, Rf=0.4. 1H NMR
(400 MHz, CDCl3): δ 7.99 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 7.1 Hz, 2H), 7.66ꢀ7.62 (m,
3H), 7.59ꢀ7.52 (m, 3H), 7.46ꢀ7.42 (m, 2H), 7.07 (d, J = 8.5 Hz, 2H), 3.32 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 195.8, 150.0, 138.7, 138.4, 133.7, 131.9, 131.7, 130.5, 129.8,
129.7, 128.5, 128.1, 122.3, 46.4. HRMS (ESI) m/z: calcd for C20H18NO2S [M + H]+
336.1058, found 336.1059.
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Nꢀ[4ꢀ(Methyloxycarbonyl)phenyl]ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2,
product 3aj)
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White solid, 89% yield (103 mg), m.p.=126ꢀ127 °C, hexane:EtOAc=1:1, Rf=0.4. 1H NMR
(400 MHz, CDCl3): δ 7.5 (d, J = 7.7 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.62ꢀ7.59 (m, 1H),
7.55ꢀ7.51 (m, 2H), 7.01 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 3.28 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 167.1, 150.2, 138.7, 133.6, 130.8, 129.7, 128.5, 122.9, 122.5, 51.7,
46.3. HRMS (ESI) m/z: calcd for C15H16NO3S [M + H]+ 290.0851, found 290.0852.
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Nꢀ[(3ꢀMethoxy)]phenylꢀSꢀphenylꢀSꢀmethylsulfoximine (Scheme 2, product 3ak)17a
Yellow oil, 82% yield (75 mg), hexane:EtOAc=2:1, Rf=0.25. 1H NMR (400 MHz, CDCl3):
δ 7.97 (d, J = 7.4 Hz, 2H), 7.59ꢀ7.49 (m, 3H), 7.00 (t, J = 8.3 Hz, 1H), 6.63ꢀ6.61 (m, 2H),
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6.44 (dd, J = 8.2, 2.2 Hz, 1H), 3.69 (s, 3H), 3.23 (s, 3H). C NMR (100 MHz, CDCl3): δ
160.2, 146.3, 139.4, 133.2, 129.6, 129.5, 128.6, 115.7, 109.0, 107.7, 55.1, 46.0.
Nꢀ[3ꢀ(5ꢀMethylꢀthiophenꢀ2ꢀyl)]phenylꢀSꢀphenylꢀSꢀmethylsulfoximine (Scheme 2,
product 3al)
Yellow oil, 92% yield (120 mg), hexane:EtOAc=3:1, Rf=0.5. 1H NMR (400 MHz, CDCl3):
δ 8.00 (d, J = 7.1 Hz, 2H), 7.57ꢀ7.50 (m, 3H), 7.28 (s, 1H), 7.10ꢀ7.08 (m, 2H), 7.03 (d, J
= 3.5 Hz, 1H), 6.94ꢀ6.92 (m, 1H), 6.69 (d, J = 4.5 Hz, 1H), 3.25 (s, 3H), 2.48 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 145.6, 142.1, 139.3, 139.2, 135.4, 133.3, 129.6, 129.4, 128.6,
126.1, 122.8, 121.7, 120.5, 119.0, 45.9, 15.5. HRMS (ESI) m/z: calcd for C18H18NOS2
[M + H]+ 328.0830, found 328.0834.
Nꢀ[4ꢀ(Cyano)phenyl]ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product 3am)9
Yellow oil, 70% yield (72 mg) for tosyl substrate, 86% yield (88 mg) for mesyl substrate,
hexane:EtOAc=2:1, Rf=0.3. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.9 Hz, 2H), 7.66ꢀ
7.62 (m, 1H), 7.58ꢀ7.54 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 3.29
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(s, 3H). C NMR (100 MHz, CDCl3): δ 150.2, 138.4, 133.8, 133.2, 129.8, 128.4, 123.2,
119.6, 103.9, 46.5.
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Nꢀ[3ꢀ(1Hꢀpyrrolꢀ1ꢀyl)]phenylꢀSꢀ(4ꢀmethylphenyl)ꢀSꢀmethylsulfoximine (Scheme 2,
product 3an)
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Yellow oil, 90% yield (106 mg), hexane:EtOAc=3:1, Rf=0.4. 1H NMR (400 MHz, CDCl3):
δ 7.88 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.17ꢀ7.13 (m, 2H), 7.04 (t, J = 1.8 Hz,
2H), 6.94ꢀ6.91 (m, 2H), 6.32 (t, J = 1.8 Hz, 2H), 3.26 (s, 3H), 2.41 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 146.7, 144.4, 141.3, 135.9, 130.4, 129.9, 128.6, 120.2, 119.2,
115.3, 113.5, 110.1, 46.3, 21.6. HRMS (ESI) m/z: calcd for C18H19N2OS [M + H]+
311.1218, found 311.1221.
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Nꢀ[(3,5ꢀDimethyl)phenyl]ꢀSꢀmethylꢀSꢀphenylsulfoximine (Scheme 2, product
3ao)10
White solid, 72% yield (75 mg), hexane:EtOAc=2:1, Rf=0.35. 1H NMR (400 MHz, CDCl3):
δ 8.01 (d, J = 7.3 Hz, 2H), 7.62ꢀ7.52 (m, 3H), 6.70 (s, 2H), 6.56 (s, 1H), 3.23 (s, 3H),
2.20 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 144.6, 139.7, 138.5, 133.1, 129.5, 128.6,
123.7, 121.1, 45.9, 21.3.
Nꢀ[(4ꢀNitro)]phenylꢀSꢀphenylꢀSꢀmethylsulfoximine (Scheme 2, product 3ap)
Pale yellow solid, 52% yield (57 mg), m.p.=131ꢀ134 °C, hexane:EtOAc=1:1, Rf=0.45. 1H
NMR (500 MHz, CDCl3): δ 8.00ꢀ7.94 (m, 4H), 7.65 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz,
2H), 7.03ꢀ7.00 (td, J = 9.0, 2.0 Hz, 2H), 3.32 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
152.6, 141.6, 138.2, 133.9, 129.9, 128.3, 125.1, 122.4, 46.5. HRMS (ESI) m/z: calcd for
C13H13N2O3S [M + H]+ 277.0641, found 277.0644.
3,5ꢀDimethylꢀ4ꢀ((methyl(oxo)(phenyl)ꢀλ6ꢀsulfanylidene)amino)phenyl 4ꢀ
methylbenzenesulfonate (Scheme 3, product 3aq)
Yellow oil, 93% yield (159 mg), hexane:EtOAc=2:1, Rf=0.25. 1H NMR (400 MHz, CDCl3):
δ 8.08 (d, J = 7.4 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.63ꢀ7.61 (m, 1H), 7.58ꢀ7.54 (m, 2H),
7.8 (d, J = 8.1 Hz, 2H), 6.64 (s, 2H), 3.05 (s, 3H), 2.43 (s, 3H), 2.26 (s, 6H). 13C NMR
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(100 MHz, CDCl3): δ 145.1, 144.8, 140.9, 139.7, 135.4, 133.2, 132.6, 129.6, 129.3,
128.5, 127.6, 121.6, 43.8, 21.8, 20.1. HRMS (ESI) m/z: calcd for C22H24NO4S2 [M + H]+
430.1147, found 430.1144.
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1ꢀMethylꢀ4ꢀ((methyl(oxo)(phenyl)ꢀλ6ꢀsulfanylidene)amino)quinolinꢀ2(1H)ꢀone
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(Scheme 4, product 5aa)
White solid, 91% yield (114 mg), m.p.=168ꢀ169 °C, hexane:EtOAc=2:1, Rf=0.2. 1H NMR
(400 MHz, CDCl3): δ 8.30 (dd, J = 7.9, 1.1 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H), 7.61ꢀ7.55
(m, 1H), 7.55ꢀ7.49 (m, 3H), 7.27ꢀ7.21 (m, 2H), 6.15 (s, 1H), 3.56 (s, 3H), 3.36 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 163.0, 151.5, 140.0, 137.7, 133.9, 130.7, 129.8, 128.1,
125.2, 121.4, 120.4, 113.9, 106.2, 46.3, 28.9. HRMS (ESI) m/z: calcd for C17H17N2O2S
[M + H]+ 313.1011, found 313.1009.
4ꢀ[(SꢀMethylꢀSꢀphenylsulfoximin)ꢀyl]ꢀ
product 5ab)
6ꢀmethylꢀ2Hꢀpyranꢀ2ꢀone
(Scheme
4,
Yellow oil, 82% yield (86 mg), hexane:EtOAc=2:1, Rf=0.2. 1H NMR (400 MHz, CDCl3): δ
7.86 (d, J = 7.7 Hz, 2H), 7.64ꢀ7.63 (m, 1H), 7.57ꢀ7.53 (m, 2H), 5.79 (s, 1H), 5.37 (s, 1H),
3.24 (s, 3H), 2.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 164.6, 161.3, 160.3, 137.4,
134.3, 130.0, 127.9, 104.7, 96.0, 46.4, 19.8. HRMS (ESI) m/z: calcd for C13H14NO3S [M
+ H]+ 264.0694, found 264.0695.
4ꢀ[(SꢀMethylꢀSꢀphenylsulfoximin)ꢀyl]ꢀ2Hꢀchromenꢀ2ꢀone (Scheme 4, product 5ac)
1
White solid, 60% yield (71 mg), m.p.=164ꢀ165 °C, hexane:EtOAc=2:1, Rf=0.2. H NMR
(400 MHz, CDCl3): δ 8.12 (dd, J = 7.9, 1.1 Hz, 1H), 7.4 (d, J = 8.1 Hz, 2H), 7.71ꢀ7.67 (m,
1H), 7.61ꢀ7.51 (m, 2H), 7.52ꢀ7.49 (m, 1H), 7.30ꢀ7.23 (m, 2H), 5.71 (s, 1H), 3.42 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 162.4, 156.0, 153.7, 137.0, 134.5, 131.7, 130.1, 127.9,
124.6, 123.6, 119.3, 116.6, 98.3, 46.4. HRMS (ESI) m/z: calcd for C16H14NO3S [M + H]+
300.0694, found 300.0694.
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((3,4ꢀDihydronaphthalenꢀ2ꢀyl)imino)(methyl)(phenyl)ꢀλ6ꢀsulfanone
product 5ad)
(Scheme 4,
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Yellow oil, 86% yield (97 mg), hexane:EtOAc=2:1, Rf=0.2. 1H NMR (500 MHz, CDCl3): δ
7.98 (d, J = 7.5 Hz, 2H), 7.65ꢀ7.56 (m, 3H), 7.05ꢀ7.00 (q, J = 7.5, 6.5 Hz, 2H), 6.94 (t, J
= 6.5 Hz, 1H), 5.92 (s, 1H), 3.24 (s, 3H), 2.86ꢀ2.75 (m, 2H), 2.43 (t, J = 8.0 Hz, 2H). 13C
NMR (125 MHz, CDCl3): δ 144.6, 139.3, 136.1, 133.3, 132.3, 129.5, 128.3, 126.8, 126.2,
124.6, 124.4, 110.9, 45.8, 30.4, 28.6 HRMS (ESI) m/z: calcd for C17H18NOS [M + H]+
284.1104, found 284.1107.
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Nꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀSꢀmethylꢀSꢀ(4ꢀmethylphenyl)sulfoximine (Scheme 5,
product 3ba)13
Yellow oil, 96% yield (116 mg). hexane:EtOAc=5:1, Rf=0.4. 1H NMR (400 MHz, CDCl3):
δ 7.88 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.95 (d, J =
8.6 Hz, 2H), 3.21 (s, 3H), 2.41 (s, 3H), 1.25 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
144.1, 144.0, 142.2, 136.8, 130.2, 128.6, 125.8, 122.7, 46.1, 34.0, 31.4, 21.5.
Nꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀSꢀmethylꢀSꢀ(4ꢀfluorophenyl)sulfoximine (Scheme 5,
product 3ca)
White solid, 90% yield (110 mg), m.p.=109ꢀ110 °C, hexane:EtOAc=5:1, Rf=0.4. 1H NMR
(400 MHz, CDCl3): δ 8.02ꢀ7.99 (m, 2H), 7.19ꢀ7.15 (m, 4H), 6.95ꢀ6.93 (d, J = 8.8 Hz, 2H),
3.23 (s, 3H), 1.25 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 165.5 (d, J = 253.6 Hz), 144.5,
141.8, 135.7, 131.4 (d, J = 9.4 Hz), 125.9, 122.7, 116.8 (d, J = 22.5 Hz), 46.1, 34.0,
31.4. HRMS (ESI) m/z: calcd for C17H21FNOS [M + H]+ 306.1328, found 306.1326.
NꢀQuinolinꢀ6ꢀylꢀSꢀmethylꢀSꢀ(4ꢀfluorophenyl)sulfoximine (Scheme 5, product 3bc)
Yellow oil, 99% yield (118 mg), hexane:EtOAc=1:2, Rf=0.5. 1H NMR (400 MHz, CDCl3):
δ 8.66 (dd, J = 4.2, 1.5 Hz, 1H), 7.99ꢀ7.96 (m, 2H), 7.89ꢀ7.86 (m, 2H), 7.44 (dd, J = 9.0,
2.4 Hz, 1H), 7.29ꢀ7.28 (m, 1H), 7.21 (q, J = 4.2 Hz, 1H), 7.17ꢀ7.12 (m, 2H), 3.28 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 165.6 (d, J = 254.6 Hz), 148.1, 144.7, 143.4, 134.9,
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134.7, 131.4 (d, J = 9.5 Hz), 130.1, 129.1, 128.3, 121.1, 117.0 (d, J = 22.4 Hz), 116.8,
46.3. HRMS (ESI) m/z: calcd for C16H14FN2OS [M + H]+ 301.0811, found 301.0800.
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NꢀQuinolinꢀ6ꢀyl-Sꢀ(4ꢀmethoxylphenyl)ꢀSꢀmethylsulfoximine (Scheme 5, product
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3dc)
Yellow oil, 87% yield (109 mg), hexane:EtOAc=2:1, Rf=0.4. 1H NMR (400 MHz, CDCl3):
δ 8.61ꢀ8.60 (m, 1H), 7.87ꢀ7.82 (m, 4H), 7.43 (dd, J = 8.9, 2.3 Hz, 1H), 7.27 (d, J = 2.2
Hz, 1H), 7.16 (q, J = 4.1 Hz, 1H), 6.90ꢀ6.88 (m, 2H), 3.71 (s, 3H), 3.24 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ163.5, 147.7, 144.4, 144.0, 134.9, 130.7, 129.8, 129.7, 129.2,
128.6, 120.9, 117.4, 114.9, 55.6, 46.5. HRMS (ESI) m/z: calcd for C17H17N2O2S [M + H]+
313.1011, found 331.0988.
Nꢀ(1ꢀNaphthyl)ꢀSꢀmethylꢀSꢀ(4ꢀmethoxyphenyl)sulfoximine
3de)
(Scheme 5, product
White solid, 89% yield (111 mg), m.p.=145ꢀ146 °C, hexane:EtOAc=2:1, Rf=0.5. 1H NMR
(400 MHz, CDCl3): δ 8.62 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.79 (d, J = 7.9
Hz, 1H), 7.58ꢀ7.48 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.15 (d, J =
6.7 Hz, 1H), 6.89 (d, J = 8.9 Hz, 2H), 3.75 (s, 3H), 3.32 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 163.4, 142.0, 134.6, 130.6, 130.4, 130.2, 127.8, 126.1, 125.9, 125.0, 124.1,
121.4, 116.5, 114.8, 55.6, 46.3. HRMS (ESI) m/z: calcd for C18H18NO2S [M + H]+
312.1058, found 312.1059.
Nꢀ[3ꢀ(1HꢀPyrrolꢀ1ꢀyl)]phenylꢀSꢀ(4ꢀmethylphenyl)ꢀSꢀmethylsulfoximine (Scheme 5,
product 3bm)
Yellow oil, 90% yield (111 mg), hexane:EtOAc=3:1, Rf=0.4. 1H NMR (400 MHz, CDCl3):
δ 7.88 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.17ꢀ7.13 (m, 2H), 7.04 (t, J = 1.8 Hz,
2H), 6.94ꢀ6.91 (m, 2H), 6.32 (t, J = 1.8 Hz, 2H), 3.26 (s, 3H), 2.41 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 146.7, 144.4, 141.3, 135.9, 130.4, 129.9, 128.6, 120.2, 119.2,
115.3, 113.5, 110.1, 46.3, 21.6. HRMS (ESI) m/z: calcd for C18H19N2OS [M + H]+
311.1218, found 311.1221.
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Nꢀ[3ꢀ(1Hꢀpyrrolꢀ1ꢀyl)]phenylꢀSꢀ(4ꢀmethoxylphenyl)ꢀSꢀmethylsulfoximine (Scheme 5,
product 3dm)
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Yellow oil, 84% yield (109 mg), hexane:EtOAc=2:1, Rf=0.4. 1H NMR (400 MHz, CDCl3):
δ 7.91 (d, J = 8.8 Hz, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 2.0 Hz, 1H), 7.04 (t, J =
2.1 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.93ꢀ6.91 (m, 2H), 6.31 (t, J = 2.1 Hz, 2H), 3.84 (s,
3H), 3.26 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.6, 146.7, 141.3, 130.7, 130.1,
129.8, 120.2, 119.2, 115.3, 114.9, 113.5, 110.1, 55.7, 46.5. HRMS (ESI) m/z: calcd for
C18H19N2O2S [M + H]+ 327.1167, found 327.1170.
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Nꢀ(1ꢀNaphthyl)ꢀS,Sꢀ(diꢀ4ꢀmethylphenyl)sulfoximine (Scheme 5, product 3ee)
White solid, 95% yield (140 mg), m.p.=153ꢀ154 °C, hexane:EtOAc=4:1, Rf=0.5. 1H NMR
(400 MHz, CDCl3): δ 8.78 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.2 Hz, 4H), 7.80 (d, J = 8.0
Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.27ꢀ
7.18 (m, 6H), 2.36 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 143.4, 141.5, 138.3, 134.6,
130.5, 130.0, 128.4, 127.8, 126.1, 125.8, 125.0, 124.1, 121.3, 116.9, 21.5. HRMS (ESI)
m/z: calcd for C24H22NOS [M + H]+ 372.1422, found 372.1425.
Nꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀS,Sꢀdiphenylsulfoximine (Scheme 5, product 3fa)
White solid, 90% yield (125 mg), m.p.=158ꢀ159 °C, hexane:EtOAc=8:1, Rf=0.5. 1H NMR
(400 MHz, CDCl3): δ 8.09 (d, J = 7.4 Hz, 4H), 7.52ꢀ7.44 (m, 6H), 7.19 (d, J = 8.6 Hz,
2H), 7.10 (d, J = 8.6 Hz, 2H), 1.27 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 144.2, 141.7,
141.2, 132.6, 129.3, 128.5, 125.8, 123.1, 34.1, 31.4. HRMS (ESI) m/z: calcd for
C22H24NOS [M + H]+ 350.1579, found 350.1581.
Nꢀ(2ꢀNaphthyl)ꢀS,Sꢀdiphenylsulfoximine (Scheme 5, product 3fb)
White solid, 90% yield (123 mg), m.p.=141ꢀ142 °C, hexane:EtOAc=6:1, Rf=0.6. 1H NMR
(400 MHz, CDCl3): δ 8.16ꢀ8.14 (m, 4H), 7.72 (t, J = 6.6 Hz, 2H), 7.67 (d, J = 8.2 Hz, 1H),
7.60 (s, 1H), 7.50ꢀ7.46 (m, 7H), 7.38 (t, J = 7.1 Hz, 1H), 7.33ꢀ7.28 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 142.6, 140.8, 134.5, 132.8, 129.6, 129.4, 128.7, 128.6, 127.5,
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126.9, 125.9, 125.2, 123.8, 119.2. HRMS (ESI) m/z: calcd for C22H18NOS [M + H]+
344.1109, found 344.1111.
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NꢀQuinolinꢀ6ꢀylꢀS,Sꢀdimethylsulfoximine (Scheme 5, product 3gc)
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Yellow oil, 93% yield (81 mg), hexane:EtOAc=1:2, Rf=0.25. 1H NMR (400 MHz, CDCl3):
δ 8.69ꢀ8.68 (m, 1H), 7.93 (t, J = 8.4 Hz, 2H), 7.40ꢀ7.38 (m, 2H), 7.24 (q, J = 4.2 Hz, 1H),
3.13 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 148.2, 144.9, 143.8, 134.8, 130.2, 129.3,
128.5, 121.2, 127.2, 42.0. HRMS (ESI) m/z: calcd for C11H13N2OS [M + H]+ 221.0749,
found 221.0748.
Nꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀS,Sꢀtetramethylenesulfoximine (Scheme 5, product 3ha)
Yellow oil, 70% yield (70 mg), hexane:EtOAc=2:1, Rf=0.35. 1H NMR (400 MHz, CDCl3):
δ 7.26 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 3.45ꢀ3.38 (m, 2H), 3.19ꢀ3.12 (m, 2H),
2.32ꢀ2.21 (m, 4H), 1.31 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 144.4, 143.2, 126.1,
122.2, 52.4, 34.1, 31.5, 23.9. HRMS (ESI) m/z: calcd for C14H22NOS [M + H]+ 252.1427,
found 252.1424.
1
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Supporting Information Available: Copies of H NMR and C NMR spectra, as well
as Xꢀray crystallographic data and HRMS spectrum of MeOꢀCMꢀphos. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgements
We thank the National Natural Science Foundation of China (NSFC: 2015ꢀ21572193),
Research Grants Council of Hong Kong, Collaborative Research Fund (CRF: C5023ꢀ
14G), General Research Fund (GRF: 153034/15P) and CUHK Direct Fund (4053269)
for financial support. We are grateful to Dr. Pui Kin So (University research facilities in
Life Science, PolyU) for HRMS analysis.
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References
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(2)
For recent references, see: (a) Reggelin, M.; Zur, C. Sulfoximines: Structures,
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sulphoximineꢀsubstituted quinazoline and quinazoline derivatives as kinase
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sequenceꢀreceptor kinase inhibitors useful to prepare medicaments to e.g. treat
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(c) Blum, A.; Gottschling, D.; Heckel, A.; Hehn, J. P.; Schmid, B.; Wiedenmayer,
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