Sulfoximine-directed ruthenium-catalyzed ortho -C-H Alkenylation of (Hetero)Arenes: Synthesis of EP3 receptor antagonist analogue

Article abstract of DOI:10.1021/jo5008465

The reusable sulfoximine directing-group-assisted Ru(II)-catalyzed chemo- and regioselective ortho-C-H alkenylation of arenes and heteroarenes with acrylates and α,β-unsaturated ketones/vinyl sulfone is shown. The N-aroyl sulfoximine undergoes annulation with diphenylacetylene, delivering isoquinolinones and methyl phenyl sulfoxide. The present protocol is successfully employed for the synthesis of the EP3 receptor antagonist analogue.

Full text of DOI:10.1021/jo5008465

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Article
Sulfoximine Directed Ruthenium Catalyzed Ortho-C-H Alkenylation
of (Hetero)Arenes: Synthesis of EP3 Receptor Antagonist Analog
M Ramu Yadav, Raja K Rit, Majji Shankar, and Akhila Kumar Sahoo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5008465 • Publication Date (Web): 06 Jun 2014
Downloaded from http://pubs.acs.org on June 18, 2014
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Sulfoximine Directed Ruthenium Catalyzed Ortho-CH
Alkenylation of (Hetero)Arenes: Synthesis of EP3
Receptor Antagonist Analog
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M. Ramu Yadav, Raja K. Rit, Majji Shankar, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
akhilchemistry12@gmail.com
RECEIVED DATE (to be automatically inserted)
ABSTRACT
The reusable sulfoximine directing group assisted Ru(II)-catalyzed chemo and regioselective ortho-CH
alkenylation of arenes and heteroarenes with acrylates, and α,β-unsaturated ketones/vinyl sulfone is
shown. The N-aroyl sulfoximine undergoes annulation with diphenylacetylene delivering
isoquinolinones and methyl phenyl sulfoxide. The present protocol is successfully employed for the
synthesis of EP3 receptor antagonist analog.
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Introduction
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The development of synthetically viable strategies for the creation of olefin-units in molecules is
always desirable; as the hydrogenated acrylate derivative 3-(2-carbamoyl-phenyl)-propionic acid, a key
structural component found in many biologically active and pharmaceutically important molecules
(Figure 1).1 The Mizoroki-Heck reaction of aryl electrophiles with alkenes and the Fujiwara-Moritani
cross-dehydrogenative oxidative coupling of arenes with alkenes are reliable approaches, invariably
employed for the formation of olefin moieties.2
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The transition-metal-catalyzed, chelation assisted activation of arene CH bonds is a straightforward
method broadly useful for the functionalization of unactivated CH bonds; one of the elegant
manifestations of this strategy is expressed in the formation of chemo- and regioselective Colefin
bonds.3,4 As these strategies do not require the pre-activated precursor, providing broad and ready access
of substrate scope, their utility in the fabrication of complex molecules with step-efficiency is thus
noteworthy.5 A variety of modifiable and non-modifiable directing groups (DGs) have successfully been
employed, accomplishing o-CH alkenylation of arenes under the influence of Pd(II),4 Rh(III)6 and/or
Ru(II)7-catalysts and oxidants. The use of inexpensive, air stable Ru(II)-catalysts under the coordination
ability of reusable DGs for the o-CH olefination of arene would promote widening the synthetic utility
of this approach.7 Dixneuf,7a,c,n Miura,7f,o,s Ackermann7e,h,m,p and Jaganmohan7d,j,q, among others, have
contributed significantly in the development of Ru-catalyzed modifiable/non-modifiable DG assisted o-
CH alkenylation of arenes. 7
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Figure 1. EP3 Receptor Antagonist Analogs
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We have recently demonstrated the sp2 CH oxidation and amidation of arenes with the aid of the
reusable S-methyl-S-phenylsulfoximine (MPS) DG.8,9 To broaden the synthetic utility of reusable MPS-
DG further, we envisioned performing alkenylation on unactivated arenes under the influence of robust
Ru-catalysts; the results are detailed herewith. The application of the current method for the synthesis of
an EP3 antagonist analog (D) is also shown.
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Results and Discussion:
Table 1. Optimization of Reaction Conditionsa
entry additive
(20 mol%)
solvent
yield (%)b
3a 4a
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ClCH2CH2Cl
<5
90
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AgSbF6 ClCH2CH2Cl
NaPF6
KPF6
<10
20
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ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
NaBF4
AgBF4 ClCH2CH2Cl 92 (84)c
-
AgBF4
AgBF4
AgBF4
ClCH2CH2Cl
CH2Cl2
CHCl3
toluene
1,4-dioxane
54d
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85
21
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10 AgBF4
11 AgSbF6
-
25d,e
aReaction conditions: 2a (0.1 mmol), alkene (0.2 mmol), [RuCl2(p-cymene)]2 (5.0 mol %),
Cu(OAc)2·H2O ( 1.0 equiv), solvent (0.5 mL), 24 h. bCrude 1H NMR conversion based on of the ratio of
starting material to product. c2a (0.5 mmol), ClCH2CH2Cl (2.0 mL), isolated yield in parenthesis. dIn the
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e
absence of Cu(OAc)2·H2O. AcOH (1.0 equiv) was used. The experiments in dichloromethane,
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chloroform, and toluene were run at 120 oC in a sealed tube.
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To begin with, the dehydrogenative alkenylation of N-(m-methylbenzoyl)-MPS (2a) with ethyl
acrylate (1a) was investigated under the influence of Ru(II)-catalyst, silver salts, Cu(OAc)2·H2O, and
solvents (Table 1). The reaction between 2a and 1a with 5.0 mol % [RuCl2(p-cymene)]2 and
Cu(OAc)2·H2O (1.0 equiv) in 1,2-dichloroethane (DCE) at 120 C produced a trace amount of N-[(E)-2-
(3-ethoxy-3-oxoprop-1-en-1-yl)-5-methyl-benzoyl]-MPS (3a), regioselectively functionalizing the
sterically less hindered o-CH bond of 2a. The yield of 3a was enhanced to 90% when AgSbF6 was
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1
employed; formation of a minor amount of hydroarylation product 4a was also observed by HNMR
(entry 2). Screening of NaPF6, KPF6, and NaBF4 salts in this reaction turned unsatisfactory (entries
35). The AgBF4 was equally efficient, delivering 3a in 92% yield (entry 6). To our delight, we
observed the exclusive formation of o-CH E-alkenylation products. The absence of Cu(OAc)2·H2O led
to lower yield of 3a (entry 7). Upon careful scrutiny of various solvents, DCE was found best (entries
810). The reaction of 2a with 1a under the Miura conditions [{RuCl2(p-cymene)}2 (5.0 mol %),
AgSbF6 (20 mol %), AcOH (1.0 equiv), 1,4-dioxane] led to the formation of 3a in only 43% yield (entry
11). Thus, the condition shown in entry 6, Table 1 was realized optimum for the sulfoximine directed
oxidative o-CH alkenylation of arenes in 2a. To our disappointment, 2a did not undergo alkenylation
with unactivated alkene (e.g., styrene) under the present reaction conditions.10
Reaction Scope:
The optimized condition was explored examining the scope and generality of o-CH alkenylation of
arenes 2 with activated olefins 1. The results are summarized in scheme 1. The less hindered o-CH
bond in electron-rich and deficient m-substituted arenes selectively alkenylated, affording 3ad in
7186% yield; the Br, ester, and –NO2 groups did not affect the reaction outcome. The ester group did
not assist the o-CH alkenylation in 2c,7l-m witnessing the effective directing group ability of the
sulfoximine moiety. The catalytic condition is suitable for the gram scale synthesis of 3a. The olefinated
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product 3e was exclusively obtained from β-naphthyl substrate 2e in good yield. The alkenylation was
effectively conducted between 2a and other electron-deficient alkenes; methyl acrylate (1b), n-butyl
acrylate (1c) and phenyl vinyl sulfone (1d) readily coupled with 2a, producing the corresponding o-
CH alkenylation products 3fh in good to excellent yields. The oxidative alkenylation of m-substituted
electron-rich and -poor substrates 2a and 2c with ethyl vinyl ketone (1e) led to 3i and 3j in 70% and
72% yield, respectively. Even more electron deficient tetrafluoro substituted arene 2f was compatible,
furnishing 3k and 3l in 79% and 81% yield, respectively. In some cases, the formation of minor amount
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of hydroarylation product along with the desired alkenylation compound was observed in H NMR; the
ratio of hydroarylation and alkenylation products is shown in parenthesis.
Scheme 1. o-CH Alkenylation of meta- and Fluoro Substituted N-Aroyl Derivativesa,b
aReaction conditions: 2 (0.5 mmol), alkene (1.0 mmol), [RuCl2(p-cymene)]2 (5.0 mol %), AgBF4 (20
mol %), Cu(OAc)2·H2O (1.0 equiv), ClCH2CH2Cl (2.0 mL), 120 °C for 24 h. bIsolated yields. c2a (1.0 g,
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3.7 mmol), AgSbF6 (20 mol %) used. Minor amount of hydroarylation product (<5%) observed by 1H
d
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NMR; the corresponding alkenylation product 3 is ~95% pure. eRatio of alkenylation and hydroarylation
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f
product observed by H NMR; in case of 3l, ratio is detected by 19F NMR. 2f (0.15 mmol) was
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employed.
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We next investigated the coupling of o-substituted N-aroyl-MPS with 1 (Table 2). The reaction
between N-(o-methylbenzoyl)-MPS (2g) and 1a surprisingly produced a major amount of o-
1
hydroarylation product 4b over the desired alkenylation compound 3m (by H NMR), suggesting the
occurrence of proto-demetalation over β-hydride elimination.11 The inseparable hydroarylation and
alkenylation products render the purification extremely difficult. To validate product isolation ease, the
non-purified mixture of compounds was subjected to hydrogenation with Pd/C in methanol, converting
the alkenylation product to the hydroarylation compound with the survival of MPS-DG.12 Following
these procedures, a wide variety of o,o-disubstituted N-aroyl MPS products 4bj were synthesized in
overall good yields (Table 2). The o-alkenylation followed by hydrogenation of o-Me/Ph/OPh
substituted compounds 2gi with 1a furnished 4bd in 7487% yield. The fluoro-bearing product 4e
was isolated in 70% yield. The desired 2-alkyl-4,6-dimethyl derivative 4f was obtained from 2k in good
yield. The α-naphthyl substrate 2l reacted well, affording 73% of product 4g. The alkenylation and
hydrogenation sequence on 2h with phenyl vinyl sulfone delivered 4h in 82% yield. The α,β-
unsaturated ketones smoothly participated, and the desired products 4i and 4j were prepared in moderate
yields.
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Table 2. Alkylation of o-Substituted Arenesa,b
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entry
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3:4
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4
R = Me (2g)
Ph (2h)
1:2
2:1
2:1
2:3
4b, 80%
4c, 87%
4d, 74%
4e, 70%
OPh (2i)
F (2j)
5
1:3
4f, 78%
2k
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7
1:2
4:3
4g, 73% (14:3)c
4h, 82%
2l
2h
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9
2:1
3:1
2i
2j
4i, 61%
4j, 64%
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aReaction conditions: 2 (0.5 mmol), alkene (1.0 mmol), [RuCl2(p-cymene)]2 (5.0 mol %), AgBF4
(20 mol %), Cu(OAc)2·H2O (1.0 equiv), ClCH2CH2Cl (2.0 mL), 120 °C for 24 h and Pd/C (50
mg, 20 wt%).bIsolated yields. c2l (0.32 mmol) was employed.
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In contrast, the reaction of electron neutral 2m or p-Me/F substituted N-aroylated sulfoximines
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2n/2o with 1a showed a complex mixture (by H NMR), displaying the possible formation of a
non-separable mixture of o-CH mono-, di-alkenylation, and their corresponding hydroarylation
products; subsequent hydrogenation of the non-purified mixture of compounds exhibited the
corresponding mono-(4km) and di-hydroarylation (4'km) products in overall good yields
(Table 3). The formation of di-hydroarylation product enables accessing highly peripheral
decorated benzoic acid derivatives.
Table 3. o-CH Alkylation of Unsubstituted and p-Substituted Arene Derivativesa,b
entry
2
4/4′
R = H,
2m
1
2
4k 69% (1:1)b 4k
R =
Me, 2n
4l 71% (1:1)b 4l
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R = F,
2o
4m 83% (9:4)b 4m
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aReaction conditions: 2 (0.5 mmol), 1a (3.5 equiv), [RuCl2(p-cymene)]2 (5.0 mol %), AgBF4 (20
mol %), Cu(OAc)2·H2O (1.0 equiv), ClCH2CH2Cl (2.0 mL), 120 °C for 24 h and Pd/C (50 mg,
b
20 wt%). Combined yield of isolated mono- and dialkylation products (the mono/di ratio is
indicated in the parentheses).
The utility of the catalytic conditions to the introduction of an olefin moiety on heteroarenes is
further examined (Table 4). The unsubstituted and 5-substituted thienyl derivatives 2ps
smoothly underwent oxidative alkenylation, affording the desired products 5ad in excellent
yields; the chloro and ester functional groups did not interfere with the reaction efficiency.
However, the N-methyl indole derivative 2t furnished a mixture of alkenylation 5e and
hydroarylation 5e at the electron rich C3 position in a 2:3 ratio; while, the reaction of
benzofuran derivative 2u with 1a exclusively produced 5f. Other activated alkenes 1c and 1d
were effective coupling partners and the CC coupled products 5gand 5h were isolated good to
excellent yields. The reaction of 2p with activated ketones (1e and 1f) is no exception, providing
5i and 5j in 91% and 86% yield, respectively. The inseparable mixture of alkenylation and
hydroarylation products in 5j is observed 3:1 ratio.
Table 4. Alkenylation of Heteroarene Derivativesa,b
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entry
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entry
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5a, 88%
5b, 90%
5c, 85%
5d, 84%
5f, 88%
5g, 82%
5h, 95%
5i, 91%
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2q
2r
2s
2u
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2p
2p
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5e, 60% (2:3)c
5j, 86% (3:1)c
2t
2p
aReaction conditions: 2 (0.5 mmol), alkene (1.0 mmol), [RuCl2(p-cymene)]2 (5.0 mol %), AgBF4
b
(20 mol %), Cu(OAc)2·H2O (1.0 equiv), ClCH2CH2Cl (2.0 mL), 120 °C for 24 h. Isolated
yields. cRatio of alkenylation and hydroarylation product observed by 1H NMR.
The practical utility of the present protocol is demonstrated with the ready cleavage amide-
linkage and recovery of methyl phenyl sulfoximine. Gratifyingly, the base promoted (NaOH in
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MeOH/H2O solvent at 60 C for 6 h) saponification of 4a yielded 6 (90%) with recovery of 81%
of methyl phenyl sulfoximine 12(eq 1).
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The current protocol has successfully been applied in the synthesis of EP3 antagonist analog 3-
(2-(naphthalen-1-ylmethylcarbamoyl)-4-(phenoxymethyl)phenyl)propanoic acid (D) (Scheme
2).1 The synthesis is begun by reacting 7 and 1a under the optimized conditions shown in entry 6,
Table 1, producing the o-CH alkenylation product 8 along with a minor amount hydroarylation
1
compound 8 (4:1 ratio by H NMR). The reduction of activated olefin with NiCl26H2O/NaBH4
in MeOH/THF gave the hydrogenated product 8 in 59% overall yield from 7. Base mediated
hydrolysis of 8 led to the dicarboxylic acid derivative 9 with the recovery of methyl phenyl
sulfoximine. The selective esterification of aliphatic acid, EDC-mediated amide formation
between naphthalen-1-ylmethanamine and benzoic acid moiety, and finally hydrolysis of ester
group delivered the desired EP3 antagonist molecule D in 34% overall yield from 9.
Scheme 2. Synthesis of EP3 Antagonist Analog
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Reaction conditions: a) 7 (2.5 g, 6.8 mmol), 1a (13.7 mmol), [RuCl2(p-cymene)]2 (10 mol %),
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AgSbF6 (40 mol %), Cu(OAc)2·H2O (1.0 equiv), ClCH2CH2Cl (10.0 mL), 120 °C for 24 h; 66%.
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
b) NiCl2·6H2O, NaBH4, MeOH/THF, 0 C to rt, overnight; 89%. c) NaOH, MeOH/H2O, 60 C,
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4h. d) cat. H2SO4, MeOH (1.0 equiv), 20 min; 85%. e) EDC·HCl, HOBt, naphthalen-1-
ylmethanamine, DMF, rt, 24 h; 64%. f) LiOH·H2O, MeOH/THF, 60 C, 4h; 62%.
To understand the mechanistic insights, a deuterium labelling experiment was performed on 2g
(eq 2). Gratifyingly, 95% deuterium incorporation at the ortho-CH in 2g occurred,13 when 2g
exposed to Ru(II)-catalyst, AgSbF6 in CD3COOD at 120 °C for 10 h. In addition, the acidic s-
methyl protons underwent deuterium exchange. These results presumably suggest that the
insertion of Ru to the o-CH bond is reversible.
The hydroarylation outcome from o-substituted N-benzoylated sulfoximine and the activated
olefin (Table 2) prompted us to examine the reaction between N-(o-methylbenzoyl)-MPS (2g)
and internal unactivated alkyne, as this would result in the trisubstituted olefin. To our surprise,
we noticed the formation of isoquinolinone 11 (40%) and 35% of methyl phenyl sulfoxide (12)
from 2g and diphenylacetylene (1g) under the Miura conditions (eq 3).14,15,16 Furthermore, the
annulation between 2j and 1g gave product 13 in 63% yield (eq 3). The compound 12 is useful
for the synthesis of MPS-DG.
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Conclusion: In summary, we report Ru(II)-catalyzed o-CH alkenylation and hydroarylation of
(hetero)arenes with activated olefins: acrylates, vinyl sulfones, and ketones with the aid of
reusable methyl phenyl sulfoximine directing group. Isoquinolinone derivatives are synthesized
from N-aroylated sulfoximines and diphenylacetylene. The isolation of MPS and the methyl
phenyl sulfoxide make these strategies synthetically viable and useful. The utility of this
transformation enables the synthesis of EP3 receptor antagonist analog.
Experimental Section
General Information:
All the reactions were performed in an oven-dried Schlenk flask. Commercial grade solvents
were distilled prior to use. Column chromatography was performed using either 100-200 Mesh
or 230-400 Mesh silica gel. Thin layer chromatography (TLC) was performed on silica gel
GF254 plates. Visualization of spots on TLC plate was accomplished with UV light (254 nm)
and staining over I2 chamber.
Proton, carbon, and fluorine nuclear magnetic resonance spectra (1H NMR, 13C NMR and 19F
13
NMR) were recorded based on the resonating frequencies as follows: (1H NMR, 400 MHz; C
NMR, 101 MHz; 19F NMR, 376 MHz) and (1H NMR, 500 MHz; 13C NMR, 126 MHz; 19F NMR,
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470 MHz) having the solvent resonance as internal standard (1H NMR, CHCl3 at 7.26 ppm; C
NMR, CDCl3 at 77.0 ppm). Few cases tetramethylsilane (TMS) at 0.00 ppm was used as
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reference standard. Data for 1H NMR are reported as follows: chemical shift (ppm), multiplicity
(s = singlet; bs = broad singlet; d = doublet; bd = broad doublet, t = triplet; bt = broad triplet; q =
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quartet; m = multiplet), coupling constants, J, in (Hz), and integration. Data for C NMR, F
NMR were reported in terms of chemical shift (ppm). IR spectra were reported in cm1. High
resolution mass spectra were obtained in (ESI-TOF analyzer) equipment. Melting points were
determined by electro-thermal heating and are uncorrected.
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Materials: Unless otherwise noted, all the reagents and intermediates were obtained
commercially and used without purification. Dichloromethane (DCM) and 1, 2-dichloroethane
(DCE) were distilled over CaH2. [RuCl2(p-cymene)]2, AgSbF6, AgBF4, AgPF6 and KPF6 were
purchased from Sigma Aldrich Ltd, and used as received. Analytical and spectral data of all the
known compounds are exactly matching with the reported values.
Following the known procedure, compounds 2a, 2c, 2d, 2e, 2g, 2h, 2j, 2k, 2l, 2m, 2n, 2o, and 2p
are prepared.8a-b Analytical and spectral data of these compounds are exactly matching with the
reported values.
Experimental Procedures:
Preparation of N-Aroyl S-methyl-S-phenylsulfoximines:
Synthesis of methyl phenyl sulfoximine from sulfoxide is well established. 8a
Scheme 3
General procedure (GP-1); EDC-coupling:8a
A solution of N'-(3-dimethylaminopropyl)-N-ethylcarbodimide, hydrochloride salt (EDC·HCl)
(2.0 equiv), 4-N,N-dimethylaminopyridine (DMAP) (2.2 equiv) and benzoic acids (1; 1.1 equiv)
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in CH2Cl2 (5.0 mL, for 1 mmol of sulfoximine) was stirred under an argon atmosphere.
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Sulfoximine (12; 1.0 equiv) was introduced drop wise at 0 C. The resulting reaction mixture
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was stirred for about 1 h at 0 C, and warmed to ambient temperature and continued for
overnight. Upon complete consumption of sulfoximine, the reaction mixture was acidified with
hydrochloric acid (HCl, 1N). The organic layer was separated; the aqueous layer was extracted
with CH2Cl2 (3 times).The combined extracts were washed with 10% aqueous NaHCO3 and
brine. The organic layer was dried over Na2SO4. Solvent was filtered and evaporated under
reduced pressure. The crude residue was purified using column chromatography on silica gel
using hexane/ ethyl acetate (3:2).
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N-[3-Bromobenzoyl]-S-methyl-S-phenylsulfoximine (2b): 0.76 g, 70% yield; colorless solid;
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m.p. 99100 C; Rf  0.34 (1:1 hexane/EtOAc); H NMR (400 MHz, CDCl3)  8.30 (s, 1H),
8.07 (d, J  7.6, 1H), 8.03 (d, J  7.6, 2H), 7.69 (bt, J  7.2 Hz, 1H), 7.657.58 (m, 3H), 7.28 (t,
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J  7.8 Hz, 1H), 3.46 (s, 3H); C NMR (101 MHz, CDCl3)  172.6, 138.5, 137.5, 134.9, 133.9,
129.7, 129.6, 127.9 (2C), 127.0 (3C), 122.1, 44.3; IR (Neat)max 3028, 2922, 1635, 1215 cm1;
HRMS (ESI) for C14H12BrNO2S (M+H)+: calcd. 337.985, found 337.9850.
N-[2,3,4,5-Tetrafluorobenzoyl]-S-methyl-S-phenylsulfoximine (2f): 0.42 g, 40% yield,
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colorless crystalline solid; m.p.  104106 C; Rf  0.50 (3:2 hexane/EtOAc); H NMR (400
MHz, CDCl3) 8.05 (d, J 7.6 Hz, 2H), 7.72 (bt, J  7.4 Hz, 1H), 7.687.60 (m, 3H), 3.48 (s,
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3H); C NMR (101 MHz, CDCl3)168.9, 147.5 (dd, J 260, 11 Hz), 146.1 (dd, J 248, 11
Hz), 142.6 (dt, J 261, 14 Hz), 141.0 (dt, J 255, 14 Hz), 137.9, 134.2, 129.8 (2C), 127.1 (2C),
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120.5, 112.9 (d, J 20 Hz), 44.3; F (376 MHz, CDCl3)135.90 (m), 139.01 (m),149.81
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(m), 154.61 (m); IR (KBr) max 3030, 2936, 1649, 1632, 1468, 1216 cm1; HRMS (ESI) for
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C14H9F4NO2S (M+Na)+: calcd. 354.0188, found 354.0189.
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N-[2-Phenoxybenzoyl]-S-methyl-S-phenylsulfoximine (2i): 0.73 g, 65% yield; colorless
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crystalline solid; m.p.  120122 C; Rf  0.42 (3:2 hexane/EtOAc); H NMR (400 MHz,
CDCl3)7.94 (d, J  7.6 Hz, 1H), 7.78 (d, J  7.6 Hz, 2H), 7.60 (t, J  7.2 Hz, 1H), 7.507.40
(m, 3H), 7.29 (t, J  7.6 Hz, 2H), 7.21 (t, J  7.6 Hz, 1H), 7.077.00 (m, 2H), 6.96 (d, J  8.0
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Hz, 2H), 3.15 (s, 3H); C NMR (101 MHz, CDCl3) 173.8, 158.7, 154.1, 138.3, 133.6, 132.4,
131.5, 130.2 (2C), 129.6 (2C), 129.4, 127.1 (2C), 124.2, 122.1, 121.8, 117.0 (2C), 43.9; IR (KBr)
max 3063, 2926, 1621, 1309, 1232 cm1; HRMS (ESI) for C20H17NO3S (M+Na)+: calcd.
374.0827, found 374.0820.
N-[5-Methylthenoyl]-S-methyl-S-phenylsulfoximine (2q): 0.65 g, 72% yield, colorless
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crystalline solid; m.p.  129131 C; Rf  0.30 (2:3hexane/EtOAc); H NMR (400 MHz,
CDCl3)8.04 (d, J  7.6 Hz, 2H), 7.68 (t, J 7.4 Hz, 1H), 7.647.56 (m, 3H), 6.73 (d, J 3.2
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Hz, 1H), 3.44 (s, 3H), 2.50 (s, 3H); C NMR (101 MHz, CDCl3)168.7, 146.9, 138.7, 138.4,
133.7, 132.4, 129.5 (2C), 127.0 (2C), 126.2, 44.3, 15.7; IR (KBr) max 3030, 2926, 1610, 1282
cm1; HRMS (ESI) for C13H13NO2S2 (M+Na)+: calcd. 302.0286, found 302.0282.
N-[5-Chlorothenoyl]-S-methyl-S-phenylsulfoximine (2r): 0.80 g, 82% yield; colorless
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crystalline solid; m.p.  120121 C; Rf  0.35 (3:2 hexane/EtOAc); H NMR (400 MHz,
CDCl3)8.03 (d, J  7.6 Hz, 2H), 7.71 (bt, J 7.4 Hz, 1H), 7.63 (bt, J  7.6 Hz, 2H), 7.57 (d, J
4.0 Hz, 1H), 6.90 (d, J  3.6 Hz, 1H), 3.45 (s, 3H); 13C NMR (101 MHz, CDCl3)167.7,
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139.2, 138.5, 136.1, 134.0, 131.4, 129.7 (2C), 127.2, 127.1 (2C), 44.4; IR (KBr) max 3024, 2931,
1610, 1435, 1221 cm1; HRMS (ESI) for C12H10ClNO2S2 (M+Na)+: calcd. 321.9739, found
321.9740.
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N-[5-Methoxycarbonylthenoyl]-S-methyl-S-phenylsulfoximine (2s): 0.71g, 68% yield;
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colorless crystalline solid; m.p.  152154 C; Rf  0.32 (3:2 hexane/EtOAc); H NMR (400
MHz, CDCl3)8.05 (d, J 7.6 Hz, 2H), 7.757.68 (m, 3H), 7.64 (t, J  7.6 Hz, 2H), 3.90 (s,
3H), 3.47 (s, 3H); 13C NMR (101 MHz, CDCl3)168.2, 162.5, 146.5, 138.3, 137.6, 134.1, 133.2,
131.6, 129.8 (2C), 127.2 (2C), 52.4, 44.4; IR (KBr) max 3024, 2926, 1720, 1610, 1254 cm1;
HRMS (ESI) for C14H13NO4S2 (M+Na)+: calcd. 346.0184, found 346.0187.
N-[N-Methyl-2-indoloyl]-S-methyl-S-phenylsulfoximine (2t): 0.73 g, 73% yield; colorless
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crystalline solid; m.p.  153155 C; Rf  0.38(3:2 hexane/EtOAc); H NMR (400 MHz,
CDCl3) 8.08 (d, J  7.2 Hz, 2H), 7.737.65 (m, 2H), 7.63 (t, J  7.4 Hz, 2H), 7.45 (s, 1H),
7.397.28 (m, 2H), 7.13 (t, J  7.2 Hz, 1H), 4.07 (s, 3H), 3.44 (s, 3H); 13C NMR (101 MHz,
CDCl3)169.7, 139.8, 139.0, 133.8, 133.3, 129.7 (2C), 127.2 (2C), 125.9, 124.5, 122.4, 120.2,
110.3, 110.1, 44.8, 31.7; IR (KBr) max 3008, 2920, 1616, 1468, 1260 cm1; HRMS (ESI) for
C17H16N2O2S (M+Na)+: calcd. 335.0830, found 335.0829.
N-[2-benzofuronoyl]-S-methyl-S-phenylsulfoximine (2u): 1.51 g, 79% yield; colorless
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crystalline solid; m.p.  130131 C; Rf  0.31 (3:2 hexane/EtOAc); H NMR (400 MHz,
CDCl3) 8.08 (d, J  7.6 Hz, 2H), 7.727.57 (m, 5H), 7.53 (s, 1H), 7.41 (t, J  7.8 Hz, 1H),
7.317.25 (m, 1H), 3.52 (s, 3H);13C NMR (101 MHz, CDCl3) 166.0, 155.4, 150.7, 138.2,
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133.9, 129.6 (2C), 127.3, 127.0 (2C), 126.8, 123.3, 122.5, 112.5, 112.2, 44.3; IR (KBr) max
3024, 2920, 1643, 1616, 1572, 1216 cm1; HRMS (ESI) for C16H13NO3S (M+H)+: calcd.
300.0694, found 300.0697.
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Optimization for ortho-CH Alkenylation:
The CH alkenylation reaction was conducted in a 50 mL Schlenk tube with high pressure valve
and side arm. The tube was charged with N-(m-methylbenzoyl)-MPS (2a, 27.3 mg, 0.1 mmol),
ethyl acrylate (1a, 21 L, 0.2 mmol), [RuCl2(p-cymene)]2 (3.1 mg, 5.0 mol %), Cu(OAc)2·H2O
(20 mg, 0.1 mmol). Subsequently, the reaction tube was taken to the glove box and the additives
were introduced. The corresponding solvent (0.5 mL) was added to the mixture and the resulting
mixture was stirred at 120 C for 24 h. The reaction mixture was cooled to ambient temperature,
filtered through a plug of Celite and then washed with CH2Cl2 (3 × 5 mL). The solvents were
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evaporated under reduced pressure and the crude material was analyzed based on H NMR
spectroscopy.
General Procedure for ortho-CH Alkenylation Reaction (GP-2):
The CH alkenylation reactions were carried out in a 50 mL Schlenk tube with high pressure
valve and side arm. The tube was charged with N-aroylated sulfoximine (2a2u, 0.5 mmol),
alkene (1af, 1.0 mmol), [RuCl2(p-cymene)]2 (15.0 mg, 5.0 mol %), and Cu(OAc)2·H2O (100
mg, 1.0 mmol). Subsequently, the reaction tube was taken to the glove box and AgSbF6/AgBF4
(20 mol %) was introduced. The solvent 1,2dichloroethane (DCE, 2.0 mL) was added to the
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mixture and the resulting mixture was stirred at 120 C for 24 h. The reaction mixture was
cooled to ambient temperature, filtered through a small plug of Celite and then washed with
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CH2Cl2 (3 × 10 mL). The solvents were evaporated under reduced pressure and the crude
material was purified using column chromatography on silica gel (3040% n-hexane/EtOAc as
an eluent) to give the desired product.
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N-[(E)-2-(3-Ethoxy-3-oxoprop-1-en-1-yl)-5-methylbenzoyl]-S-methyl-S-phenylsulfoximine
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(3a): 156 mg, 84% yield; colorless crystalline solid; m.p. 9597 C; H NMR (400 MHz,
CDCl3) d, J  15.2 Hz, 1H), 8.09 (d, J 8.4 Hz, 2H), 7.83 (s, 1H), 7.69 (bt, J  7.4 Hz,
1H), 7.62 (bt, J  7.8 Hz, 2H), 7.47 (d, J  7.6 Hz, 1H), 7.27 (bd, J  7.6 Hz, 1H), 6.26 (d, J 
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15.6 Hz, 1H), 4.24 (q, J  6.9 Hz, 2H), 3.50 (s, 3H), 2.39 (s, 3H), 1.30 (t, J  7.2 Hz, 3H); C
NMR (101 MHz, CDCl3)175.4, 167.1, 144.9, 139.6, 138.4, 136.2, 133.9, 132.3, 132.0, 131.0,
129.7 (2C), 127.5, 127.2 (2C), 118.7, 60.3, 44.4, 21.2, 14.3; IR (KBr) max 2980, 2931, 1719,
1615, 1308, 1210 cm1; HRMS (ESI) for C20H21NO4S (M+H)+: calcd. 372.1269, found
372.1269.
The same reaction was carried out in bulk scale using 2a (1.0 g, 3.7 mmol), ethyl acrylate (1a,
5.55 mmol), [RuCl2(p-cymene)]2 (113 mg, 5.0 mol %), Cu(OAc)2·H2O (736 mg, 3.7 mmol),
AgSbF6 (254 mg, 0.74 mmol) in 1,2-DCE (10.0 mL) at 120 C for 24 h. The product 3a (0.98 g)
was obtained in 72% yield.
N-[(E)-2-(3-Ethoxy-3-oxoprop-1-en-1-yl)-5-bromobenzoyl]-S-methyl-S-phenylsulfoximine
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(3b): 155 mg, 71% yield; colorless crystalline solid; m.p.  110112 C; H NMR (400 MHz,
CDCl3)8.48 (d, J 15.6 Hz, 1H), 8.19 (d, J 2.0 Hz, 1H), 8.06 (d, J  7.2 Hz, 2H), 7.70 (t, J 
7.4 Hz, 1H), 7.63 (t, J  7.4 Hz, 2H), 7.58 (dd, J 8.0, 2.0 Hz, 1H), 7.40 (d, J  8.4 Hz, 1H),
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NMR (101 MHz, CDCl3)173.5, 166.6, 143.8, 138.1, 137.5, 134.2, 134.1, 134.0, 133.5, 129.7
(2C), 129.1, 127.1 (2C), 123.3, 120.1, 60.4, 44.3, 14.2; IR (KBr) max 3018, 2980, 2936, 1719,
1621, 1100 cm1; HRMS (ESI) for C19H18BrNO4S (M+H)+: calcd. 436.0218, found 436.0223.
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N-[3-Methoxycarbonyl-(E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)-benzoyl]-S-methyl-S-phenyl
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sulfoximine (3c): 164 mg, 79% yield; colorless crystalline solid; m.p.  126128 C; H NMR
(400 MHz, CDCl3)8.70 (s, 1H), 8.54 (d, J 16.0 Hz, 1H), 8.138.05 (m, 3H), 7.70 (t, J  7.2
Hz, 1H), 7.677.57 (m, 3H), 6.32 (d, J 16.0 Hz, 1H), 4.24 (q, J 7.1 Hz, 2H), 3.93 (s, 3H),
3.49 (s, 3H), 1.30 (t, J  7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)174.1, 166.4, 165.9, 143.8,
139.5, 138.0, 136.1, 133.9, 131.8 (2C), 130.5, 129.6 (2C), 127.8, 127.0 (2C), 121.3, 60.4, 52.2,
44.2, 14.1; IR (KBr)max 3019, 2926, 1704, 1632, 1200 cm1; HRMS (ESI) for C21H21NO6S
(M+Na)+: calcd. 438.0988, found 438.1006.
N-[(E)-2-(3-Ethoxy-3-oxoprop-1-en-1-yl)-5-methyl-4-nitrobenzoyl]-S-methyl-S-phenyl
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sulfoximine (3d): 180 mg, 86% yield; yellow crystalline solid; m.p. 145147 C; H NMR
(400 MHz, CDCl3)8.45 (d, J  16.0 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J 7.6 Hz, 2H), 7.96 (s,
1H), 7.71 (t, J  7.4 Hz, 1H), 7.64 (t, J  7.6 Hz, 2H), 6.34 (d, J  16.0 Hz, 1H), 4.24 (q, J  7.1
Hz, 2H), 3.50 (s, 3H), 2.61 (s, 3H),1.30 (t, J  7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)173.3,
166.3, 149.9, 142.2, 139.6, 137.8, 134.9, 134.1 (2C), 133.9, 129.8 (2C), 127.0 (2C), 123.5, 121.1,
60.6, 44.2, 20.1, 14.2; IR (KBr)max 2997, 2931, 1715, 1638, 1523, 1221, 1189 cm1; HRMS
(ESI) for C20H20N2O6S (M+H)+: calcd. 417.1120, found 417.1121.
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sulfoximine
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(3e): 170 mg, 83% yield; viscous liquid; H NMR (400 MHz, CDCl3)8.64 (bd, J  15.6 Hz,
1H), 8.61 (bs,1H), 8.09 (d, J 7.6 Hz, 2H), 7.97 (s, 1H), 7.88 (d, J  7.6 Hz, 1H), 7.82 (d, J 
7.6 Hz, 1H), 7.66 (bt, J  7.2 Hz, 1H), 7.59 (t, J  7.2 Hz, 2H), 7.577.46 (m, 2H), 6.36 (d, J 
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15.6 Hz, 1H), 4.24 (q, J  7.1 Hz, 2H), 3.50 (s, 3H), 1.30 (t, J  7.2 Hz, 3H); C NMR (101
MHz, CDCl3)174.9, 166.9, 145.7, 138.4, 134.1, 133.8, 133.2, 132.8, 132.5, 131.6, 129.6 (2C),
128.7, 128.0, 127.9, 127.5, 127.1 (3C), 119.0, 60.3, 44.3, 14.2; IR (Neat)max 3063, 2980, 1709,
1638, 1282, 1221 cm1; HRMS (ESI) for C23H21NO4S (M+Na)+: calcd. 430.1089, found
430.1090.
N-[(E)-2-(3-Methoxy-3-oxoprop-1-en-1-yl)-5-methylbenzoyl]-S-methyl-S-phenylsulfoximine
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(3f): 141 mg, 79% yield; colorless crystalline solid; m.p.  123125 C; H NMR (400 MHz,
CDCl3)8.55 (d, J 16.0 Hz, 1H), 8.07 (d, J  7.6 Hz, 2H), 7.84 (s, 1H), 7.68 (t, J  7.4 Hz,
1H), 7.61 (t, J  7.6 Hz, 2H), 7.45 (d, J  8.0 Hz, 1H), 7.26 (d, J  8.0 Hz, 1H), 6.25 (d, J  16.0
Hz, 1H), 3.75 (s, 3H), 3.47 (s, 3H), 2.37 (s, 3H); 13C NMR (101 MHz, CDCl3)175.3, 167.4,
145.1, 139.6, 138.3, 136.0, 133.8, 132.2, 131.9, 131.0, 129.6 (2C), 127.4, 127.1 (2C), 118.2,
51.5, 44.3, 21.2; IR (Neat)max 3013, 2947, 1704, 1627, 1210 cm1; HRMS (ESI) for
C19H19NO4S (M+Na)+: calcd. 380.0933, found 380.0937.
N-[(E)-2-(3-n-Butoxy-3-oxoprop-1-en-1-yl)-5-methylbenzoyl]-S-methyl-S-phenylsulfoxi-
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mine (3g):167 mg, 84% yield; viscous liquid; H NMR (400 MHz, CDCl3)8.55 (d, J 15.6
Hz, 1H), 8.09 (d, J  8.0 Hz, 2H), 7.82 (s, 1H), 7.69 (t, J  7.4 Hz, 1H), 7.62 (t, J 7.6 Hz, 2H),
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7.47 (d, J = 8.0 Hz, 1H), 7.25 (bd, J 5.2 Hz, 1H), 6.27 (d, J  16.0 Hz, 1H), 4.17 (t, J 6.6 Hz,
2H), 3.49 (s, 3H), 2.38 (s, 3H), 1.701.59 (m, 2H), 1.471.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) 175.5, 167.3, 145.0, 139.7, 138.5, 136.3, 133.9, 132.3, 132.0,
131.1, 129.7 (2C), 127.5, 127.2 (2C), 118.7, 64.3, 44.4, 30.8, 21.3, 19.2, 13.8; IR (Neat) max
2964, 2926, 1704, 1627, 1315, 1210 cm1; HRMS (ESI) for C22H25NO4S (M+H)+: calcd.
400.1582, found 400.1583.
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N-[(E)-2-(2-(Phenylsulfonyl)vinyl)-5-methylbenzoyl]-S-methyl-S-phenylsulfoximine (3h):
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198 mg, 90% yield; colorless crystalline solid; m.p.  157159 C; H NMR (400 MHz,
CDCl3)8.71 (d, J 15.2 Hz, 1H), 8.09 (d, J  7.6 Hz, 2H), 7.91 (d, J  7.6 Hz, 2H), 7.82 (s,
1H), 7.707.53 (m, 4H), 7.49 (t, J  7.6 Hz, 2H), 7.32 (d, J  8.0 Hz, 1H), 7.22 (d, J  7.6 Hz,
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1H), 6.67 (d, J  15.2 Hz, 1H), 3.50 (s, 3H), 2.34 (s, 3H); C NMR (101 MHz, CDCl3)174.6,
143.4, 140.7, 138.1, 136.4, 133.8, 133.1, 131.9, 131.2, 129.8, 129.7 (2C), 129.1(2C), 127.5,
127.4 (2C), 127.0 (2C), 126.9, 44.2, 21.1 (one 13C–value is merged with other peak); IR (KBr)
max 3052, 2920, 1621, 1221 cm1; HRMS (ESI) for C23H21NO4S2 (M+H)+: calcd. 440.0990,
found 440.0990.
N-[(E)-2-(3-Oxopent-1-enyl)-5-methylbenzoyl]-S-methyl-S-phenylsulfoximine (3i):
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124 mg, 70% yield; colorless viscous oil; H NMR (400 MHz, CDCl3)8.45 (d, J 17.2 Hz,
1H), 8.08 (d, J  8.4 Hz, 2H), 7.89 (s, 1H), 7.71 (t, J  7.8 Hz, 1H), 7.63 (bt, J 7.6 Hz, 2H),
7.49 (d, J  8.4 Hz , 1H), 7.327.26 (m, 1H), 6.53 (d, J  16.4 Hz , 1H), 3.49 (s, 3H), 2.722.61
(m, 2H), 2.41 (s, 3H), 1.11 (t, J  7.2 Hz , 3H); 13C NMR (101 MHz, CDCl3)201.7, 175.5,
142.8, 139.7, 138.4, 136.0, 133.9, 132.7, 132.1, 131.2, 129.7 (2C), 127.4, 127.1 (3C), 44.4, 33.2,
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21.2, 8.2; IR (KBr) max 3013, 2920, 1665, 1621, 1276, 1210 cm1; HRMS (ESI) for C20H21NO3S
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(M+H)+: calcd. 356.1320, found 356.1322.
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N-[3-Methoxycarbonyl-(E)-6-(3-oxopent-1-enyl)-5-methylbenzoyl]-S-methyl-S-phenyl
sulfoximine (3j): Following GP-2, reaction between 2c and 1e gave the inseparable alkenylation
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3j and hydroarylation products (4:1 by H NMR; 144 mg, 72% yield) as colorless crystalline
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solid. H NMR (400 MHz, CDCl3)8.76 (s, 1H), 8.45 (d, J  16.4 Hz, 1H), 8.158.03 (m, 3H),
7.72 (bt, J  7.6 Hz, 1H), 7.64 (bt, J  8.4 Hz, 3H), 6.57 (d, J  16.4 Hz, 1H), 3.95 (s, 3H), 3.49
(s, 3H), 2.702.65 (m, 2H), 1.12 (t, J  7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) 201.3, 174.4,
166.1, 141.7, 140.1, 138.2, 136.1, 134.0, 132.0, 130.6, 129.8 (2C), 129.4, 127.8, 127.1 (3C),
52.3, 44.4, 28.8, 8.0; IR (Neat) max 2926, 1720, 1671, 1627, 1315 cm1; HRMS (ESI) for
C21H21NO5S (M+H)+: calcd. 400.1218, found 400.1223.
N-[(E)-2-(3-Ethoxy-3-oxoprop-1-en-1-yl)-tetrafluorobenzoyl]-S-methyl-S-phenylsulfoximi-
ne (3k): Following GP-2, reaction between 2f and 1a gave the inseparable alkenylation 3k and
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hydroarylation products (3.3:1 by H NMR; 170 mg, 79% yield) as pale yellow solid. H NMR
(400 MHz, CDCl3) 8.06 (d, J  8.4 Hz, 2H), 7.777.62 (m, 4H), 6.60 (d, J 16.0 Hz, 1H), 4.25
(q, J  7.1 Hz, 2H), 3.49 (s, 3H), 1.32 (t, J  7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)172.1,
169.7, 166.2, 137.4, 134.4, 133.5, 130.0 (2C), 127.2 (2C), 60.9, 44.2, 14.1 (The large number of
19
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less-intense 13C values arise from F and C coupling are omitted due to lack of clarity); F
(470 MHz, CDCl3)137.46, 141.04, 152.26, 154.52IR (KBr) max 3013, 2926, 1715,
1632, 1512, 1473, 1232 cm1; HRMS (ESI) for C19H15F4NO4S (M+Na)+: calcd. 452.0556, found
452.0556.
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N-[(E)-2-(2-(Phenylsulfonyl)vinyl)-tetrafluorobenzoyl]-S-methyl-S-phenylsulfoximine (3l):
Following GP-2, reaction between 2f and 1d gave the inseparable alkenylation 3l and
hydroarylation products (6:1 by 19F NMR; 60 mg, 81% yield) as yellow viscous liquid. 1H NMR
(400 MHz, CDCl3)8.10 (bd, J 7.2 Hz, 2H), 7.89 (bd, J 7.6 Hz, 2H), 7.80 (bd, J 15.6 Hz,
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1H), 7.767.60 (m, 4H), 7.55 (bt, J 7.4 Hz, 2H), 7.10 (d, J 16.0 Hz, 1H), 3.54 (s, 3H); C
NMR (101 MHz, CDCl3)169.0, 139.5, 137.2, 134.5, 133.8, 131.5, 130.0 (2C), 129.5 (2C),
127.8 (2C), 127.1 (3C), 44.0 (The large number of less-intense 13C values arise from 19F and C
coupling are omitted due to lack of clarity); 19F (470 MHz, CDCl3)136.13, 139.85, 149.83,
153.74IR (Neat) max 3079, 2926, 1627, 1506, 1369, 1238 cm1; HRMS (ESI) for
C22H15F4NO4S2 (M+H)+: calcd. 498.0457, found 498.0457.
General Procedure for ortho-CH Alkenylation and Hydrogenation on ortho and para-
Substituted N-Aroyl-MPS Derivatives (GP-3):
Following GP-2, the CH alkenylation on ortho-substituted-N-aroyl-MPS derivatives gave non-
separable mixture of alkenylation and hydroarylation products. To make the purification ease,
the non-purified mixture of compounds were subjected to hydrogenation.
Accordingly, a solution of non-purified mixture of compounds in methanol was subjected to
hydrogenation in the presence of Pd/C (50 mg, 20 wt%) under hydrogen balloon for overnight at
room temperature. The solvent was evaporated under reduced pressure and the crude material
was purified using column chromatography on silica gel (3040% n-hexane/EtOAc as eluent) to
give the desired hydroarylation product.
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N-[2-(3-Ethoxy-3-oxopropyl)-6-methylbenzoyl]-S-methyl-S-phenylsulfoximine(4b): 150 mg,
80% yield; colorless crystalline solid; m.p.  9597 C; 1H NMR (400 MHz, CDCl3)8.05 (d, J
 7.2 Hz, 2H), 7.66 (bt, J  7.2 Hz, 1H), 7.59 (t, J  7.4 Hz, 2H), 7.13 (t, J  7.6 Hz, 1H), 7.01
(d, J  7.6 Hz, 2H), 4.10 (q, J  7.1 Hz, 2H), 3.47 (s, 3H), 3.062.96 (m, 2H), 2.702.60 (m,
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2H), 2.35 (s, 3H), 1.21 (t, J  7.0 Hz, 3H); C NMR (101 MHz, CDCl3)178.7, 173.1, 139.0,
138.4, 135.9, 134.0, 133.8, 129.6 (2C), 128.24, 128.18, 127.0 (2C), 126.3, 60.3, 43.9, 36.1, 29.0,
19.4, 14.1; IR (KBr) max 3030, 2926, 1731, 1632, 1293,1216 cm1; HRMS (ESI) for
C20H23NO4S (M+H)+: calcd. 374.1426, found 374.1426.
N-[2-(3-Ethoxy-3-oxopropyl)-6-phenylbenzoyl]-S-methyl-S-phenylsulfoximine (4c): 190 mg,
87% yield; colorless viscous liquid; 1H NMR (400 MHz, CDCl3) 7.607.50 (m, 3H), 7.457.28
(m, 8H), 7.287.22 (m, 1H), 7.21 (d, J  7.2 Hz, 1H), 4.11 (q, J 7.1 Hz, 2H), 3.21 (s, 3H),
3.203.01 (m, 2H), 2.782.69 (m, 2H), 1.22 (t, J  7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3)178.2, 173.0, 141.9, 138.8, 138.4, 138.0, 137.4, 133.6, 129.2 (2C), 129.1(2C), 128.6,
128.4, 128.0 (2C), 127.8, 127.0, 126.9 (2C), 60.2, 42.8, 35.8, 28.8, 14.1; IR (Neat) max 3063,
2980, 1726, 1627, 1221 cm1; HRMS (ESI) for C25H25NO4S (M+H)+: calcd. 436.1582, found
436.1581.
N-[2-(3-Ethoxy-3-oxopropyl)-6-phenoxybenzoyl]-S-methyl-S-phenylsulfoximine (4d): 166
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mg, 74% yield; colorless crystalline solid; m.p.  146148 C; H NMR (400 MHz,
CDCl3)7.86 (d, J 8.0 Hz, 2H), 7.59 (t, J 7.4 Hz, 1H), 7.45 (t, J  7.8 Hz, 2H), 7.31 (t, J
7.8 Hz, 2H), 7.21 (t, J  7.8 Hz, 1H), 7.107.00 (m, 4H), 6.82 (d, J 8.4 Hz, 1H), 4.11 (q, J
7.1 Hz, 2H), 3.23 (s, 3H), 3.09 (t, J 7.8 Hz, 2H), 2.71 (t, J  8.0 Hz, 2H), 1.22 (t, J  7.0 Hz,
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3H); 13C NMR (101 MHz, CDCl3)175.6, 172.9, 157.9, 152.7, 139.4, 138.0, 133.7, 132.1, 129.6
(2C), 129.5, 129.4 (2C), 127.2 (2C), 124.9, 122.7, 117.9 (2C), 117.8, 60.2, 43.9, 35.7, 28.5, 14.1;
IR (KBr) max 3024, 2926, 1736, 1638, 1216 cm1; HRMS (ESI) for C25H25NO5S (M+H)+: calcd.
452.1531, found 452.1532.
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N-[2-(3-Ethoxy-3-oxopropyl)-6-fluorobenzoyl]-S-methyl-S-phenylsulfoximine (4e): 132 mg,
70% yield; colorless crystalline solid; m.p.  6466 C; 1H NMR (400 MHz, CDCl3)8.08 (d, J
 7.6 Hz, 2H), 7.68 (bt, J  7.4 Hz, 1H), 7.61 (bt, J  7.4 Hz, 2H), 7.297.18 (m, 1H), 7.00 (d, J
 7.6 Hz, 1H), 6.93 (t, J  9.0 Hz, 1H), 4.09 (q, J  7.2 Hz, 2H), 3.43 (s, 3H), 3.06 (t, J  7.8 Hz,
2H), 2.65 (td, J 7.8 Hz, 2H), 1.20 (t, J  7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3)173.8,
172.7, 159.3 (d, J  248 Hz, 1C), 140.2, 138.0, 134.0, 129.9 (d, J  9.1 Hz, 1C), 129.7 (2C),
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127.2 (2C), 127.0, 125.0, 113.6 (d, J  22 Hz, 1C), 60.3, 44.2, 35.7, 28.4, 14.1; F(470 MHz,
CDCl3)IR (Neat) max 2975, 2936, 1731, 1627, 1287, 1227 cm1; HRMS (ESI) for
C19H20FNO4S (M+H)+: calcd. 378.1175, found 378.1178.
N-[2-(3-Ethoxy-3-oxopropyl)-4,6-dimethylbenzoyl]-S-methyl-S-phenylsulfoximine (4f): 151
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mg, 78% yield; colorless crystalline solid; m.p. 113115 C; H NMR (400 MHz,
CDCl3)8.08 (d, J  7.6 Hz, 2H), 7.68 (bt, J  6.8 Hz, 1H), 7.61 (bt, J  7.6 Hz, 2H), 6.85 (bd, J
 2.4 Hz,, 2H), 4.12 (q, J  7.2 Hz, 2H), 3.48 (s, 3H), 3.072.91 (m, 2H), 2.702.61 (m, 2H),
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2.35 (s, 3H), 2.26 (s, 3H), 1.24 (t, J  7.2 Hz, 3H); C NMR (101 MHz, CDCl3)178.9, 173.3,
138.7, 138.0, 136.3, 136.2, 134.2, 133.8, 129.6 (2C), 129.1, 127.2 (2C), 127.1, 60.3, 44.0, 36.3,
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C21H25NO4S (M+H)+: calcd. 388.1582, found 388.1577.
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N-[2-(3-Ethoxy-3-oxopropyl)-α-naphtholoyl]-S-methyl-S-phenylsulfoximine and N-[2-(3-
Methoxy-3-oxopropyl)-α-naphtholoyl]-S-methyl-S-phenylsulfoximine (4g & 4'g):
Following GP-3, reaction between 2l (100 mg, 0.32 mmol) and ethyl acrylate (1a, 69 μL, 0.65
mmol) under the optimized conditions followed by hydrogenation in MeOH afforded the
inseparable mixture of products 4g & 4g (94 mg, 4.6:1; 1H NMR) in 73% yield. 1H NMR (400
MHz, CDCl3)8.11 (d, J = 7.6 Hz, 2H), 7.98 (d, J  8.4 Hz, 1H), 7.817.73 (m, 2H), 7.69 (t, J 
7.4 Hz, 1H), 7.62 (t, J  7.6 Hz, 2H), 7.517.38 (m, 2H), 7.367.29 (m, 1H), 4.14 (q, J  7.1 Hz,
0.5 H), 3.68 (s, 2.3H), 3.53 (s, 3H), 3.253.16 (m, 2H), 2.802.72 (m, 2H), 1.24 (t, J  7.2 Hz,
0.75H); 13C NMR (101 MHz, CDCl3)178.3, 173.5, 173.1, 138.4, 135.7, 133.9, 133.5, 132.1,
129.8, 129.7, 128.8, 127.8, 127.1, 126.6, 125.5, 125.1, 60.4, 51.6, 44.2, 36.1, 35.9, 29.4, 14.2.
N-[2-(2-(Phenylsulfonyl)ethyl)-6-phenylbenzoyl]-S-methyl-S-phenylsulfoximine (4h): 206
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mg, 82% yield; colorless viscous liquid; H NMR (400 MHz, CDCl3) 7.95 (d, J 7.6 Hz, 2H),
7.687.59 (m, 2H), 7.55 (bt, J 7.2 Hz, 2H), 7.507.28 (m, 10H), 7.21 (bt, J 8.6 Hz, 2H), 3.55
(bt, J 8.0 Hz, 2H), 3.333.19 (m, 4H), 3.183.08 (m, 1H); 13C NMR (101 MHz, CDCl3)
177.5, 141.2, 139.1, 138.6, 138.3, 137.7, 134.1, 133.6, 133.4, 129.2 (2C), 129.0 (2C), 128.72
(3C), 128.68, 128.5, 128.0 (2C), 127.8 (2C), 127.1, 126.7 (2C), 56.8, 42.6, 27.1; IR (neat) max
3068, 2920, 1626, 1451, 1308, 1150 cm1; HRMS (ESI) for C28H25NO4S2 (M+Na)+: calcd.
526.1123, found 526.1125.
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N-[2-(3-Oxopentyl)-6-phenoxybenzoyl]-S-methyl-S-phenylsulfoximine (4i): 134 mg, 61%
yield; colorless viscous liquid; 1H NMR (400 MHz, CDCl3)7.83 (bd, J 7.6 Hz, 2H), 7.58 (t, J
7.2 Hz, 1H), 7.44 (t, J  7.8 Hz, 2H), 7.31 (t, J 7.8 Hz, 2H), 7.19 (t, J 8.0 Hz, 1H),
7.126.97 (m, 4H), 6.80 (d, J 8.0 Hz, 1H), 3.21 (s, 3H), 3.062.97 (m, 2H), 2.902.77 (m, 2H),
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2.37 (q, J  6.9 Hz, 2H), 1.00 (t, J  7.2 Hz, 3H); C NMR (101 MHz, CDCl3)210.8, 175.9,
157.9, 152.6, 140.0, 137.9, 133.7, 132.0, 129.6 (2C), 129.4 (3C), 127.2 (2C), 125.2, 122.6, 117.9
(2C), 117.6, 43.9, 43.8, 35.8, 27.6, 7.6; IR (neat) max 3057, 2931, 1709, 1632, 1451, 1226 cm1;
HRMS (ESI) for C25H25NO4S (M+Na)+: calcd. 458.1402, found 458.1402.
N-[2-(3-Oxopentyl)-6-fluorobenzoyl]-S-methyl-S-phenylsulfoximine (4j): 117 mg, 64% yield;
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colorless viscous liquid; H NMR (400 MHz, CDCl3) 8.07 (bd, J 8.0 Hz, 2H), 7.68 (bt, J 
7.0 Hz, 1H), 7.62 (bt, J  7.2 Hz, 2H), 7.257.16 (m, 1H), 6.98 (bd, J  7.6 Hz, 1H), 6.91 (t, J 
8.8 Hz, 1H), 3.42 (s, 3H), 3.052.95 (m, 2H), 2.75 (bt, J 7.6 Hz, 2H), 2.35 (q, J  7.2 Hz, 2H),
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0.98 (t, J  7.2 Hz, 3H); C NMR (101 MHz, CDCl3) 210.6, 174.1, 159.2 (d, J  247 Hz),
140.8, 137.9, 134.0, 130.0 (d, J  9.1 Hz), 129.7 (2C), 127.2 (2C), 127.0 (d, J  17 Hz), 125.3,
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113.5 (d, J  22 Hz),44.3, 43.7, 35.8, 27.5, 7.6; F (470 MHz, CDCl3)116.0; IR (Neat) max
3018, 2975, 2931, 1709, 1637, 1287, 1226, 1133 cm1; HRMS (ESI) for C19H20FNO3S (M+Na)+:
calcd. 384.1046, found 384.1051.
N-[2-(3-Ethoxy-3-oxopropyl)-benzoyl]-S-methyl-S-phenylsulfoximine (4k):
Following GP-3, reaction between 2m (129 mg, 0.5 mmol) and 1a (0.19 mL, 1.75 mmol) under
the optimized conditions followed by flash column chromatography purification of crude
material on silica gel eluting with 110% CHCl3/THF gave 4k (61 mg, 34%) and 4′k (80 mg,
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35%) as pale brown viscous oil. H NMR (400 MHz, CDCl3)8.07 (bd, J  7.6 Hz, 2H), 8.04
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(bd, J  7.6 Hz, 1H), 7.70 (bt, J  7.4 Hz, 1H), 7.63 (bt, J  7.2 Hz, 2H), 7.37 (t, J  7.4 Hz, 1H),
7.307.22 (m, 2H), 4.09 (q, J  7.2 Hz, 2H), 3.44 (s, 3H), 3.393.22 (m, 2H), 2.772.60 (m,
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2H),1.21 (t, J  7.4 Hz, 3H); C NMR (101 MHz, CDCl3) 176.2, 173.4, 141.4, 138.8, 135.4,
133.8, 131.1, 130.9, 129.7, 127.1, 126.2, 60.2, 44.4, 36.1, 29.9, 14.2; IR (Neat) max 3063, 2931,
1726, 1632, 1260 cm1; HRMS (ESI) for C19H21NO4S (M+H)+: calcd. 360.1269, found
360.1269.
N-[2,6-Di(3-ethoxy-3-oxopropyl)-benzoyl]-S-methyl-S-phenylsulfoximine (4′k): 1H NMR
(400 MHz, CDCl3)8.09 (d, J  7.6 Hz, 2H), 7.68 (bt, J  7.4 Hz, 1H), 7.62 (bt, J  7.4 Hz, 2H),
7.19 (t, J  7.6 Hz, 1H), 7.08 (bd, J  7.6 Hz, 2H), 4.11 (q, J  7.1 Hz, 4H), 3.52 (s, 3H),
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3.082.97 (m, 4H), 2.722.60 (m, 4H), 1.22 (t, J  7.2 Hz, 6H); C NMR (101 MHz, CDCl3)
178.4, 173.1, 139.0, 138.5, 136.6, 133.8, 129.7, 128.5, 127.3, 127.0, 60.3, 43.8, 36.0, 29.0, 14.2;
IR (Neat) max 3068, 2980, 2926, 1726, 1627, 1293, 1221 cm1; HRMS (ESI) for C24H29NO6S
(M+H)+: calcd. 460.1794, found 460.1796.
N-[2-(3-Ethoxy-3-oxopropyl)-4-methylbenzoyl]-S-methyl-S-phenylsulfoximine (4l):
Following GP-3, reaction between 2n (136 mg, 0.5 mmol) and 1a (0.19 mL, 1.75 mmol) under
the optimized conditions followed by flash column chromatography purification of crude
material on silica gel eluting with 110% CHCl3/THF gave 4l (66 mg, 35%) and 4′l (85 mg,
36%) as pale brown viscous oil. 1H NMR (400 MHz, CDCl3)8.05 (d, J  7.6 Hz, 2H), 7.97 (d,
J 8.0 Hz, 1H), 7.68 (bt, J  7.2 Hz, 1H), 7.60 (bt, J 7.6 Hz, 2H), 7.087.02 (m, 2H), 4.08 (q,
J 7.2 Hz, 2H), 3.42 (s, 3H), 3.343.20 (m, 2H), 2.692.60 (m, 2H), 2.33 (s, 3H), 1.20 (t, J 
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