Synthesis and arylation of unprotected sulfonimidamides

Article abstract of DOI:10.1016/j.tet.2012.06.072

Herein we evaluate different methodologies for the synthesis of unprotected sulfonimidamides. Three different procedures that allow orthogonal deprotection of the imine nitrogen under acidic, nucleophilic, and basic conditions were established. Moreover,

Full text of DOI:10.1016/j.tet.2012.06.072

Tetrahedron 68 (2012) 7456e7462
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and arylation of unprotected sulfonimidamides
,
y
a
a
a
a
Matías Funes Maldonado a , Fernando Sehgelmeble , Fanny Bjarnemark , Mats Svensson , Jens Ahman ,
ꢀ
,c,d,
Per I. Arvidsson b
*
a
€
€
€
€
Medicinal Chemistry, iScience, CNSP iMed, AstraZeneca R&D Sodertalje, S-151 85, Sodertalje, Sweden
b
€
€
€
€
Project Management, CNSP iMed, AstraZeneca R&D Sodertalje, S-151 85 Sodertalje, Sweden
c Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
d School of Pharmacy and Pharmacology, Westville Campus, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we evaluate different methodologies for the synthesis of unprotected sulfonimidamides. Three
different procedures that allow orthogonal deprotection of the imine nitrogen under acidic, nucleophilic,
and basic conditions were established. Moreover, we present a highly efficient methodology for
functionalization of the imine nitrogen through Pd-catalyzed CeN arylation. RuPhos ligand was shown to
allow short reaction time, excellent yields, and allowed coupling of both aryl halides and heteroaryl
bromides.
Received 18 February 2012
Received in revised form 28 May 2012
Accepted 18 June 2012
Available online 26 June 2012
Keywords:
Sulfonimidamides
Arylation
Ó 2012 Elsevier Ltd. All rights reserved.
Isostere
CeN coupling
Pd catalysis
1. Introduction
asymmetric hydrogenation of cyclic enamides.9 The use of sulfoni-
midamides as a functional group in biologically active compounds is
Sulfonimidamides are aza-analogs of sulfonamides, in which
one oxygen atom has been replaced by a nitrogen group. This
structural modification creates a stereogenic sulfur center and
thereby offers the possibility of introducing additional structural
diversity around this functional group. We recently disclosed that
sulfonimidamides represent an interesting bioisostere of sulfon-
amides, a widely used functional group in medicinal chemistry.1
So far, the sulfonimidamide motif has received little attention in
the chemical literature. Such compounds were first described in the
1960s by Levechenko et al.2 However it was only during the last
years that some research has focused on their applications in or-
ganic synthesis and their biological activity. The use of sulfonimi-
damides as reagent in organic synthesis has been studied by
Malacriaet al.3 Sulfonimidamides have been applied in the imina-
tions of sulfides,4a aziridination of olefins,4b,c and CeH aminations of
hydrocarbons4d,5,6 by Dodd, Dauban, and others. Bolm et al. ex-
plored the application of sulfonimidamides as organocatalyst in
asymmetric reactions,7 as chiral ligands in asymmetric metal ca-
talysis,8 and more recently their use in iridium-catalyzed
less explored. Researchers from Lilly Research Laboratories explored
their use as analogs of oncolytic sulfonylureas,10 while the use of
sulfonimidamide as a transition state analog for aspartic acid and
metallo-proteases was explored by Schloss.11
The synthesis of N-protected sulfonimidamides has been de-
scribed by Bolm et al.;12 however, only few synthetic approaches
for their preparation have been reported. A patent application was
published describing the synthesis and the use of sulfonimida-
mides as pesticidal agents, especially against insects and acaridae.13
The synthesis of unprotected sulfonimidamides, i.e., R4¼H Fig. 1,
has initially been investigated by Johnson and Lavergne.14 From
a pharmaceutical standpoint it is important to be able to access
R4
R4
R4
HN
S
N
S
O
N
S
NH2
NH
R1
NR2R3
O
O
I
IIA
IIB
* Corresponding author. Tel.: þ46 8 553 25923; e-mail addresses: Per.Arvidsson@
Fig. 1. Structure of sulfonimidamides I (1ꢀ R2, R3¼H; 2ꢀ R2¼H, R3sH; 3ꢀ R2, R3sH).
Tautomerism of sulfonimidamides II (IIA most stable (1.0 kcal/mol) when R4¼Me,
while IIB most stable (4.2 kcal/mol) when R4¼acyl).
astrazeneca.com, Per.Arvidsson@orgfarm.uu.se (P.I. Arvidsson).
y
Current address: Department of Chemistry, Faculty of Mathematics and Natural
Sciences, Oslo University, 0371 Oslo, Norway.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.072

M. Funes Maldonado et al. / Tetrahedron 68 (2012) 7456e7462
7457
NeH sulfonimidamides, i.e., R4¼H, as these would be the closest
analogs of sulfonimidamides and serve as versatile precursors for
the substituted (R4¼Alk, Ar) analogs. The present work aims to
develop such NeH derivatives, and also explore novel methodology
for their functionalization by arylation of the imine nitrogen.
Table 1
Summary of protection and oxidation steps for the synthesis of sulfonimidamides
O
O
O
1) nBuLi
2) PG-X
1) NCS
S
PG
S
PG
S
N
N
NH2
2) Morpholine
N
H
3
5
4
O
2. Results and discussion
Sulfonamides and sulfonimidamides can be primary (1ꢀ), sec-
ondary (2ꢀ) or tertiary (3ꢀ), (structure I, Fig. 1). Primary and sec-
ondary sulfonimidamides represent interesting structures, as they
may undergo tautomerization by migration of a proton from one
nitrogen atom to another (i.e., structure II, Fig. 1). We undertook
some initial theoretical calculations on this tautomeric equilibrium.
Our results confer that tautomer IIA is more stable by 1.0 kcal/mol
(when R4¼Me), while the tautomer IIB is more stable by 4.2 kcal/
mol (when R4¼COMe) (for computational details see Section 5 in
the experimental part).15
Entry
1
PG
Producta 4 Yieldb (%)
Productc
5
Yieldb (%)
61
O
4a
4b
4c
45
77
74
5a
O
O
2
3
5b
5c
79
87
Ph
O
O
This tautomerism of sulfonimidamides was described in 1979 by
Johnson et al., who demonstrated rapid proton exchange on the
NMR time scale.16 Tautomerization can be avoided by having an
acyl-protecting group on the imine nitrogen, thus making tautomer
IIB more stable. Similarly, tertiary sulfonimidamides will not un-
dergo tautomerization. In order to avoid the complexity of tauto-
meric equilibrium, we decided to focus on tertiary substituted
sulfonimidamide, i.e., R2, R3sH, Fig. 1.
Our synthesis strategy for the NeH sulfonimidamide was based
on finding an appropriate N-protecting group that allows for syn-
thesis and manipulation of the core combined with a late stage
deprotection to release the NeH functionality. It was important to
find protecting groups with orthogonal removal conditions to allow
for a wide variety of structures to be made.
We based our synthesis of N-protected sulfonimidamides on
Bolm’s approach (Scheme 1): first, sodium benzenesulfinate salt 1
was treated with thionyl chloride to convert it into methyl ester 2 in
up to 96% yield via the treatment of the corresponding sulfinic acid
chloride with methanol. Next, ester 2 was reacted with lithium
hexamethyldisilazide (LiHMDS), which upon hydrolysis gave ben-
zenesulfinamide 3 in 90% yield after recrystallization.17 Protection
of sulfinamide 3 with 2.5 equiv of n-BuLi, followed by the addition
of the corresponding anhydride18 afforded the N-acylsulfinamide 4
(Table 1); alternatively, the reaction of the corresponding sulfinic
acid chloride with 2-(trimethylsilyl)ethanesulfonamide or benzyl-
amine provided sulfinamides 4e and 4f, respectively (Table 1, en-
tries 5 and 6). Oxidative chlorination using N-chlorosuccinimide12
O
4
5
4d
63
5d
75
18
O
Ph
Si
O
O
4ed
Not isolated 5e
S
6
4fe
94
5f
8
Ph
a
Reaction conditions: n-butyl lithium (2.5 M in hexane, 2.5 equiv), corresponding
anhydride (1.2 equiv), THF, ꢁ78 ꢀC, overnight.
b
Isolated yield determined after column chromatography.
c
Reaction conditions: NCS (3 equiv), morpholine (3 equiv), MeCN, rt, 17e43 h.
NaH (1.2 equiv), 2-(trimethylsilyl)ethanesulfonamide (1.2 equiv), benzene-
d
sulfinic chloride (1.1 equiv).
e
Benzylamine (1.1 equiv), Et3N (1.5 equiv), benzenesulfinic chloride (1.0 equiv).
(NCS) in acetonitrile and treatment of the resulting sulfonimidoyl
chloride with 3.0 equivalents of morpholine afforded N-substituted
sulfonimidamide 5 in moderate to good yield 8e87% (Table 1).
The best result for the protection step was obtained with N-
benzyl (94%, Table 1, entry 6), which provided product 4f that was
readily purified through recrystallization. Reaction of N-benzoyl
and ethyl carbamate derivative also gave the desired products 4b
and 4c in good yields (77 and 74%, respectively; Table 1, entries 2
and 3). Other carbamate protecting groups, i.e., N-benzyl and tert-
butyl, gave the desired products 4d and 4a in slightly lower yields
(63 and 45%, respectively; Table 1, entries 4 and 1). Product 4e was
not isolated due to decomposition during column chromatography;
instead this product was used directly in the next step.
O
S
O
S
O
S
a
b
ONa
O
NH2
The reactivity of the protected sulfinamides 4ae4f during the
oxidation step can be compared in Table 1. For this reaction the best
result was obtained with N-ethyl carbamate sulfinamide 4c
(87%, Table 1, entry 3). However, reaction of N-benzoyl and N-
benzyl carbamate sulfinamide 4b and 4d also gave the desired
products 5b and 5d in good yields (79%, 75%, entries 2, 4, re-
spectively). Further evaluation of the cleavage of these protecting
groups was necessary in order to determine, which would be the
methodology of choice.
1
2
3
c
O
NH
N
O
S
O
d
S
S
PG
e
PG
N
N
N
H
O
O
Bolm’s group,12 as well as internal work at AstraZeneca, has only
explored electron-withdrawing protecting groups for sulfinamides
4. In order to evaluate the electronic influence of the nitrogen-
protecting group on the subsequent chlorination and substitution,
we employed N-benzyl sulfinamide 4f. The use of this non electron-
withdrawing group led to the formation of 5f in only 8% yield (Table
1, entry 6), thus demonstrating the need for an electron-
6
5
4
Scheme 1. Synthesis of unprotected sulfonimidamide 6. (a) SOCl2 (3 equiv), DCM,
ꢀC/rt, 3 h; concentrated in vacuum, then methanol 0 ꢀC, triethylamine (3 equiv), rt,
0
overnight, 96%; (b) LiHMDS (1.5 equiv), THF, ꢁ78 ꢀC/RT, 1.5 h; then satd aq NH4Cl, rt,
overnight, recrystallization from hexane/ethyl acetate 2:1, 90%; (c) n-butyl lithium
(2.5 equiv), corresponding anhydride (1.2 equiv), THF, ꢁ78 ꢀC/rt, overnight; (d) NCS
(3 equiv), acetonitrile, rt, 2 h; then morpholine (3 equiv), 43 h; (e) conditions
summarized in Table 2.

7458
M. Funes Maldonado et al. / Tetrahedron 68 (2012) 7456e7462
withdrawing substituent for the oxidative chlorination step to
proceed smoothly.
is cleaved under very mild conditions using heterogeneous palla-
dium on carbon (Pd/C) catalyst in the presence of hydrogen gas.
Finally, benzoyl group gave good yields in all the synthesis steps
except for the deprotection, since this is a difficult group to remove
that sometimes require harsh conditions.
Bolm previously reported the arylation of N-protected sulfoni-
midamides using aryl halides and stoichiometric amounts of cop-
per.21 Later, Malacria et al.22 developed an efficient copper-
catalyzed method for introducing aryl substituents on the amino
end of sulfonimidamides. We decided to explore functionalization
of unprotected sulfonimidamides through arylation of the imine
nitrogen.
The cleavage of the protecting groups was one of the most im-
portant steps in our synthesis because it will lead us to the un-
protected sulfonimidamide 6 that is of interest on its own, but also
offers the possibility for further functionalization through arylation
in this position. Sulfonimidamide 5a was treated with 5 equiv of
trifluoroacetic acid (TFA) in DCM at room temperature to yield the
‘free’ sulfonimidamide 6 in excellent yield (87%, Table 2, entry 1). A
Table 2
Optimized conditions for deprotection of sulfonimidamides
Our first attempt at the arylation step was to use copper-
mediated reactions, since they provide a low-cost alternative
compared to palladium cross-couplings. Unsatisfactory results were
obtained when using stoichiometric amounts of copper salts with
iodo-, bromo-, and chlorobenzene as precursors, decomposition of
starting material was observed and only a small amount of the
desired product was observed by LCeMS and HPLC when iodo-
benzene was used as the aryl halide. We tried to improve this re-
action by using a catalytic amount of copper in presence of a ligand.
PG
O
N
O
NH
N
Deprot.
S
S
N
O
O
5
6
Entry Substrate
PG
Conditions
TFA/DCM
Yielda (%) Overall yieldb (%)
O
Malacria
successfully
used
N,N’-dimethylethylenediamine
1
2
3
5a
5b
5c
87
53
21
28
51
O
O
(DMEDA) as a ligand for introducing aryl substituents on the amino
end of sulfonimidamides22 and Buchwald also reported good results
when using this ligand for the amidation of aryl halides,23 but when
attempting these conditions for the arylation of the imine nitrogen
of sulfonimidamides it did not provide satisfactory results. A recent
publication by Jiang et al.24 reported 8-hydroxyquinolin-N-oxide as
a superior ligand for CuBr catalyzed coupling reactions, but again no
CeN cross-coupling reaction was observed when attempting this
with sulfonimidamides under the reported conditions.
We finally attempted the arylation using Pd-catalyzed CeN
coupling reaction. As ligand of choice we tried RuPhos ligand,
which is commercially available, easy to handle, air stable, and was
reported by Buchwald as the ligand of choice for secondary alkyl
amines.25 Buchwald reaction also offers low catalyst loading and
short reaction times.26 The Pd source was a Pd(II) amine complex
(Fig. 2), which undergoes reduction of Pd(II) to Pd(0) before entry
into the catalytic cycle. The amine nitrogen is deprotonated and the
resulting intermediate undergoes a reductive elimination gener-
ating indoline and the active monoligated Pd(0) complex.
HCl
Ph
O
C2H5ONa/EtOH 91
O
O
4
5
5d
5e
Pd/H2
TBAF
64
85
36
9
O
Ph
Si
O
O
S
a
Isolated yield determined after column chromatography.
Overall yield of the synthesis of 4-(phenylsulfonimidoyl)morpholine 6 starting
b
from 1.
simple procedure for cleavage of the N-benzoyl protecting group
with borane tetrahydrofuran complex was reported by Bolm in
a paper related to the
a
-arylation of sulfoximines;19 however,
employing this methodology to sulfonimidamides did not prove
satisfactory results, due to competing benzoyl to benzyl reduction.
Instead, exposing 5b to acidic conditions (1.0 M HCl in dioxane) at
room temperature afforded 4-(phenylsulfonimidoyl)morpholine 6
in moderate yield (53%, Table 2, entry 2). The cleavage of the pro-
tecting groups on sulfonimidamides 5ce5e was based on a pro-
PCy2
i-PrO
Oi-Pr
NH2
Pd
L
Cl
L
RuPhos precatalys 7
RuPhos
cedure reported in
a patent related to the synthesis of
sulfoximines.20 Sulfonimidamide 5c was deprotected under basic
conditions, using a solution of sodium ethoxide in ethanol and
stirring at room temperature for 21 h, to afford the desired product
6 in excellent yield (91%, Table 2, entry 3). The treatment of sulfo-
nimidamide 5d in an H-cube continuous-flow hydrogenation re-
actor using a cartridge of palladium 10% in carbon at room
temperature cleaved the benzyl carbamate group, giving the un-
protected sulfonimidamide in moderate yield (64%, Table 2, entry
4). Finally, 5e was treated with tetrabutylammonium fluoride in
THF at 40 ꢀC to give 6 in excellent yield (85%, Table 2, entry 5).
The best overall yield for the whole reaction sequence from 1
was obtained when using ethyl carbamate group (51%, Table 2,
entry 3) and therefore was the N-protecting group of choice for this
methodology. Benzyl carbamate also looks promising, especially for
those compounds that are not stable under basic conditions, since it
Fig. 2. Structure of RuPhos ligand (L) and precatalyst 7 used in CeN cross-coupling.
We were pleased to see that the desired arylation of the imine
nitrogen of sulfonimidamides did indeed proceed under these
conditions (Table 3). The coupling of unprotected sulfonimidamide
6 with iodo-, bromo-, and chlorobenzene at catalyst loading of
3 mol %, using sodium tert-butoxide (NaOt-Bu) as base in THF and
2.5 h under microwave irradiation gave the desired product in ex-
cellent yields 88e95%. Even the less reactive aryl chloride gave the
expected product in 95% yield (Table 3, entry 3).
Encouraged by the good results obtained with this novel
methodology we next attempted coupling of heteroaryl halides.
Heteroaryl halides are typically more challenging substrates than

M. Funes Maldonado et al. / Tetrahedron 68 (2012) 7456e7462
7459
Table 3
catalyzed CeN coupling methodology that allows the imine nitro-
gen of tertiary sulfonimidamides to be functionalized through
arylation with both aryl and heteroaryl groups. To the best of our
knowledge, this is the first time sulfonimidamides have been
employed as substrates in these kinds of reactions. Work to extend
this methodology to primary and secondary sulfonimidamides has
so far proven to be challenging, but additional work is on-going.
Pd-catalyzed cross-coupling of sulfonimidamide 6 and aryl halidesa
O
NH
N
O
N
X
3 mol% Pd cat. 7
S
S
+
N
NaOt-Bu, THF
100 oC, 2.5h, MW
O
O
8a: X = I
6
9
4. Experimental
4.1. General
8b: X = Br
8c: X = Cl
Entry
Aryl halide
Yieldb (%)
NMR spectra were recorded on a 500 MHz NMR spectrometer
from Bruker fitted with a probe of suitable configuration. Spectra
were recorded at ambient temperature unless otherwise stated.
Chemical shifts are given in parts per million. The following refer-
1
2
3
8a
8b
8c
88
87
95
a
Reaction conditions: sulfonimidamide (1.0 equiv), aryl halide (1.5 equiv), NaOt-
Bu (1.2 equiv), 3 mol % Pd cat. in THF at 100 ꢀC, 2.5 h in microwave.
ence signals were used: TMS
DMSO-d6 2.49, or CDCl3
d
0.00, or the residual solvent signal of
7.26 (unless otherwise indicated).
b
Isolated yield determined after column chromatography.
d
d
Resonance multiplicities are denoted s, d, t, q, m, br, and app for
singlet, doublet, triplet, quartet, multiplet, broad, and apparent,
respectively. IR spectra were recorded by a Thermo Nicolet 4700
spectrometer using an attenuated total reflection (ATR) unit. High-
resolution mass spectra (HRMS) were recorded on a Waters Synapt-
G2 mass spectrometer as described in detail in Supplementary
data. Column chromatography was performed by manual flash
chromatography (wet packed silica, 0.04e0.063 mm) or by auto-
mated column chromatography on Isco CombiFlash system using
pre-packed RediSepÔ columns. Microwave reactions were per-
formed in a Biotage Initiator reactor with fixed hold time. All re-
agents were purchased from commercial suppliers and used
without further purification.
aryl halides in Pd-catalyzed CeN cross-coupling reactions;26 but
the obtained products are often of larger interest in the pharma-
ceutical industry. Nevertheless, this catalyst system even allows the
coupling of electron-poor heteroaryl bromides with excellent
yields (86%, Table 4, entry 2). All reactions were extremely clean
and gave the desired product in excellent yield 86e98% with rel-
atively low catalyst loading (3e6 mol %) and short reaction times.
Table 4 summarizes these results.
Table 4
Pd-catalyzed cross-coupling of sulfonimidamide 6 and heteroaryl bromidesa
Ar
O
NH
N
O
N
3 mol% Pd cat. 7
S
S
4.2. Methyl benzenesulfinate 227
Ar-Br
+
N
NaOt-Bu, THF
100 oC, 2.5h, MW
O
O
Sodium benzenesulfinate 1 (5.00 g, 30.3 mmol) was dissolved in
dichloromethane (80 mL). The solution was cooled down to 0 ꢀC
and kept under argon atmosphere. Thionyl chloride (6.60 mL,
90.8 mmol) was added dropwise at 0 ꢀC. After 20 min the ice bath
was removed and the reaction mixture was allowed to warm to
room temperature. The reaction mixture was stirred for 3 h and
then concentrated in vacuum to give benzenesulfinic chloride.
Benzenesulfinic chloride was then dissolved in a small amount of
dry dichloromethane and added to a round bottom flask with dry
methanol (200 mL) at 0 ꢀC, after 10 min triethylamine (12.5 mL,
89.7 mmol) was added and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was concentrated and
then dissolved in dichloromethane, washed with water and brine,
dried with MgSO4, filtered, and concentrated under reduced pres-
sure to give methyl benzenesulfinate 2 (4.49 g, 96%) as a pale yellow
oil. MS (ESþ), m/z: 156.9 [(MþH)þ]. 1H NMR (500 MHz, DMSO-d6)
10
6
11
Entry
1
Aryl bromide
Product
Yieldb (%)
98
Br
11a
N
10a
2
11b
11c
86
86
N
Br
10b
Br
3c
d
ppm 3.44 (s, 3H), 7.60e7.69 (m, 3H), 7.69e7.75 (m, 2H). 13C NMR
(125 MHz, DMSO-d6) ppm 50.1, 125.1, 129.3, 132.5, 143.6.
N
N
d
10c
a
Reaction conditions: sulfonimidamide (1.0 equiv), aryl halide (1.5 equiv), NaOt-
Bu (1.2 equiv), 3 mol % Pd cat. in THF at 100 ꢀC, 2.5 h in microwave.
4.3. Benzenesulfinamide 3
b
Determined after column chromatography.
c
Pd cat. (6 mol %).
To a solution of methyl benzenesulfinate 2 (4.48 g, 28.7 mmol) in
anhydrous THF (60 mL), lithium bis(trimethylsilyl)amide (43 mL,
43 mmol) was added dropwise over 10 min at ꢁ78 ꢀC. The mixture
was stirred for 10 min at ꢁ78 ꢀC and 1.5 h at room temperature. Then
a saturated sol of NH4Cl (100 mL) was added and the mixture stirred
overnight at room temperature. The reaction mixture was diluted by
addition of ethyl acetate, the organic layer was separated and the
aqueous phase was extracted with ethyl acetate. The combined or-
ganic layers were washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. The product was recrystal-
lized from hexane/ethyl acetate 2:1. Benzenesulfinamide 3 (3.66 g,
3. Conclusion
We have established a synthesis of unprotected sulfonimida-
mides from three different precursors that allows orthogonal pro-
tecting group removal, i.e., acidic, nucleophilic, and hydrogenation,
to give NeH sulfonimidamide in excellent to good overall yield. N-
Ethyl carbamate group gave the desired product 6 in excellent
overall yields and was therefore chosen as the best N-protecting
group for this methodology. Next, we developed an efficient Pd-

7460
M. Funes Maldonado et al. / Tetrahedron 68 (2012) 7456e7462
90%)wasisolatedascolorless crystals. MS(ESþ), m/z:141.9[(MþH)þ].
temperature and then concentrated under vacuum to give benze-
nesulfinic chloride. A slurry of sodium hydride (0.088 g, 2.20 mmol)
in dichloromethane (9.50 mL) was cooled down to 0 ꢀC under argon
1H NMR (500 MHz, DMSO-d6)
d ppm 6.25 (s, 2H), 7.45e7.60 (m, 3H),
7.60e7.72 (m, 2H).13C NMR (125 MHz, DMSO-d6)
d ppm 125.3,128.6,
130.2, 148.1. Data in accordance with literature values.28
atmosphere.
2-(Trimethylsilyl)ethanesulfonamide
(0.388 g,
2.10 mmol) was dissolved in a small amount of DCM and added to the
slurry at 0 ꢀC and stirred for 1 h. Benzenesulfinic chloride was dis-
solved in a small amount of DCM and added dropwise to the mixture
at 0 ꢀC, which was stirred overnight at room temperature. The re-
action mixture was quenched with saturated NH4Cl and extracted
with DCM. The combined organic phases were dried in MgSO4 and
concentrated under reduced pressure to give a crude yellow oil, the
product was not isolated. MS (ESꢁ), m/z: 304 [(MꢁH)ꢁ].
4.4. tert-Butyl phenylsulfinylcarbamate 4a
Benzenesulfinamide 3 (0.40 g, 2.80 mmol) was dissolved in dry
THF (12 mL) and cooled down to ꢁ78 ꢀC in a round bottom flask.
The mixture was stirred for 10 min at ꢁ78 ꢀC and n-butyl lithium
(2.80 mL, 7.10 mmol) was added dropwise over 10 min. The mix-
ture was stirred for 10 more minutes at ꢁ78 ꢀC, followed by rapid
addition of di-tert-butyl dicarbonate (0.742 g, 3.40 mmol), stirring
was continued for 10 min at ꢁ78 ꢀC and then overnight at room
temperature. A saturated solution of NaHCO3 was added to the
reaction mixture and diluted with dichloromethane. The water
phase was extracted with dichloromethane, dried with MgSO4,
filtered, and concentrated under reduced pressure. Flash chroma-
tography using dichloromethane as eluent yielded 4a (0.306 g, 45%)
as a white solid. MS (ES-), m/z: 240 [(MꢁH)ꢁ]. 1H NMR (500 MHz,
4.9. N-Benzylbenzenesulfinamide 4f30
Sodium benzenesulfinate 1 (1.00 g, 6.10 mmol) was dissolved in
dichloromethane (20 mL). The solution was cooled down to 0 ꢀC
and kept under argon atmosphere. Thionyl chloride (1.30 mL,
18.2 mmol) was added dropwise at 0 ꢀC. After 20 min the ice bath
was removed and the solution allowed to warm to room temper-
ature. The reaction mixture was stirred for 2 h and then concen-
trated in vacuum to give benzenesulfinic chloride, which was
dissolved again in DCM (20 mL) and phenylmethanamine (0.70 mL,
6.70 mmol) was added dropwise, subsequently triethylamine
(1.30 mL, 9.10 mmol) was added to the reaction mixture and ev-
erything went into solution, the reaction mixture was stirred
overnight. The reaction mixture was concentrated in vacuum to
remove all the solvents and then diluted in DCM and washed with
a saturated solution of NH4Cl. The organic layers were dried with
MgSO4, filtered, and the solvent was removed under reduced
pressure to give N-benzylbenzenesulfinamide 4f (1.307 g, 93%). MS
CDCl3)
d ppm 1.53 (s, 9H), 6.63 (br s, 1H), 7.54e7.59 (m, 3H),
7.73e7.80 (m, 2H). 13C NMR (125 MHz, DMSO-d6)
d ppm 27.8, 81.5,
124.9, 125.5, 129.0, 131.3, 143.4.
4.5. N-(Phenylsulfinyl)benzamide 4b
The same procedure as described for 4a was used with the ex-
ception of use of benzoic anhydride (0.77 g, 3.40 mmol) instead of
di-tert-butyl dicarbonate. The product was recrystallized from
hexane/ethyl acetate (2:1) to obtain 4b (0.533 g, 77 %) as a white
solid. MS (ES-), m/z: 245.9 [(MꢁH)ꢁ]. 1H NMR (500 MHz, DMSO-d6)
d
ppm 7.47e7.55 (m, 2H), 7.59e7.68 (m, 4H), 7.73e7.84 (m, 2H),
(ESþ), m/z: 231.9 [(MþH)þ]. 1H NMR (500 MHz, DMSO-d6)
d ppm
7.86e7.95 (m, 2H), 11.65 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
3.69 (dd, J¼14.3, 7.1 Hz, 1H), 4.00 (dd, J¼14.3, 5.0 Hz, 1H), 7.10 (dd,
d
ppm 125.5, 128.4, 128.5, 129.1, 131.4, 131.9, 132.9, 143.5, 168.1. Data
J¼6.7, 5.5 Hz, 1H), 7.20e7.26 (m, 3H), 7.26e7.31 (m, 2H), 7.51e7.60
in accordance with literature values.29
(m, 3H), 7.66e7.70 (m, 2H). 13C NMR (125 MHz, DMSO-d6)
d ppm
43.2, 125.9, 127.0, 128.2, 129.9, 130.6, 138.6, 144.5.
4.6. Ethyl phenylsulfinylcarbamate 4c
4.10. tert-Butyl[morpholin-4-yl(oxido)phenyl-l6
-
The same procedure as described for 4a was used with the ex-
ception of use of diethyl dicarbonate (0.50 mL, 3.40 mmol) instead of
di-tert-butyl dicarbonate. The product was purified using flash
chromatography by slowly increasing the gradient from 100% hep-
tane to 50:50 heptane/ethyl acetate to yield 4c (0.446 g, 74 %) as
a white solid. MS (ESþ), m/z: 213.9 [(MþH)þ]. 1H NMR (500 MHz,
sulfanylidene]carbamate 5a
Under an inert atmosphere of argon, N-chlorosuccinimide
(0.083 g, 0.62 mmol) was added to a solution of 4a (0.05 g,
0.20 mmol) in dry acetonitrile (1.50 mL). After 2 h LCeMS showed
no starting material. Morpholine (54 mL, 0.60 mmol) was added and
DMSO-d6)
d
ppm 1.22 (t, J¼7.1 Hz, 3H), 4.17 (q, J¼7.1 Hz, 2H),
the mixture stirred for 43 h (until no starting material was left
checked by LC-MS). The reaction was stopped by addition of water
(5 mL), and the phases were separated. The aqueous phase was
extracted with ethyl acetate. The combined organic layers were
dried (MgSO4), filtered, and the solvent was removed under re-
duced pressure. The product was purified using flash chromatog-
raphy by slowly increasing the gradient from 100% heptane to
50:50 heptane/ethyl acetate to yield 5a (0.041 g, 61 %) as a white
solid. Mp¼104e105 ꢀC. MS (ESþ), m/z: 327 [(MþH)þ]. IR (ATR):
7.58e7.61 (m, 3H), 7.67e7.70 (m, 2H), 10.78 (s, 1H). 13C NMR
(125 MHz, DMSO-d6) ppm 14.2, 63.2,124.7,129.4,132.0,143.4,153.6.
d
4.7. Benzyl phenylsulfinylcarbamate 4d
The same procedure as described for 4a was used with the ex-
ception of use of dibenzyldicarbonate (0.973 g, 3.40 mmol) instead of
di-tert-butyl dicarbonate. The product was purified using flash
chromatography by slowly increasing the gradient from 100% hep-
tane to 50:50 heptane/ethyl acetate to yield benzyl phenyl-
sulfinylcarbamate 4d (0.492 g, 63.1%) as a white solid. MS (ESꢁ), m/z:
n
¼1693, 1677, 1446, 1251, 1155, 1107, 1087, 1064, 929, 896, 777, 736,
526 cmꢁ1. 1H NMR (500 MHz, CDCl3)
ppm 1.41 (s, 9H), 3.09e3.17
(m, 4H), 3.73e3.78 (m, 4H), 7.55e7.60 (m, 2H), 7.62e7.67 (m, 1H),
7.85e7.89 (m, 2H). 13C NMR (125 MHz, CDCl3)
ppm 27.9, 45.7, 66.1,
d
274 [(MꢁH)ꢁ]. 1H NMR (500 MHz, DMSO-d6)
d
ppm 5.20 (s, 2H),
d
7.32e7.44 (m, 5H), 7.57e7.62 (m, 3H), 7.67e7.73 (m, 2H),10.93 (s,1H).
80.5, 127.8, 129.2, 133.2, 135.2, 156.2. HRMS (ESI) C15H22N2O4S calcd
[MþH]þ 327.1379; found 327.1376.
4.8. N-(Phenylsulfinyl)-2-(trimethylsilyl)ethanesulfonamide 4e
4.11. N-[Morpholin-4-yl(oxido)phenyl-l
6-sulfanylidene]
Sodium benzenesulfinate 1(0.30 g, 1.82 mmol) was dissolved in
dichloromethane (8.60 mL), the solution was cooled down to 0 ꢀC
and kept under argon atmosphere. Thionyl chloride (0.50 mL,
7.30 mmol) was added dropwise at 0 ꢀC and after 20 min the ice bath
was removed. The reaction mixture was stirred for 2 h at room
benzamide 5b
The same procedure as described for 5a but with 4b (0.05 g,
0.2 mmol) as starting material was employed. The product was
purified using flash chromatography by slowly increasing the

M. Funes Maldonado et al. / Tetrahedron 68 (2012) 7456e7462
7461
gradient from 100% heptane to 50:50 heptane/ethyl acetate to yield
NMR (500 MHz, DMSO-d6)
d
ppm 2.74e2.83 (m, 4H), 3.56e3.61 (m,
5b (0.053 g, 79%) as a white solid. MS (ESþ), m/z: 331 [(MþH)þ]. 1H
4H), 4.52 (s, 1H), 7.58e7.64 (m, 2H), 7.64e7.70 (m, 1H), 7.74e7.79
NMR (500 MHz, DMSO-d6)
d
ppm 3.02e3.12 (m, 4H), 3.64e3.72 (m,
(m, 2H). 13C NMR (125 MHz, DMSO-d6)
d ppm 46.7, 65.6, 127.8,
4H), 7.46e7.52 (m, 2H), 7.57e7.62 (m, 1H), 7.68e7.73 (m, 2H),
128.8, 132.3, 135.5. HRMS (ESI) C10H14N2O2S calcd [MþH]þ
7.75e7.81 (m, 1H), 7.86e7.90 (m, 2H), 8.02e8.10 (m, 2H). 13C NMR
227.0854; found 227.0860.
(125 MHz, DMSO-d6)
d ppm 45.4, 65.3, 127.6, 128.3, 129.0, 132.4,
133.7, 134.3, 135.3, 171.4.
4.16. 4-(Phenylsulfonimidoyl)morpholine 6 starting from 5b
4.12. Ethyl[morpholin-4-yl(oxido)phenyl-
carbamate 5c
l
6-sulfanylidene]
To a solution of 5b (0.02 g, 0.06 mmol) in ethanol (0.40 mL),
hydrogen chloride 1 M sol in 1,4-dioxane (0.2 mL, 0.18 mmol) was
added and stirred at room temperature until the starting material
was consumed (monitored by LCeMS). The mixture was diluted
with water and extracted with DCM, the combined organic layers
were dried (MgSO4), filtered, and the solvent was removed under
reduced pressure. The product was purified using flash chroma-
tography by slowly increasing the gradient from 100% heptane to
50:50 heptane/ethyl acetate to yield 6 (7.30 mg, 53.3 %) as a white
solid. Analytical data as above.
The same procedure as described for 5a but with 4c (0.05 g,
0.2 mmol) as starting material was employed. The product was
purified using flash chromatography by slowly increasing the gra-
dient from 100% heptane to 50:50 heptane/ethyl acetate to yield 5c
(0.060 g, 87%) as a white solid. Mp¼145e146 ꢀC. MS (ESþ), m/z: 299
[(MþH)þ]. IR (ATR):
n
¼1666,1448,1275,1110,1089,1065, 1020, 786,
748, 687, 611 cmꢁ1
.
1H NMR (500 MHz, DMSO-d6)
d
ppm 1.11 (t,
J¼6.9 Hz, 3H), 2.94e2.99 (m, 4H), 3.60e3.65 (m, 4H), 3.91e4.01 (m,
2H), 7.66e7.72 (m, 2H), 7.74e7.83 (m, 3H). 13C NMR (125 MHz,
4.17. 4-(Phenylsulfonimidoyl)morpholine 6 starting from 5c
DMSO-d6)
d ppm 14.5, 45.9, 61.5, 65.6, 127.9, 129.9, 134.0, 134.5,
156.9.HRMS (ESI) C13H18N2O4S calcd [MþH]þ 299.1066; found
A solution of 5c (2.25 g, 7.54 mmol) in ethanol (67.5 mL) was
treated with sodium ethoxide solution (7.90 mL, 21.12 mmol) and
stirred at room temperature for 21 h (until no starting material was
observed by LCeMS). The reaction mixture was diluted with ethyl
acetate and brine. The resulting mixture was extracted with ethyl
acetate. The combined organic layers were dried (MgSO4), filtered,
and the solvent was removed under reduced pressure. The product
was purified using flash chromatography by slowly increasing the
gradient from 100% heptane to 50:50 heptane/ethyl acetate to yield
6 (1.555 g, 91 %) as a white solid. Analytical data as above.
299.1069.
4.13. Benzyl[morpholin-4-yl(oxido)phenyl-
carbamate 5d
l
6-sulfanylidene]
The same procedure as described for 5a but with 4d (0.05 g,
0.18 mmol) as starting material was employed. The product was
purified using flash chromatography by slowly increasing the gra-
dient from 100% heptane to 50:50 heptane/ethyl acetate to yield 5d
(0.049 g, 75%) as a white solid. MS (ESþ), m/z: 361 [(MþH)þ]. 1H
NMR (500 MHz, DMSO-d6)
d
ppm 2.92e3.00 (m, 4H), 3.58e3.64 (m,
4.18. 4-(Phenylsulfonimidoyl)morpholine 6 starting from 5d
4H), 4.97e5.04 (m, 2H), 7.26e7.36 (m, 5H), 7.66e7.71 (m, 2H),
7.75e7.82 (m, 3H). 13C NMR (125 MHz, DMSO-d6)
ppm 45.7, 66.0,
67.8, 127.8, 127.9, 128.2, 128.3, 129.3, 133.4, 134.6, 136.2, 157.0.
d
Sulfonimidamide 5d (0.01 g, 0.03 mmol) was dissolved in
methanol (1 mL). The resulting solution was treated in an H-cube
continuous-flow hydrogenation reactor using a cartridge of palla-
dium 10% on carbon at room temperature. The solvent was re-
moved under reduced pressure to yield 6 (4.0 mg, 64%) as a white
solid. Analytical data as above.
4.14. N-[Morpholin-4-yl(oxido)phenyl-l
6-sulfanylidene]-2-
(trimethylsilyl)ethanesulfonamide 5e
Under an inert atmosphere of argon, N-chlorosuccinimide
(0.117 g, 0.87 mmol) was added to a crude solution of N-(phenyl-
sulfinyl)-2-(trimethylsilyl)ethanesulfonamide (0.089 g) in dry ace-
4.19. 4-(Phenylsulfonimidoyl)morpholine 6 starting from 5e
tonitrile (1.40 mL) and stirred for 2 h. Morpholine (76
m
L,
A solution of 5e (0.01 g, 0.03 mmol) in THF (0.2 mL) was treated
with 1 M solution of tetrabutylammonium fluoride (0.15 mL,
0.15 mmol) and stirred overnight. The reaction mixture was heated
to 40 ꢀC for 6 h to get full conversion (monitored by LCeMS). After
cooling to room temperature, aqueous NaHCO3 and brine were
added and extracted with ethyl acetate. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. The product
was purified by preparative HPLC to give yield 6 (4.90 mg, 85%) as
a white solid. Analytical data as above.
0.87 mmol) was added and subsequently the solution was stirred
overnight at room temperature. The reaction was stopped by ad-
dition of water, and the phases were separated. The aqueous phase
was extracted with ethyl acetate. The combined organic layers were
washed with brine and dried (MgSO4), filtered, and the solvent was
removed under reduced pressure. The product was purified using
flash chromatography by slowly increasing the gradient from 100%
heptane to 50:50 heptane/ethyl acetate to yield 5e (0.020 g, 18%) as
a white solid. MS (ESþ), m/z: 391 [(MþH)þ]. 1H NMR (500 MHz,
DMSO-d6)
d
ppm 0.02 (s, 9H), 0.92e1.02 (m, 2H), 2.94e3.02 (m, 2H),
4.20. General procedure for arylation of 6
3.02e3.12 (m, 4H), 3.61e3.69 (m, 4H), 7.72 (t, J¼7.7 Hz, 2H), 7.81 (t,
J¼7.4 Hz, 1H), 7.85e7.91 (m, 2H). 13C NMR (125 MHz, DMSO-d6)
An oven-dried microwave tube, which was equipped with
a magnetic stir bar, was charged with sulfonimidamide 6 (0.05 g,
0.22 mmol, 1.0 equiv), NaOt-Bu (0.025 g, 0.27 mmol, 1.2 equiv), and
chloro-(2-dicyclohexylphosphino-20,60-diisopropoxy-1,10-biphenyl)
[2-(2-aminoethyl)phenyl]palladium(II)/methyl-tert-butyl ether ad-
duct 7 (3.0 mol % for aryl halides 8ae8c and 10ae10b) and (6.0 mol %
for aryl bromide 10c). The vessel was evacuated and backfilled with
argon (this process was repeated a total of 3 times), then the aryl
halide (1.5 equiv) or the heteroaryl halide (1.5 equiv) and THF
(0.15 mL/mmol) were added under argon atmosphere (the hetero-
aryl halides that were solids at room temperature were added with
d
ppm -1.9, 10.0, 46.0, 52.4, 65.2, 127.5, 129.7, 134.2, 134.3.
4.15. 4-(Phenylsulfonimidoyl)morpholine 6 starting from 5a
To a solution of 5a (0.01 g, 0.03 mmol) in dichloromethane
(0.2 mL), trifluoroacetic acid (12 mL, 0.15 mmol) was added and the
mixture was stirred overnight. The solvent was removed and the
product was purified using preparative HPLCþto yield 6 (6.00 mg, þ87
%) as a white solid. Mp¼103e105 ꢀC. MS (ES ), m/z: 227 [(MþH) ].
IR (ATR):
n
¼1251, 1108, 1067, 992, 924, 722, 688, 600, 523 cmꢁ1. 1H

7462
M. Funes Maldonado et al. / Tetrahedron 68 (2012) 7456e7462
the precatalyst and base). The tube was degassed and sealed with
a Teflon septum. The solution mixturewas set in a microwave system
(Biotage Initiator 2.5 Power range 0e400 W from magnetron at
2.45 GHz) and was heated at 100 ꢀC (external temperature) for 2.5 h.
The reaction mixture was then diluted with ethyl acetate, washed
with water, concentrated in vacuo, and purified with flash
chromatography.
127.8, 129.5, 133.2, 133.7, 139.1, 150.6, 151.7; HRMS (ESI)
C
14H16N4O2S calcd [MþH]þ 305.1072, found 305.1065.
5. Computational details
The geometries were optimized in vacuo using the DFT func-
tional B3LYP with a 6-31G** quality basis set. Solvent effects (water)
were included using a PBF continuum available in the B3LYP
functional with a 6-31þG** basis. All calculations were done using
Jaguar.15
4.21. 4-(N,S-Diphenylsulfonimidoyl)morpholine 9
Following the general procedure for arylation, the product was
purified with flash chromatography by slowly increasing the gra-
dient from 100% heptane to 60:40 heptane/ethyl acetate to give 4-
(N,S-diphenylsulfonimidoyl)moþrpholine 9(0.059 g, 88%) as a white
solid. Mp¼110e112 ꢀC. MS (ES ), m/z: 303.1 [(MþH)þ]. IR (ATR):
Acknowledgements
M.F. is grateful to the leadership team at Medicinal Chemistry,
CNSP iMED, AstraZenca R&D Sodertalje, Sweden, for allowing him
to conduct his M.Sc. work there.
€
€
n
¼1484, 1301, 1256, 1222, 1211, 1105, 1069, 1043, 1018, 921, 776, 736,
627, 534 cmꢁ1. 1H NMR (500 MHz, DMSO-d6)
d ppm 2.83e2.94 (m,
4H), 3.47e3.52 (m, 2H), 3.53e3.59 (m, 2H), 6.95 (t, J¼7.2 Hz, 1H),
Supplementary data
7.13e7.16 (m, 2H), 7.22e7.26 (m, 2H), 7.66e7.70 (m, 2H), 7.73e7.76
(m, 1H), 7.91e7.94 (m, 2H). 13C NMR (125 MHz, DMSO-d6)
d ppm
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.06.072.
46.4, 65.4, 121.8, 123.3, 127.8, 129.0, 129.2, 133.0, 134.4, 143.3; HRMS
(ESI) C16H18N2O2S calcd [MþH]þ 303.1167, found 303.1174.
References and notes
4.22. 4-[S-Phenyl-N-(pyridin-3-yl)sulfonimidoyl]morpholine 11a
1. Sehgelmeble, F.; Janson, J.; Ray, C.; Rosqvist, S.; Gustavsson, S.; Nilsson, L.;
Minidis, A.; Holenz, J.; Rotticci, D.; Lundkvist, J.; Arvidsson, P. I. ChemMedChem
2012, 7, 396e399.
2. (a) Levechenko, E. S.; Derkach, N. Y.; Kirsanov, A. V. Zh. Obshch. Khim. 1962, 32,
1208e1212; For reviews see: (b) Levchenko, E. S.; Markovskii, L. N.;
Shermolovich, Y. G. Russ. J. Org. Chem. 2000, 36, 143e177; (c) Rashatasakhan, P.;
Following the general procedure for arylation, the product was
purified with flash chromatography by slowly increasing the gra-
dient from 100% heptane to 5:95 heptane/ethyl acetate to give
sulfonimidamide 11a (0.066 g, 98 %) as a yellow oil. MS (ESþ), m/z:
304.3 [(MþH)þ]. IR (ATR):
n
¼1445, 1412, 1186, 1015, 997, 806, 598,
Harmata, M. Chemtracts: Org. Chem. 2006, 19, 143e151.
ˇ
510 cmꢁ1. 1H NMR (500 MHz, DMSO-d6)
d
ppm 2.84e2.97 (m, 4H),
3. (a) Leca, D.; Toussaint, A.; Mareau, C.; Fensterbank, L.; Lacote, E.; Malac
ˇ ria, M.
Org. Lett. 2004, 6, 3573e3575; (b) Azzaro, S.; Fensterbank, L.; Lacote, E.;
Malacria, M. Synlett 2008, 2253e2256.
4. (a) Collet, F.; Dodd, R. H.; Dauban, P. Org. Lett. 2008, 10, 5473e5476; (b) Di
3.46e3.53 (m, 2H), 3.53e3.60 (m, 2H), 7.27 (dd, J¼8.2, 4.41 Hz, 1H),
7.51e7.55 (m, 1H), 7.68e7.73 (m, 2H), 7.75e7.80 (m, 1H), 7.93e7.97
(m, 2H), 8.17 (dd, J¼4.6, 1.10 Hz, 1H), 8.38 (d, J¼2.5 Hz, 1H). 13C NMR
Chenna, P. H.; Robert-Peillard, F.; Dauban, P.; Dodd, R. H. Org. Lett. 2004, 6,
€
4503e4505; (c) Fruit, C.; Robert-Peillard, F.; Bernardinelli, G.; Muller, P.; Dodd,
(125 MHz, DMSO-d6)
d ppm 46.4, 65.3, 128.8, 127.8, 129.4, 129.6,
R. H.; Dauban, P. Tetrahedron: Asymmetry 2005, 16, 3484e3487; (d) Lian, C.;
€
133.3, 133.8, 140.2, 142.7, 144.9; HRMS (ESI) C15H17N3O2S calcd
Collet, F.; Robert-Peillard, F.; Muller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem. Soc.
[MþH]þ 304.1120, found 304.1110.
2008, 130, 343e350.
5. Tsushima, S.; Yamada, Y.; Oshima, K.; Chaney, M. O.; Jones, N. D.;
Swartzendruber, J. K. Bull. Chem. Soc. Jpn. 1989, 62, 1167e1178.
6. Collet, F.; Lescot, C.; Liang, C.; Dauban, P. Dalton Trans. 2010, 39, 10401e10413.
7. Worch, C.; Bolm, C. Synlett 2009, 2425e2428.
4.23. 4-[S-Phenyl-N-(pyridin-2-yl)sulfonimidoyl]morpholine 11b
8. Steurer, M.; Bolm, C. J. Org. Chem. 2010, 75, 3301e3310.
9. Patureau, F. W.; Worch, C.; Siegler, M. A.; Spek, A. L.; Bolm, C.; Reek, J. N. H. Adv.
Synth. Catal. 2012, 354, 59e64.
10. Toth, J. E.; Grindey, G. B.; Ehlhardt, W.; Ray, J.; Boder, G. B.; Bewley, J. R.;
Klingerman, K.; Gates, S.; Rinzel, S.; Schultz, R.; Weir, L.; Worzalla, J. J. Med.
Chem. 1997, 40, 1018e1025.
11. Cathers, B.; Schloss, J. V. Bioorg. Med. Chem. Lett. 1999, 9, 1527e1531.
12. (a) Bolm, C.; Garcia Machenco, O. Beilstein J. Org. Chem. 2007, 3.
13. Paulini, R.; Breuninger, D.; Von Deyn, W.; Bastians, H.; Maria, M.; Beyer,
C.; Anspaugh, D.; Oloumi-Sadeghi, H. (BASF SE) U.S. Patent WO 2009/156.
336 A1.
Following the general procedure for arylation, the product was
purified with flash chromatography by slowly increasing the gra-
dient from 100% heptane to 5:95 heptane/ethyl acetate to give
sulfonimidamide 11b (0.058 g, 86 %) as a yellow oil. MS (ESþ), m/z:
305 [(MþH)þ]. IR (ATR):
n
¼1587, 1421, 1315, 1256, 1235, 1069, 1050,
922, 757, 732, 687, 599, 512 cmꢁ1
.
1H NMR (500 MHz, DMSO-d6)
d
ppm 2.92e3.03 (m, 4H), 3.52e3.62 (m, 4H), 6.88 (ddd, J¼7.2, 4.89,
0.79 Hz, 1H), 6.96 (d, J¼8.2 Hz, 1H), 7.59e7.68 (m, 3H), 7.68e7.74
(m, 1H), 7.84e7.89 (m, 2H), 8.11 (dd, J¼4.9, 1.4 Hz, 1H). 13C NMR
14. (a) Johnson, C. R.; Lavergne, O. J. Org. Chem. 1989, 54, 986e988; (b) Johnson, C.
R.; Lavergne, O. J. Org. Chem. 1993, 58, 1922e1923.
(125 MHz, DMSO-d6)
d ppm 46.0, 65.4, 117.0, 117.1, 127.7, 129.3,
€
15. Jaguar, Version 7.8; Schrodinger: New York, NY, 2007.
132.9, 135.4, 137.9, 148.0, 157.1; HRMS (ESI) C15H17N3O2S calcd
16. Johnson, C.; Jonsson, E.; Bacon, C. J. Org. Chem. 1979, 44, 2055e2061.
17. Worch, C.; Atodiresei, I.; Raabe, G.; Bolm, C. Chem.dEur. J. 2010, 16, 677e683.
18. Ellman, J. A.; Dragoli, D. R.; Backers, B. J. J. Org. Chem. 1999, 64, 5472e5478.
19. Bolm, C.; Young, G. Org. Lett. 2005, 7, 1351e1354.
[MþH]þ 304.1120, found 304.1116.
4.24. 4-[S-Phenyl-N-(pyrimidin-5-yl) sulfonimidoyl]
morpholine 11c
€
€
20. Lucking, U; Kettshau, G.; Biem, H.; Schwede, W.; Schafer, M.; Thierauch, K.;
Mann, M. (Shering Aktiengesellschaft) WO 2006/108695 A2.
21. Bolm, C.; Worch, C. Synthesis 2008, 5, 0739e0742.
ˇ
22. Azarro, S.; Desage-El Murr, M.; Fensterbank, L.; Lacote, E.; Malacria, M. Synlett
Following the general procedure for arylation, the product was
purified with flash chromatography by slowly increasing the gra-
dient from 100% heptane to 5:95 heptane/ethyl acetate to give
sulfonimidamide 11c (0.058 g, 86%) as a yellow oil. MS (ESþ), m/z:
2011, 849e851.
23. Buchwald, S.; Huang, X.; Klapars, A. J. Am. Chem. Soc. 2002, 124, 7421e7428.
24. Jiang, S.; Wang, Z.; Li, Z.; Qiu, Y.; Yang, K. J. Org. Chem. 2011, 76, 3151e3159.
25. Surry, D.; Buchwald, S. Chem. Sci. 2011, 2, 27e50.
26. Maiti, D.; Fors, B.; Henderson, J.; Nakamura, Y.; Buchwald, S. Chem. Sci. 2011, 2,
305 [(MþH)þ]. IR (ATR):
¼1541, 1412, 1293, 1257, 1234, 1124, 1068,
n
57e68.
1045,1015, 922, 738, 722, 637, 547 cmꢁ1. 1H NMR (500 MHz, DMSO-
27. Douglass, I. B. J. Org. Chem. 1965, 30, 633e635.
28. Savile, C.; Magloire, V.; Kazluaskas, R. J. Am. Chem. Soc. 2005, 127, 2104e2113.
29. Kowalczyk, R.; Edmunds, A. J.; Hall, R.; Bolm, C. Org. Lett. 2011, 13, 768e771.
30. García Ruano, J.; Parra, A.; Marzo, L.; Yuste, F.; Mastranzo, V. M. Tetrahedron
2011, 67, 2905e2910.
d6)
7.70e7.75 (m, 2H), 7.78e7.82 (m, 1H), 7.95e8.00 (m, 2H), 8.59 (s,
2H), 8.79 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
ppm 46.4, 65.3,
d ppm 2.87e2.99 (m, 4H), 3.47e3.54 (m, 2H), 3.55e3.61 (m, 2H),
d