Straightforward Strategies for the Preparation of NH-Sulfox-imines: A Serendipitous Story

Article abstract of DOI:10.1055/s-0036-1590874

Sulfoximines are emerging as valuable new isosteres for use in medicinal chemistry, with the potential to modulate physicochemical properties. Recent developments in synthetic strategies have made the unprotected 'free' NH-sulfoximine group more readily available, facilitating further study. This account reviews approaches to NH-sulfoximines, with a focus on our contribution to the field. Starting from the development of catalytic strategies involving transition metals, more sustainable metal-free processes have been discovered. In particular, the use of hypervalent iodine reagents to mediate NH-transfer to sulfoxides is described, along with an assessment of the substrate scope. Furthermore, a one-pot strategy to convert sulfides directly into NH-sulfoximines is discussed, with N- and O-transfer occurring under the reaction conditions. Mechanistic evidence for the new procedures is included as well as relevant synthetic applications that further exemplify the potential of these approaches. 1 Introduction 2 Strategies to Form NH-Sulfoximines Involving Transition-Metal Catalysts 3 Metal-Free Strategies to Prepare NH-Sulfoximines 4 Mechanistic Evidence for the Direct Synthesis of NH-Sulfoximines from Sulfoxides and Sulfides 5 Further Applications 6 Conclusion.

Full text of DOI:10.1055/s-0036-1590874

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
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J. A. Bull et al.
Account
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Straightforward Strategies for the Preparation of
NH-Sulfoximines: A Serendipitous Story
James A. Bull*a
Leonardo Degennarob
Renzo Luisi*b
sources of
sources of
O
S
O
N H
NH3
NH3
S
S
PhI(OAc)2
PhI(OAc)2
a Department of Chemistry, Imperial College London, South
Kensington, London, SW7 2AZ, UK
direct one-pot
NH- and O-transfer
direct NH-transfer
j.bull@imperial.ac.uk
b Department of Pharmacy — Drug Sciences, University of Bari
“A. Moro”, Via E. Orabona 4, Bari 70125, Italy
renzo.luisi@uniba.it
= alkyl, aryl, vinyl, cyclic and acyclic
Received: 31.05.2017
Accepted after revision: 18.07.2017
Published online: 05.09.2017
recting groups for C–H functionalization,5 as well as agro-
chemicals6 and medicinal chemistry.7 Much of the develop-
ment over the last decade has been facilitated by the intro-
duction of new and more practical synthetic
methodologies.8–10 These advances in the field brought
about an increasing interest in sulfoximines in life sciences
and drug discovery.11–14 Examples of some biologically rele-
vant molecules bearing the sulfoximine moiety are shown
in Figure 1.
DOI: 10.1055/s-0036-1590874; Art ID: st-2017-a0415-a
Abstract Sulfoximines are emerging as valuable new isosteres for use
in medicinal chemistry, with the potential to modulate physicochemical
properties. Recent developments in synthetic strategies have made the
unprotected ‘free’ NH-sulfoximine group more readily available, facili-
tating further study. This account reviews approaches to NH-sulfoxi-
mines, with a focus on our contribution to the field. Starting from the
development of catalytic strategies involving transition metals, more
sustainable metal-free processes have been discovered. In particular,
the use of hypervalent iodine reagents to mediate NH-transfer to sulf-
oxides is described, along with an assessment of the substrate scope.
Furthermore, a one-pot strategy to convert sulfides directly into NH-
sulfoximines is discussed, with N- and O-transfer occurring under the
reaction conditions. Mechanistic evidence for the new procedures is in-
cluded as well as relevant synthetic applications that further exemplify
the potential of these approaches.
Our understanding of the potential of the sulfoximine
group in drug discovery is growing. Compounds containing
NH-sulfoximines
from
Bayer
(BAY1000394
and
BAY1143572) and AstraZeneca (AZD6738) are paving the
way in current clinical trials.12 While there remain relative-
ly few published studies on sulfoximine properties relevant
to medicinal chemistry, high metabolic stability, hydrogen-
bond acceptor/donor capabilities and desirable physico-
1
2
Introduction
Strategies to Form NH-Sulfoximines Involving Transition-Metal
Catalysts
3
4
Metal-Free Strategies to Prepare NH-Sulfoximines
Mechanistic Evidence for the Direct Synthesis of NH-Sulfoximines
from Sulfoxides and Sulfides
Further Applications
Conclusion
G
[O]
O
N
G
N
S
S
R
R'
R
R'
5
6
sulfilimine
[N]
deprotection
Key words NH-sulfoximines, N-transfer, hypervalent iodine, ni-
trenoids, catalysis
O
NH
simultaneous
N-, O-transfer
S
S
R
R'
R
R'
Direct NH-
transfer
1 Introduction
[O]
deprotection
Since the discovery of the first sulfoximine in 1949,1 the
chemistry of sulfoximines has developed from a rather
niche area into a field with wide and expanding applica-
tions.2–7 The sulfoximine group is chemically stable, is sta-
ble to hydrolysis, and has stable configuration. As such, the
utility of the sulfoximine functional group encompasses
chiral auxiliaries,3 ligands in asymmetric catalysis,4 and di-
O
S
[N]
O
N
PG
S
R
R'
R
R'
sulfoxide
PG = SO2Ar, CF3CO, R''OCO
G = CN
Scheme 1 Strategies for accessing NH-sulfoximines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

B
J. A. Bull et al.
Account
Synlett
chemical properties have been observed.7,13,14 As isosteres
for sulfones, the sulfoximine group often provides im-
proved solubility, and also presents further complexity
with an additional attachment point. In a recent study,
Bolm and co-workers from Boehringer Ingelheim reported
the analysis of a series of matched molecular pairs to com-
pare sulfoximines against other sulfur functionalities on
various simple substrates.13 Sirvent and Lücking from Bayer
evaluated the sulfoximine functionality as an isostere for
amines by incorporation into analogues of marketed drugs
and advanced clinical candidates with favorable compari-
son of the physical and biological properties.14
From NH-sulfoximines, the nitrogen atom offers poten-
tial to introduce further molecular diversity through an in-
creasingly broad array of transformations, as exemplified
by N-trifluoromethylation,15 arylation,16 aroylation,17 alky-
nylation,18 alkylation,19 propargylation,20 cyanation,21 thio-
etherification,22,23 and intramolecular halocyclization reac-
tions.24 Racemic NH-sulfoximines can also be subjected to
catalytic kinetic resolution.25
As a consequence of the importance of the sulfoximine
functionality, the development of strategies for the synthe-
sis and incorporation of this structural motif is still a vigor-
ous research area. To access NH-sulfoximines, different syn-
thetic approaches are now available (Scheme 1). Either the
Biographical Sketches
James A. Bull is a University
Research Fellow in the Depart-
ment of Chemistry at Imperial
College London. He obtained his
M.Sci. degree from the Universi-
ty of Cambridge, then spent a
year at GlaxoSmithKline. He re-
turned to the University of
Cambridge to obtain his Ph.D.
in organic chemistry under the
supervision of Professor Steven
V. Ley (2006). He then spent
two years undertaking postdoc-
toral research with Professor
André B. Charette at Université
de Montréal. In 2009, he joined
Imperial College London as a
Ramsay Memorial Research Fel-
low. In 2011, he was awarded an
EPSRC Career Acceleration Fel-
lowship, and in 2016 was
awarded a University Research
Fellowship from The Royal Soci-
ety. His research focuses on the
development of efficient syn-
thetic and catalytic methods to
access novel structural motifs
and heterocycles of interest in
drug discovery.
Leonardo Degennaro is an
Assistant Professor at the Uni-
versity of Bari “A. Moro”. He ob-
tained his master’s degree in
Chemistry and Pharmaceutical
Technology at the University of
Bari in 1999, and in 2003 his
Ph.D. in Chemical Applied and
Enzymatic Synthesis. In 2002,
he was a visiting scholar at the
Institute of Organic and Molecu-
lar Inorganic Chemistry, Univer-
sity
of
Groningen
(The
Kyoto University (Japan), work-
ing in the group of Prof. J.-i.
Yoshida. His research activity
concerns the development of
new stereoselective syntheses,
organometallic chemistry, the
reactivity of small heterocycles,
flow chemistry, and the study of
dynamic phenomena at the mo-
lecular level.
Netherlands) under the supervi-
sion of Prof. B. L. Feringa. In
2006, he was appointed Assis-
tant Professor in Organic Chem-
istry at the Faculty of Pharmacy
of the University of Bari. In
2011, he became a visiting as-
sistant professor at the Depart-
ment of Synthetic Chemistry
and Biological Chemistry, Grad-
uate School of Engineering,
Renzo Luisi is an Associate
Professor of Organic Chemistry
at the University of Bari “A. Mo-
ro”, Italy. He obtained an M.Sci.
(summa cum laude) in Chemis-
try and Pharmaceutical Technol-
ogy at the University of Bari
(Italy) in 1996. In 2000, he ob-
tained his Ph.D. in Chemical Sci-
ences, and in 2001 was hired as
Assistant Professor at the Uni-
versity of Bari. Four years later,
in 2005, he was appointed As-
sociate Professor of Organic
Chemistry at the same Universi-
ty. In 2014, he received his na-
tional habilitation to full
professor. He has been a visiting
scholar at the University of Illi-
nois (USA) working in the group
of Prof. P. Beak, and a visiting
professor at the University of
Manchester (UK), Brown Univer-
sity (RI, USA) and the University
of North Carolina (Charlotte,
USA). His main research inter-
ests include organometallic
chemistry (mainly lithium and
boron chemistry), the synthesis
and reactivity of small heterocy-
cles, asymmetric synthesis and
dynamic NMR spectroscopy. In
2010, he was awarded with a
special funding program for
young scientists from the Italian
Ministry of Education and Re-
search to start independent re-
search in the field of sustainable
chemistry and microreactor
technology.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

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J. A. Bull et al.
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CF3
HN
O
N
N
OMe
O
N
O
S
OH
N
N
Me
H
N
N
F
BAY 1143572
PTEFb inhibitor
HN
O
HN
N
S
NH
N
HN
O
Me
S
S
N
COOH
NH2
O
NH
R
BAY 1000394
pan-CDK inhibitor
AZD6738
ATR inhibitor
methionine sulfoximine (MSO); R = Me
buthionine sulfoximine (BSO); R = n-Bu
O
NH
O
N
N
O
NH
O
O
S
S
S
OOC
Me
Me
Ph
H
Ph
O
N
(HOCH2)3CNH3
Cl
S
N
RU 31156 (sudexanox)
CF3
N
N
Sulfoxaflor
N
Ph
Ph
OH
O
NH
NEt2
H
H
Go 4962
HO
O
N
N
S
N
OH
CYP24 inhibitor
S
O
O
Ph
Ph
HO
Suloxifen
HIV-1 protease Inhibitor
MeO
O
Me
O
MeO
O
S
S
N
N
O
H
O
N Me
MeO
N
O
N
S
N
O
CF3
Me
N
N
N
O
F
N
N
N
HNE inhibitor
α-adrenergic receptor blocker
H
H
NMe2
PYK2 inhibitor
N
N
HN
O
O
S
H
Me
O
N
N
S
O
S
CF3
N
N
O
N
HNE inhibitor
Amgen
CF3
H2N
Figure 1 Examples of biologically relevant sulfoximine compounds
oxygen or the nitrogen group may be introduced first, af-
fording the corresponding sulfoxide or sulfilimine,26 respec-
tively, using electrophilic reagents. Further oxidation of sul-
filimines or imination of sulfoxides affords the sulfoximine.
Commonly, a protected nitrogen group is involved, meaning
three-step sequences are required to access the free NH-
sulfoximine from sulfides.
In this account, we review methods for the synthesis of
NH-sulfoximines through transition-metal-catalyzed and
metal-free methods. In 2015, Bolm produced a comprehen-
sive review on methods for sulfoximine synthesis.8a Here,
we aim to highlight important advances for the preparation
of NH-sulfoximines since 2015, with a focus on our own
contributions. In particular, we recently reported straight-
forward strategies for the preparation of NH-sulfoximines
by deprotection of easily removable N-protecting groups,
the direct introduction of the NH group on sulfoxides, and
the simultaneous transfer of O and NH groups on sulfides.
Herein, we report our perspective on the progress of the
work, how our strategies complement other available pro-
cedures, and underlying mechanistic investigations.
2 Strategies to Form NH-Sulfoximines
Involving Transition-Metal Catalysts
When we first entered the field in 2015, there were sev-
eral powerful methods available for transition-metal-cata-
lyzed N-transfer to sulfoxides, being the most common
route to protected sulfoximines (Scheme 2).8a The use of
various transition-metal catalysts allows the generation
and stabilization of metal-nitrenoid species responsible for
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

D
J. A. Bull et al.
Account
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the N-transfer to the sulfur atom. The use of Cu, Rh, Ag and
Fe catalysis has been employed for the transfer of sulfon-
amide groups by activated nitrogen species (e.g.,
PhI=NSO2Ar) (Scheme 2, a).27,28 Bolm reported the use of a
combination of trifluoroacetamide and PhI(OAc)2 in the
presence of Rh2(OAc)4 as the catalyst for transferring the N–
COCF3 group to sulfoxides (Scheme 2, b).28 The same author
developed the N-acyl transfer to sulfoxides using 1,4,2-di-
oxazol-5-ones under Ru-catalyzed photochemical condi-
tions (Scheme 2, c).29 With these methods, removal of the
nitrogen substituent could give access to free NH-sulfoxi-
mines. While N-tosyl groups are quite challenging to re-
move, it has been demonstrated that the nosyl (Ns) group
could be removed by treatment with thiophenol and cesium
carbonate (Scheme 3, a).26b On the other hand, N-trifluoro-
acetyl sulfoximines can be effectively N-deprotected by
treatment with K2CO3/MeOH (Scheme 3, b).28
For the purposes of our initial investigations, we were
interested in carbamate-protected sulfoximines. We envi-
sioned that these would be stable to allow synthetic trans-
formations prior to revealing the NH-sulfoximine, and
would be straightforward to deprotect under well-under-
stood conditions. In particular, sulfoximine carbamates
bearing N-Boc and N-Cbz groups would present orthogonal
N-deprotection strategies. However, we were surprised that
similar catalytic methods to form carbamate-protected
sulfoximines from carbamates were not available. Indeed,
carbamate protecting groups were commonly installed
through reaction of NH-sulfoximines formed by other
methods.12a The only direct method, developed by Bach,
used FeCl2-catalyzed transfer of the N-Boc group to the sul-
fur atom of sulfoxides, using potentially explosive azides as
the nitrogen source (Scheme 2, d).31 Bach demonstrated the
removal of the Boc group under acidic conditions using TFA
(Scheme 3, c).
With the aim of providing new N-protected sulfoxi-
mines, we developed a Rh-catalyzed nitrogen transfer from
tert-butyl, benzyl, methyl, ethyl, phenyl and allyl carba-
mates (Scheme 4).32 We began our study exploring the use
of BocNH2 and PhI(OAc)2 in the presence of Rh2(OAc)4 in or-
der to generate an activated nitrenoid species (i.e.,
BocN=Rh) for the N-transfer to methyl tolylsulfoxide 1a.
Adapting Bolm’s protocol,28 using rhodium catalysis and
magnesium oxide as the base,33 we were delighted to ob-
serve the direct formation of the N-Boc sulfoximine 2a in a
very good yield when running the reaction at 40 °C. It is
worth pointing out that the reaction required the metal ca-
talysis; no reaction occurred in the absence of Rh2(OAc)4,
and the reaction was performed under air without requir-
ing anhydrous dichloromethane.
PhI=NSO2Ar
or PhI(OAc)2, ArSO2NH2
N
SO2Ar
O
S
O
a)
b)
c)
d)
S
S
Cu, Rh, Ag or Fe catalysts
R
R'
R
R
R'
R'
O
CF3CONH2
PhI(OAc)2
O
S
N
O
CF3
Rh2(OAc)4 catalyst
R
R'
O
O
N
O
S
O
hν
O
+
R"
S
S
O
Ru(TPP)CO
R
R'
R
R'
N
R"
N
Boc
O
S
O
BocN3
R
R'
FeCl2 catalyst
R
R'
Scheme 2 Metal-based approaches to N-protected sulfoximines
The scope of this reaction was widely explored, with ex-
amples shown in Scheme 4. Several N-Boc sulfoximines 2a–
i were prepared in good to excellent yields. Under opti-
mized reaction conditions, it was also possible to transfer
methyl and ethyl carbamates to the sulfur atom of sulfox-
ides to afford sulfoximines 3a–d and 4a–c, respectively. In
the case of four-membered thietane 1-oxide, 5 mol% of the
Rh catalyst was needed for the N-transfer of the carbamates
leading to thietane sulfoximines 2i, 3d and 4c (Scheme 4).
The stereospecificity of the transfer of the N-Boc group to
the sulfur was demonstrated by performing the reaction on
enantioenriched (S)-1a (er 97:3). The reaction occurred
with complete retention of configuration and preservation
of the er in N-Boc-sulfoximine 2a.32,34
Cs2CO3
thiophenol
N
SO2Ar
O
a)
b)
d)
S
S
R
R'
Ar = nosyl
O
K2CO3
MeOH
N
O
N
Boc
H+
O
NH
R'
O
CF3
c)
S
S
R
R'
R
R'
R
O
Rh2(esp)2
O2N
S
R
R'
ONH2
NO2
Scheme 3 Strategies for accessing NH-sulfoximines
Slightly different reaction conditions were needed for
the transfer of benzyl, phenyl and allyl carbamates, which
may undergo unfavorable coordination between the π-sys-
tem in the carbamate substituents and the catalyst. These
substrates were less reactive, but this could be somewhat
ameliorated by running the reaction at an increased 0.3 M
concentration of sulfoxide. Under these optimized condi-
tions, N-benzyloxycarbonyl sulfoximines 5a–c, N-phenyl-
To date, there is only one direct transition-metal-cata-
lyzed method for the preparation NH-sulfoximines. Richards
reported a direct Rh-catalyzed method for NH-transfer to
sulfoxides using O-(2,4-dinitrophenyl)hydroxylamine as
the nitrogen source, and Rh2(esp)2 as the catalyst (Scheme
3, d).30
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

E
J. A. Bull et al.
Account
Synlett
oxycarbonyl sulfoximines 6a,b and N-allyloxycarbonyl sulf-
oximines 7a,b could be prepared in acceptable yields
(Scheme 4).
TFA
CH2Cl2
TFA
CH2Cl2
O
NBoc
Me
O
NH
O
NBoc
O NH
S
S
S
S
Me
rt, 1 h
98%
rt, 1 h
69%
2a
8a
2i
9
O
O
S
O
N
Rh2(OAc)4 (2.5 mol%)
PhI(OAc)2
O
O
S
NCbz H2 (1 atm), Pd/C
EtOH, rt, 1 h
O
NH
OR''
S
S
R
R'
R
R'
H2N
OR''
Me
Me
MgO, CH2Cl2, 0.1 or 0.3 M
77%
1
2
40 °C, 8 h
5a
8a
NBoc
O
NBoc
Me
NBoc
Et
NBoc
O
O
O
S
S
S
S
Scheme 5 Deprotection of N-protected sulfoximines
i-Pr
Cl
Cl
2a 98% (er 97:3)
2b 85%
NBoc
2c 54%
NBoc
2d 93%
80% (4 mmol scale)
methionine sulfoxide 10 (a 1:1 mixture of diastereoiso-
mers) by Rh-catalyzed N-Boc transfer, was fully deprotect-
ed under acidic conditions affording MSO in 54% yield over
the two steps (Scheme 6).
NBoc
NBoc
NBoc
O
O
O
O
O
S
S
S
S
S
Ph
Ph
2e 70%
2f 89%
2g 66%
2h 78%
2i 85%
NCO2Me
O
S
O
O
BocN
Me
O
BocNH2
Rh cat.
NCO2Me
Me
O
NCO2Me
O
S
NCO2Me
O
O
S
S
S
Me
Ot-Bu
NHBoc
10
Ot-Bu
S
82%
NHBoc
Cl
11
3a 98%
3b 66%
3c 78%
NCO2Et
3d 83%
O
HN
O
NCO2Et
Me
O
O
NCO2Et
O
HCl
80 °C, 3 h
S
S
S
S
Me
OH
66%
NH2
Ph
Ph
MSO
4a 77%
4b 76%
4c 78%
NCbz
Me
NCbz
NCbz
O
O
O
S
Scheme 6 Preparation of methionine sulfoximine (MSO)
S
S
Et
This carbamate transfer protocol appears to be a general
and convenient procedure for the preparation of sulfox-
imine carbamates. Our approach complements well with
other available strategies to N-protected sulfoximines, and
may facilitate synthetic planning by allowing flexible re-
moval of protecting groups to access NH-sulfoximines.
Cl
5a 60%
5b 52%
(24 h, 1.1 mmol)
5c 40%
NCO2Ph
Me
NCO2Ph
NCO2allyl
NCO2allyl
O
O
O
O
S
S
S
S
Me
Et
Ph
Ph
Cl
6a 54%
6b 40%
7a 40%
7b 38%
Scheme 4 Examples of Rh-catalyzed N-transfer of carbamates
3 Metal-Free Strategies to Prepare NH-Sulf-
oximines
The usefulness of N-protected sulfoximines was demon-
strated by further manipulations: N-Boc and N-Cbz sulfox-
imines 2b and 5b underwent smooth Pd- and Fe-catalyzed
cross-coupling reactions.32 The possibility to generate free
NH-sulfoximines was demonstrated with the deprotection
of N-Cbz- and N-Boc-sulfoximines 2a, 5a and 2i (Scheme 5).
By using standard acidic conditions, the Boc group was re-
moved from N-Boc sulfoximines 2a and 2i, in good to excel-
lent yields, affording the corresponding NH-sulfoximines 8a
and 9, respectively. By using hydrogenolysis conditions
(Scheme 5), the corresponding NH-sulfoximine 8a was ob-
tained in 77% yield from N-Cbz sulfoximine 5a.
The use of transition-metal catalysts such as rhodium
can be expensive on large scale, and presents toxicological
issues in the late-stage preparation of pharmaceutical prod-
ucts. In order to render the preparation of sulfoximines
more sustainable, several transition-metal-free strategies
have been developed (Scheme 7). For the direct preparation
of NH-sulfoximines from sulfoxides, one of the oldest but
still used procedures relies on the use of NaN3 under acidic
conditions (Scheme 7, a).36 However, the harsh reaction
conditions and the hazards related to the development of
HN3 makes this strategy unattractive. Interestingly, the use
of flow technology has been suggested as a possible solu-
tion for the safer use of azides.9b However, even under flow
conditions, this strategy was not compatible with enantio-
enriched starting materials. The use of the Eaton’s reagent
(phosphorus pentoxide, in methanesulfonic acid) and NaN3
This synthetic strategy for the preparation of N-protect-
ed sulfoximines was effectively employed for the prepara-
tion of the target molecule methionine sulfoximine
(MSO).32,35 N-Boc sulfoximine 11, formed from protected
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

F
J. A. Bull et al.
Account
Synlett
has recently been proposed by Liang for accessing NH-sulf-
oximines.37 Another old strategy for the preparation of NH-
sulfoximines uses O-mesitylene sulfonylhydroxylamine
(MSH) for the direct transfer of the NH group to a sulfoxide
(Scheme 7, b). However, MSH is an unstable reagent that
needs to be prepared before use.38
O
N
CN
O
N
O
a)
Tf2O
S
CF3
S
R
R'
R
R'
K2CO3
MeOH
50% H2SO4
110 °C
10 mA/cm2
Pt cathode
NH
R'
N
Phth
O
O
b)
NH
R'
O
S
NaN3/H+
Me
S
O
S
a)
b)
R
R
R'
Bu4NBF4
MeOH
S
R
R
R'
Scheme 8 Removal of the N-protecting groups in selected sulfoximines
Me
SO3NH2
NH
R'
O
O
Me
S
S
R
We considered that development of a safe, metal-free
and direct method for the NH-transfer to sulfoxides, partic-
ularly using convenient inexpensive nitrogen sources,
would offer considerable value. Building on our previous
work on the Rh-catalyzed transfer of alkyl carbamates to
sulfoxides (Scheme 4), we explored the possibility of using
a carbamic salt as the nitrogen source, expecting the NH-
sulfoximine to be formed directly due to the driving force
for decarboxylation to occur, either before or after the N-
transfer.
Ammonium carbamate was chosen as an inexpensive
and easily handled nitrogen source, and was tested in
metal-catalyzed (Rh and Fe) as well as metal-free N-trans-
fer reactions. To our delight, we were able to obtain the de-
sired NH-sulfoximine.45 However, unexpectedly and seren-
dipitously, we found that the reaction proceeded efficiently
without requiring a transition-metal catalyst. This metal-
free protocol opened up new perspectives in the field of the
direct preparation of NH-sulfoximines as well as in N-trans-
fer methodologies. The reaction was optimized using sulf-
oxide 1a, and could be conducted under different reaction
conditions (Scheme 9).
R
R'
c)
d)
e)
f)
NsNH2
PhI(OAc)2
O
S
N
Ns
O
S
S
S
R
R'
R
R'
MeCN
NH2CN
NCS
O
S
N
CN
Phth
O
t-BuOK, H2O
R
R'
R'
R
R'
PhthNH2
PhI(OAc)2
O
S
N
O
R
R
R'
CH2Cl2
O
S
N
Phth
O
PhthNH2
S
R
R'
R
R'
Pt anode, +1.8 V
Scheme 7 Reported metal-free strategies for the preparation of NH-
sulfoximines
Several alternative milder metal-free iminations of sulf-
oxides have been developed leading to N-protected sulfox-
imines (Scheme 7). In one of the earlier reports, Bolm de-
veloped a metal-free transfer of the p-nitrobenzenesulfo-
nylamide (NsNH2) to the sulfur of sulfoxides in the presence
of PhI(OAc)2 as the oxidant (Scheme 7, c).39 Very recently,
Bolm reported a metal-free synthesis of N-cyanosulfox-
imines by N-transfer from cyanamide (NH2CN) in presence
of N-chlorosuccinimide (NCS) as the oxidant and potassium
tert-butoxide as the base (Scheme 7, d).40 Yudin introduced
two metal-free methodologies leading to N-phthalimido-
sulfoximines. One simple protocol relies on the use of N-
aminophthalimide (PhthNH2) in the presence of PhI(OAc)2 as
the oxidant in dichloromethane (Scheme 7, e).41 Yudin also
developed a ‘green’ and mild electrochemical sulfoxide im-
ination using PhthNH2 as the iminating agent (Scheme 7, f).42
Removal of these N-protecting groups has been demon-
strated in isolated examples. Deprotecting the CN group
needed two additional steps to reveal the NH-sulfoximine
consisting of treatment with Tf2O followed by basic hydro-
lysis (Scheme 8, a).43 The direct removal of the cyano group
is also possible under rather forcing conditions: 50% aque-
ous sulfuric acid at 110 °C.44 Yudin proved that the N-
phthalimido group could be removed electrochemically us-
ing a Pt cathode in the presence of a methanolic solution of
an ammonium salt (Scheme 8, b).42
O
O
S
NH
O
S
H2N
O NH4
Me
Me
PhI(OAc)2, solvent
8a
1a
Conditions
Yield
90%
90%
96%
91%
a) toluene, H2NCO2NH4 (2 equiv), PhI(OAc)2 (2 equiv), MgO, 35 °C, 16 h
b) MeCN, H2NCO2NH4 (2.5 equiv), PhI(OAc)2 (1.5 equiv), 25 °C, 3 h
c) MeOH, H2NCO2NH4 (4 equiv), PhI(OAc)2 (3 equiv), 25 °C, 30 min
Conditions c), 10 mmol scale
Scheme 9 Metal-free protocols for the formation of NH-sulfoximines
Indeed, the reaction could be run in toluene, acetonitrile
and methanol. Using toluene as the solvent (Scheme 9, con-
ditions a), mixing ammonium carbamate with bisacetoxy-
iodobenzene and magnesium oxide at 35 °C for 16 hours led
to sulfoximine 8a in 90% yield. The heterogeneous nature of
the reaction in toluene affected the rate of dissolution of
ammonium carbamate; therefore, to reduce the reaction
time, more polar solvents were employed. Acetonitrile and
methanol were both successful, providing full conversion in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

G
J. A. Bull et al.
Account
Synlett
the absence of the base (Scheme 9, conditions b or c). How-
ever, a higher yield (96%) and a shorter reaction time (30
min) were achieved in methanol (Scheme 9, conditions c).
This protocol is very simple and easy to perform in an open
flask, and is scalable, as demonstrated by performing the
reaction on a 10 mmol scale (1a: 91% yield of 8a). To high-
light the practical nature of this method, we prepared a vid-
eo of the protocol.46
The scope of the reaction has been widely investigated,
mainly using MeOH as the solvent (Scheme 10).45 Different
protocols and solvents can also be used depending on the
solubility of the starting sulfoxide.
As reported in Scheme 10,45 the NH-transfer occurred on
various sulfoxides leading to the corresponding NH-sulfox-
imines 8b–t in good to excellent yields. We found that the
protocol was compatible with aryl- and alkyl-substituted
sulfoxides (e.g., 8b–o), as well as with cyclic sulfoxides (as
in the cases of 8p–t). A lower yield was observed with phe-
nyl vinyl sulfoxide, leading to 8l in 54% yield. A trifluoro-
methylsulfoxide provided 8u in only 9% yield due to the
lower nucleophilicity of the sulfoxide. Concerning the ste-
reochemical outcome of the NH-transfer methodology,
complete stereoselectivity was observed in sulfoximines
8q–t derived from diastereomerically pure cyclic sulfoxides.
Similarly, the 9:1 diastereomeric ratio of an α-chlorinated
sulfoxide was retained in sulfoximine 8i. The reaction on
enantioenriched sulfoxides resulted in enantioenriched
sulfoximines (S)-8a, (R)-8b and (R)-8h (er > 97:3), with
complete retention of the configuration from the starting
materials.45 The scalability of the procedure was also
demonstrated with thietanesulfoximine 9, prepared on an
11 mmol scale in 81% yield.
H2NCO2NH4
PhI(OAc)2
O
O
NH
R'
S
S
R'
O
R
Solvent:
MeOH or MeCN or toluene
R
O
NH
NH
O
NH
O NH
S
Ph
S
F
S
S
Ph
8b 76%
Ph
i-Pr
8d 88%
Ph
8c 69%
8e 84%
Functional group compatibility of this NH-transfer to
form sulfoximines is important to ensure synthetic efficien-
cy, and in later-stage applications. In particular, for applica-
tions in medicinal chemistry, compatibility with heterocy-
cles is crucial. The conditions were shown to be tolerant of
various functional groups in the sulfoxides, including free
hydroxy groups in sulfoximines 8r–t (Scheme 10). Further-
more, protected methionine sulfoxide smoothly underwent
NH-transfer providing protected MSO derivative 12 in good
yield (Scheme 10). To give an indication of the tolerance of
the reaction to a much wider array of possible sulfoxide
substrates, the procedure was subjected to the Glorius ro-
bustness screen.45,47 The standard reaction with sulfoxide
1a was performed in the presence of stoichiometric quanti-
ties of various functionalized additives (Figure 2). The ma-
jority of the heterocycles tested were found to be compati-
ble giving the product 8a in yields ranging from 85–95%.
Importantly, heterocycles with basic nitrogen groups were
found to be compatible with the reaction. Very high yields
were observed in the presence of pyridine, pyrimidine,
quinoline, imidazole, thiazole, benzoxazole and benzothi-
azole. According to this robustness screen, sulfoxides bear-
ing benzothiazole and imidazole groups were expected to
provide very good yields of the corresponding sulfoximines.
Therefore, sulfoximine 13, bearing a benzothiazole substit-
uent, was targeted, and was successfully prepared in 84%
yield. Similarly, oxfendazole, an anthelmintic containing
benzimidazole, was shown to undergo NH-transfer furnish-
ing the corresponding sulfoximine 14 in 70% yield (Scheme
10).
O
NH
O
O
NH
Et
NH
O
NH
S
Cl
S
S
S
Ph
Cl
Cl
Cl
Br
8f 84%
8g 87%
8h 74%
8i 85%
(dr 9:1)
O
NH
O
NH
O
NH
O
NH
S
S
Ph
Me
S
S
Ph
8l 54%
Ph
Ph
8j 64%
8k 90%
8m 89%
O
O
NH
O
NH
O NH
O
NH
O
NH
S Ph
OH
Ph
Ph
S
S
S
S
Ph
t-Bu
Me
Ph
8n 86%
8o 79%
8p 84%
(
)-8q 83%
(
)-8r 83%
O
NH
O
(
NH
O NH
S
OH
Ph
Ph
)-8s 62%
OH
HO
CF3
S
S
Br
O
(
)-8t 82%
8u 9%
O
NH
O
NH
S
S
Me
Ot-Bu
NHBoc
9 90%
12 78%
(81% 11 mmol)
O
NH
O
N
S
NH
S
N
S
NH
Ph
N
CO2Me
H
13 84%
14 70%
Scheme 10 Scope of the NH-transfer reaction to sulfoxides
On the other hand, electron-rich heterocycles such as
indole, furan and thiophene were tolerated less well, lead-
ing to a poor recovery of the added heterocycle. The pyrrole
group required N-protection with electron-withdrawing
substituents such as the Boc group in order to be tolerated
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

H
J. A. Bull et al.
Account
Synlett
in the reaction. Various other functional groups were test-
ed, and the NH-transfer protocol proved to be compatible
with alkene, alkyne, alkyl amine, phenol, ester, aldehyde,
and nitrile functionalities. The results in Figure 2 demon-
strate a high degree of compatibility of the reaction condi-
tions for a wide range of pharmaceutically relevant func-
tionalities.
Figure 2 Robustness test
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

I
J. A. Bull et al.
Account
Synlett
NH
O
NH
PhI(OAc)2 (2.5 equiv)
NH4COONH2 (2 equiv)
PhI(OAc)2 (2.5 equiv)
O
NH
S
S
S
S
N source
S
R1
Me
Me
R2
R1
R2
Me
MeOH, 25 °C, 3h
solvent, time
15
8
expected but
not observed
15a
8a
O
NH
O
NH
O
NH
O
NH
S
Me
Conditions
Conversion Yield 8a
S
S
Ph
S
Ph
Ph
a) MeOH, NH2COONH4 (4 equiv), 25 °C, 2 h
b) MeCN, NH2COONH4 (2.5 equiv), 25 °C, 3 h
c) toluene, MgO, NH2COONH4 (4 equiv), 25 °C, 16 h
99%
88%
99%
95%
80%
95%
Ph
8b
93%
8g
78%
8h
76%
8l
14%
Cl
Br
Scheme 11 Metal-free NH-transfer with sulfides
NH
O
O
O
S
NH
Me
O
NH
O
NH
S
NH
S
S
Ph
S
Ph
Ph
Ph
Next, we considered the use of this straightforward di-
rect NH-transfer procedure with sulfides as substrates.48
Aiming to develop a method for the direct preparation of
NH-sulfilimines by imination of the sulfur atom, sulfide 15a
was reacted under the same conditions employed for the
imination of sulfoxides (Scheme 11). Surprisingly, by using
PhI(OAc)2 and NH2CO2NH4 in methanol, sulfoximine 8a was
obtained in very high yield rather than the expected sulfil-
imine. Considering that most preparations of NH-sulfox-
imines are based on multistep syntheses starting from sul-
fides (Scheme 1), the availability of a selective strategy for
N- and O-transfer in the same reaction to generate NH-sulf-
oximines was extremely attractive, and promised a consid-
erable advance. In preliminary experiments on sulfide 15a,
the efficacy of the protocol used for the imination of sulfox-
ides was proven. The use of ammonium carbamate
(NH2COONH4) in the presence of PhI(OAc)2 (2.5 equiv) at
25 °C, in MeOH, toluene or acetonitrile, led to exclusive for-
mation of the corresponding sulfoximine 8a (Scheme 11).
This straightforward protocol was tested with several
sulfides verifying the robustness of the methodology
(Scheme 12).48 The reaction tolerated aryl-, alkyl-, cycloal-
kyl-, benzyl- and alkenyl-substituted sulfides. Various func-
tional groups (OMe, CF3, N-Boc, allyl) and heterocycles were
also found to be compatible with this protocol.
MeO
Cl
8m
97%
8n
86%
8p
94%
8v
85%
8w
80%
O
NH
O
NH
O
NH
O
NH
S
S
Me
S
S
Me
Bu
Bu
Ph
nhex
8x
99%
F
Me
8y
89%
8z
89%
8aa
95%
MeO
O
S
NH
O
NH
S
Ph
O
NH
S
MeO
MeO
Br
8ab
8ac
99%
8ad
54%
MeO
85%
O
NH
S
CF3
O
NH
S
O
NH
NBoc
Me
S
S
8af
72%
O
N
Me
8ag
83%
8ae
76%
Scheme 12 Scope of the NH-transfer reaction with different sulfides
and by no means clear. This prompted us to undertake con-
siderable investigations to provide mechanistic insights. In
the NH-transfer to sulfoxides, our approach involved chem-
ical experiments combined with NMR and HRMS investiga-
tions to prove the role of ammonium carbamate and to de-
termine the structures of the most likely intermediates.45
Ultimately the role of ammonium carbamate was shown
to simply be as a convenient source of ammonia. As report-
ed in Scheme 13, using methanol as the solvent, a fast li-
gand exchange reaction with PhI(OAc)2 releases acetic acid,
which decomposes the ammonium carbamate to ammonia
and ammonium acetate.49 The role of ammonia, as the ef-
fective nitrogen source, was further demonstrated by using
alternative sources of ammonia such as a solution of ammo-
nia in methanol and ammonium acetate (Scheme 13, b).45
In all cases, complete conversion of sulfoxide 1a into the
corresponding sulfoximine 8a was observed.
The wide scope and functional group tolerance makes
this strategy useful for the direct introduction of the sulfox-
imine moiety in organic molecules. Currently, this approach
affords racemic sulfoximine products. The direct enantiose-
lective synthesis of sulfoximines from sulfides presents an
important future aim.
4 Mechanistic Evidence for the Direct Syn-
thesis of NH-Sulfoximines from Sulfoxides
and Sulfides
The mechanisms of these direct NH-transfer methods
mediated by hypervalent iodine reagents were intriguing
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J
J. A. Bull et al.
Account
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a) Formation of ammonia from ammonium carbamate
Ph
NH3
source
O
S
fast in MeOH
+
H2NCO2NH4
+
AcONH4
CO2
+
NH3
N
I
AcOH
O
R
supported by
NMR studies
slow in toluene or MeCN
S
R
R'
PhI(OAc)2
solvent
b) Effect of alternative ammonia sources
R'
AcO
N-source
PhI(OAc)2 (3 equiv)
iodonium salt 16
O
O
NH
S
S
Me
Me
OMe
MeOH
Ph
TsO
I
25 °C, 1 h
N
I
O
R
Ph
separates
as a solid
1a
8a
S
N-Source
Yield
99%
99%
99%
96%
94%
TsO
0.3 mmol
0.5 M
R'
MeCN, rt, 30 s
(a)
O
H2NCO2NH4 (4 equiv)
NH3/MeOH (8 equiv)
NH3/MeOH (4 equiv)
AcONH4 (8 equiv)
17
NH
S
R
R'
AcONH4 (4 equiv)
TsOH
MeCN, rt
Ph
(b)
N
I
O
Scheme 13 Ammonia sources for NH-transfer to sulfoxides
PhI(OAc)2
MeCN, rt
S
R
R'
AcO
not isolated,
detected by NMR
The reactions monitored by NMR in deuterated toluene,
acetonitrile or methanol were found to undergo complete
conversion in each case, and a faster reaction in MeOH and
MeCN over toluene.45 However, NMR experiments did not
provide evidence about likely intermediates; the iodonium
salt 16 was the only detectable species (Scheme 14), which
collapsed to the NH-sulfoximine over time. The hypervalent
iodonium salt could also be prepared by simply mixing the
NH-sulfoximine with PhI(OAc)2. At this stage, it seemed
most likely that the sulfoximine product could be reacting
very rapidly with excess PhI(OAc)2 while the reaction is
progressing to give the iodonium salts. However, HRMS
studies indicated this may not be the full story. The iodoni-
um salts were found to be labile when aged for a prolonged
time in solution, or under basic work-up conditions giving
the corresponding NH-sulfoximine.
Interestingly, similar hypervalent iodonium salts were
recently reported by Bolm, and used as sources of sulfox-
imines for N–C bond-forming reactions.18b In the Bolm
work, the sulfinimidoyl iodonium salts, of general structure
17, precipitated from acetonitrile by mixing a NH-sulfoxi-
mine with methoxy(tosyloxy)iodobenzene (Scheme 14,
path a). Considering this report, and surprised by some
spectroscopic discrepancies, we found that sulfinimidoyl
iodonium salt 17 could be obtained by mixing the NH-sulf-
oximine with PhI(OAc)2 in acetonitrile and adding tosic ac-
id. A white solid, corresponding to iodonium salt 17, sud-
denly separated from the solution. Running the experiment
in deuterated acetonitrile allowed us to conclude that, in
solution, a fast ligand exchange around the hypervalent io-
dine occurs, and that the most stable (or insoluble) com-
plex, the tosylate salt, separated as the solid.50
Scheme 14 Isolation of sulfinimidoyl iodonium salts
16. The identity of the iodonitrene (PhI=N+) was also con-
firmed via HRMS by labeling experiments using 15N-labeled
ammonium acetate.45
To summarize the mechanistic studies, it is likely that
the nitrogen source provides a sufficient concentration of
ammonia which reacts with PhI(OAc)2 forming either im-
inoiodinane 18 or iodonitrene 19 that react with the sulfox-
ide (Scheme 15). Assuming the involvement of 18 [Scheme
15, path (a)], the formation of the sulfoximine may occur by
direct attack of the sulfoxide at nitrogen with displacement
of iodobenzene,53 or by attack at the iodine center with
subsequent reductive elimination leading to the sulfox-
imine.54 With iodonitrene 19 [path (b)], the direct nucleo-
philic attack of the sulfur at the electrophilic nitrogen
would directly furnish the iodonium salt according to NMR
and MS observations. In both pathways, the nucleophilicity
of the sulfoxide plays a role.
sulfoximine
iodonium salt
Ph
PhI(OAc)2
work-up
NH
R'
O
R
N
I
O
R
S
S
R'
O
S
O
S
path (a)
path (b)
Ph
R
R'
R
I
R'
NH
Ph
Ph
I
NH
PhI=O
PhI(OAc)2
NH3
+
– H2O
– PhI
– 2AcOH
NH
Flow HRMS analysis provided additional evidence to
probe the mechanism of the NH-transfer reaction.45,51 In
fact, signals consistent with an iminoiodinane (PhI=NH) as
well as an unprecedented iodonitrene (PhI=N+) species52
were observed after mixing a solution of PhI(OAc)2 and am-
monium carbamate or acetate. Addition of the sulfoxide re-
sulted only in the formation of hypervalent iodonium salt
I
Ph
I
NH
iminoiodinane 18
short-lived
detected by flow HRMS
iodonitrene 19
short-lived
detected by flow HRMS
and 15N labeling
Scheme 15 Two possible pathways for the formation of NH-sulfoximines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

K
J. A. Bull et al.
Account
Synlett
In the reaction forming sulfoximines from sulfides,48 the
mechanism for both NH- and O-transfer with the same re-
agents posed an even bigger question. Building on the data
obtained in the reaction of sulfoxides, a similar electrophil-
ic nitrene or nitrenoid species would likely be involved.
However, mechanistic differences, including the sequence
of introduction of the heteroatoms, could be envisaged.
Firstly, we observed that two equivalents of the oxidant
were required. When less oxidant was used, only the start-
ing material and the product sulfoximine were present and
intermediate species were not observed. This indicates that
a more reactive intermediate species is formed. Therefore,
we performed a series of experiments to establish whether
N or O is transferred first. It is worth pointing out that
mechanistic aspects related to this process, have also been
reported recently by Reboul and co-workers.55 In Scheme
16, a combination of the data from the chemical investiga-
tions reported by ourselves48 as well as by Reboul are pre-
sented.
imine 8m, was also observed starting either from diphenyl
sulfoxide (1m) (Scheme 16, b), or diphenylsulfilimine 20.
From sulfilimine 20, reaction with PhI(OAc)2 in the absence
of the nitrogen source led to sulfoximine 8m resulting from
an oxidation process (Scheme 16, c). However, either sulf-
oxide 1m, or sulfide 15m in the absence of the nitrogen
source gave little or no reaction, which appears crucial to
the excellent chemoselectivity of the processes (Scheme 16,
d and e). Further useful insights were obtained by studying
the reactivity of benzyl phenyl sulfide (15b). On reacting
15b with PhI(OAc)2, a complex mixture was obtained, in
striking contrast, with a 92% yield of sulfoximine 8b in the
presence of ammonium carbamate [Scheme 16, f, condi-
tions (i)]. Interestingly, Reboul demonstrated that water
could be playing a role in the reaction; in acetonitrile, no re-
action occurred when water was removed from the reac-
tion mixture [Scheme 16, f, conditions (ii)]. However, it is
not necessary to be the source of the sulfoximine oxygen.
By contrast, in the presence of 10 equivalents of water and
using acetonitrile as the reaction solvent, a 1:1 mixture of
sulfoximine 8b and the corresponding N-acyl derivative 21
was observed [Scheme 16, f, conditions (iii)]. These results
support the hypothesis that the nitrogen is likely trans-
ferred first, and that the corresponding sulfilimine is fur-
ther oxidized to intermediates that are broken down by the
methanol solvent or by water.
By using diphenyl sulfide (15m) in the presence of am-
monia and PhI(OAc)2 in acetonitrile and water, diphenyl
sulfoximine (8m) could be obtained in 78% yield (Scheme
16, a). Complete selectivity, for the formation of sulfox-
NH3 (5 equiv)
O
O
NH
PhI(OAc)2
S
+
S
S
a)
1
Based on labeling experiments, HRMS and H, 13C and
Ph
Ph
Ph
Ph
Ph
Ph
MeCN,
15N NMR investigations, Reboul proposed the mechanism
reported in Scheme 17.55 The previously proposed iodo-
nitrene 19 is likely to be the N-donor to the sulfur,45,48 lead-
ing to a short lived sulfilimine iodonium species 22. Inter-
mediate 22 is attacked by a methoxy or acetate anion with
formation of methoxy- or acetoxy-λ6-sulfanenitrile 23 or
24, respectively. Interestingly, intermediates 23 and 24 have
been characterized by HRMS, isotopic labeling and multi-
nuclear magnetic resonance.55
H2O (10 equiv)
15m
8m
78%
1m
traces
NH4CO2NH2
PhI(OAc)2
NH4CO2NH2
PhI(OAc)2
O
S
NH⋅H2O
O
NH
b)
c)
S
S
Ph
Ph
Ph
Ph
Ph
Ph
MeOH, rt, 3 h
94%
MeOH, rt, 3 h
87%
1m
8m
20
no N source
PhI(OAc)2
NH⋅H2O
O
NH
S
S
Ph
Ph
Ph
Ph
MeOH, rt, 3 h
90%
20
8m
Methoxy-λ6-sulfanenitrile 23 could undergo nucleophil-
ic attack by methanol with formation of dimethyl ether and
the corresponding sulfoximine 26. Similarly, acetoxy-λ6-
sulfanenitrile 24 may behave as an acetylating agent either
toward the sulfoximine or methanol leading to N-acyl-sulf-
oximine 25 and NH-sulfoximine 26 (Scheme 17). This
mechanism supports the hypothesis that the oxygen is de-
rived from methanol or acetate.
no N source
PhI(OAc)2
O
S
d)
e)
no reaction
Ph
Ph
Ph
MeOH, rt, 3 h
1m
no N source
PhI(OAc)2
O
S
S
Ph
iii)
Ph
O
Ph
MeOH, rt, 3 h
13%
15m
1m
NH
N
Ac
Ph
O
S
Ph
S
Ph
S
+
f)
Ph
Ph
Ph
15b
8b
21
ii)
5 Further Applications
i)
92%
traces of 8b and 21
In this section, we report further interesting applica-
tions of the strategies described herein for the preparation
of NH-sulfoximines. Firstly, the potential to use alternative
nitrogen sources, such as cheap and easy to handle ammo-
nium acetate, was demonstrated in the preparation of sulf-
oximines (S)-8a, 8p and the MSO precursor 12 in good
yields (Scheme 18).45
8b
conditions:
i): PhI(OAc)2 (3 equiv), NH4CO2NH2 (2.5 equiv), MeOH, rt, 30 min
ii): PhI(OAc)2 (3 equiv), NH4CO2NH2 (2.5 equiv), MeCN, rt, 2 h
iii): PhI(OAc)2 (3 equiv), NH3 (5 equiv), MeCN, H2O (10 equiv), rt, 30 min
Scheme 16 Mechanistic aspects for the N-transfer to sulfoxides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

L
J. A. Bull et al.
Account
Synlett
PhI
N2
S
X
R
R1
I
OAc
NH3
N
Ph
OMe
OAc
MeOH
Ph
I
Ph
I
Ph
I
N
X
S
OAc
R
R1
iodonitrene 19
22
short lived
X= AcO, MeO
short lived
Me
HOMe
NH
O
N
O
S
S
R
R1
R
R1
MeOMe
26
23
MeO
HRMS, 15N-, 2H-labeling
NMR evidence
I
N
Ph
PhI
S
R
R1
22
short lived
O
AcO
O
HN
S
N
R1
R
N
Ac
O
R
NH
O
O
S
S
+
S
R
R1
R
R1
MeOH
R1
24
26
25
NH
O
AcOMe
+
S
R
R1
26
Scheme 17 Proposed mechanism for the N,O-transfer to sulfides
PhI(OAc)2 (2.5 equiv)
AcONH4 (4 equiv)
PhI(OAc)2 (3 equiv)
O
S
O
NH
R'
O
15NH
AcO15NH4
S
S
S
R'
R
R
R'
R'
R
R
MeOH
25 °C, 30 min
MeOH, 25 °C, 3 h
(0.3 mmol)
Me
Me
O
O
O
O
NH
O
NH
O
15NH
O
15NH
O
15NH
O
NH
H
N
S
S
S
S
S
S
BocHN
Me
Me
Me
MeO
Me
Me
Ot-Bu
NHBoc
NHBoc
COOMe
(S)-8a 94%
8p 79%
12 68%
15N-8a 96%
15N-27 88%
15N-28 85%
dr = 1:1
dr = 1:1
O
Scheme 18 Preparation of NH-sulfoximines (S)-8a, 8p and the MSO
precursor 12
Ph
HN
H
NH
O
O
15NH
O
H
The preparation of 15N-labeled sulfoximines from bio-
logically relevant sulfides was readily achieved by exploit-
ing the functional group compatibility of the NH- and O-
transfer strategy. Using 15N-labeled ammonium acetate as
the nitrogen source, the reaction with protected methi-
onine, dipeptides, and biotin afforded the corresponding
15NH-sulfoximines 15N-27–30 in good yields as mixtures of
diastereoisomers (Scheme 19).48
MeO
O
S
N
Me
S
15NH
OH
H
NHFmoc
O
15N-29 78%
dr = 1:1
15N-30 75%
dr = 3:1
Scheme19 Preparation of 15NH-sulfoximines 15N-27–30
Lücking employed the Rh-catalyzed strategy for the
preparation of sulfoximine carbamates in the synthesis of
sulfoximine analogue of palbociclib and ribociclib, which
are selective CDK4/6 inhibitors used in cancer therapy. N-
Boc sulfoximine 32 was the key intermediate in the prepa-
ration of analogues 33 and 34 obtained after facile removal
of the Boc group (Scheme 20, a).14
ing disease progression. The synthesis of analogue 36 was
accomplished in two steps including a stereospecific N-
transfer with ammonium carbamate and PhI(OAc)2 fol-
lowed by TBS deprotection (Scheme 20, b).14
6 Conclusion
The strategy for the direct NH-transfer to a sulfoxide has
been applied by Lücking for the preparation of the sulfox-
imine analogues of fulvestrant, a selective estrogen receptor
degrader (SERD) that both antagonizes and degrades ER-α
and is active in patients on antihormonal agents experienc-
In this account, we have collected our recent achieve-
ments in the development of straightforward strategies for
accessing NH-sulfoximines, and reviewed these in the con-
text of the field. Both metal-based and metal-free ap-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–N

M
J. A. Bull et al.
Account
Synlett
H
N
N
N
N
N
N
O
N
Boc
S O
O
a) H2NCOOt-Bu
Rh2(OAc)4 (2.5 mol%)
MgO, PhI(OAc)2
b) H2 (1 atm), Pd/C
S
N
S
NH
O
O
palbociclib sulfoximine analogue
N
33
a)
56%
H
over two steps
N
N
N
N
N
N
NH2
N
NO2
NH
N
S
Me
Me
31
32
N
O
key intermediate
O
ribociclib sulfoximine analogue
34
OTBS
OH
a) H2NCO2NH4
PhI(OAc)2, MeOH
b) TBAF, THF, Δ
b)
H
H
O
F
F
NH
O
F
F
H
H
H
H
42%
over two steps
S
S
( )7
( )7
HO
CF3
HO
CF3
fulvestrant sulfoximine analogue
35
36
Scheme 20 Preparation of the sulfoximine-containing analogues of drug compounds
proaches have been described, as well as useful synthetic
applications. The rhodium-catalyzed synthesis of sulfox-
imine carbamates allows the introduction of orthogonal
and easily removable protecting groups into a molecule.
From a sustainability point of view, the metal-free ap-
proach avoids the use of expensive transition-metal-cata-
lysts and offers synthetic efficiency toward free NH-sulfoxi-
mines. The metal-free protocols are suitable for converting
both sulfoxides and sulfides directly into sulfoximines, and
appear to be widely applicable. In addition, the protocols
tolerate functionality in the substrate, and are suitable for
both the late-stage introduction of the sulfoximine moiety
and for 15N-labeling. From a mechanistic point of view, the
available spectroscopic and spectrometric measurements
suggest iodonitrene or iminoiodinane species as reactive
and short-lived intermediates. In the near future, it is ex-
pected that these strategies will lead to further progress in
sulfoximine chemistry, drug discovery programs, as well as
in other N-transfer reactions.
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Acknowledgment
We gratefully acknowledge The Royal Society for a University Re-
search Fellowship (to J.A.B.) and the University of Bari for financial
support.
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