A Convenient, Mild, and Green Synthesis of NH-Sulfoximines in Flow Reactors

Article abstract of DOI:10.1002/ejoc.201700850

NH-sulfoximines are emerging as useful and important targets in drug discovery and synthetic organic chemistry. We report herein the development of an efficient, convenient, and sustainable continuous-flow strategy, for the direct, straightforward preparation of NH-sulfoximines by using sulfides or sulfoxides as suitable starting material. The flow process uses PhI(OAc)₂ as the oxidant and aqueous solutions of ammonia as the N source. The scope of the reaction has been demonstrated by using several substituted sulfides and sulfoxides including enantioenriched and biologically relevant starting materials. The flow strategy was found to be more convenient with respect to conventional batch processing.

Full text of DOI:10.1002/ejoc.201700850

A Journal of
Accepted Article
Title: A convenient, mild and green synthesis of NH-sulfoximines in
flow reactors
Authors: Leonardo Degennaro, Arianna Tota, Sonia De Angelis,
MICHAEL ANDRESINI, Cosimo Cardellicchio, Maria
Annunziata Capozzi, Giuseppe Romanazzi, and RENZO
LUISI
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700850
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700850
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700850
COMMUNICATION
A convenient, mild and green synthesis of NH-sulfoximines in
flow reactors
,
[a]
†,[a]
†,[a]
†,[a]
Leonardo Degennaro,* Arianna Tota,
Sonia De Angelis,
Michael Andresini,
Cosimo
[a]
[
b]
[c]
[d]
Cardellicchio, Maria Annunziata Capozzi, Giuseppe Romanazzi, and Renzo Luisi*
Abstract: NH-Sulfoximines are emerging as useful and important
targets in drug discovery and synthetic organic chemistry. We report
herein the development of an efficient, convenient, and sustainable
continuous flow strategy, for the direct straightforward preparation of
NH-sulfoximines using sulfides or sulfoxides as suitable starting
moiety have been evaluated for medical studies, and several
sulfoximines-bearing molecules entered clinical trials.[6]
Remarkably, Bayer’ researchers evaluated the biological
activities of marketed drug analogues, and advanced clinical
candidates in which a portion of the molecule was replaced by a
sulfoximine functionality.[7] Over the last decade, several
material. The flow process uses PhI(OAc)
2
as the oxidant and
aqueous solutions of ammonia as the N-source. The scope of the
reaction has been demonstrated by using several substituted
sulfides and sulfoxides including enantioenriched and biologically
relevant starting materials. The flow strategy was found more
convenient with respect to conventional batch processing.
methodologies for the preparation of sulfoximines have been
introduced, mostly based on the electrophilic transfer of an N-R
group to sulfoxides or by a different sequence starting from
sulfides. [8] Moreover, for accessing NH-sulfoximines, additional
deprotection steps of N-protected sulfoximines would be
required (Scheme 1). As for NH-sulfoximines, the availability of a
free nitrogen group offers an additional site to introduce
molecular diversity, as proved by the development of
Introduction
[
9]
methodologies
such
as
kinetic
resolution,
N-
[12]
[10]
[11]
trifluoromethylation,
trifluoromethylthiolation,
aroylation,
alkynylation,[14] alkylation,[15]
and thioetherification.[16] In collaboration with Bull’s group, we
The chemistry of sulfoximines encompass valuable applications
spanning from CH-activation or ortho-metallation,[1] to the
preparation of sulfurated functionalities,[2] useful as chiral
auxiliaries,[ ligands for asymmetric catalysis,[4] and active
[13]
intramolecular halocyclization,
recently contributed to the field, by developing convenient metal-
3]
free and straightforward protocols for the direct preparation of
NH-sulfoximines either starting from sulfoxides or sulfides. [17]
[5]
ingredients for medicinal chemistry. Neverthless, this mono-
aza analogue of sulfone still attracts interest in synthetic organic
chemistry and drug discovery. The lack of a comprehensive
exploitation of this remarkable class of compounds could be
ascribed to their relatively recent discovery, and to hazards
associated with older synthetic procedures as well as to the
general inapplicability of these methodologies for large-scale
productions. Only recently, with the aim to remark the
importance of this underrepresented functional group in drug
discovery, a number of compounds containing the sulfoximine
simultaneous N- and O-transfer
O
O-transfer
Direct NH-transfer
S
S
O
NH
R1
R1
R
R
S
1
R
R
N-transfer
PG
N-transfer
sulfoximine
N
S
O
N
G
deprotection
deprotection
S
R1
R1
sulfilimine
R
[
a]
L. Degennaro, A. Tota, S. De Angelis, M. Andresini, R. Luisi
Flow Chemistry and Microreactor Technology FLAME-Lab,
Department of Pharmacy – Drug Sciences
University of Bari “A. Moro”
R
O-transfer
O
R
N
PG
S
Via E. Orabona 4, I-70125 Bari
E-mail: leonardo.degennaro@uniba.it; renzo.luisi@uniba.it
http://www.farmchim.uniba.it/chimica_organica/Luisi2.html
C. Cardellicchio
R1
PG = SO
CF CO, ROCO
G = CN
2 2 2
Ar, SO OCH CCl3,
3
[
b]
CNR ICCOM
Department of Chemistry
Scheme 1. Strategies for accessing NH-sulfoximines.
University of Bari “A. Moro”
Via E. Orabona 4, I-70125 Bari
M. A. Capozzi
Department of Chemistry
University of Bari “A. Moro”
Via E. Orabona 4, I-70125 Bari
G. Romanazzi
[
[
c]
d]
Given the importance of the NH-sulfoximine functionality, the
development of efficient and sustainable strategies, aimed at
introducing this structural motif into a molecule, is still a
demanding research area. In particular, the development of new,
efficient, atom economic, and safe synthetic protocols for the
synthesis of NH-sulfoximines, could have impact for industrial
applications. In this context, the use of flow chemistry
technology, capable to bring about benefits such as enhanced
DICATECh, Politecnico di Bari
Via E. Orabona, 4 I-70125 Bari.
†
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
1
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European Journal of Organic Chemistry
10.1002/ejoc.201700850
COMMUNICATION
heat and mass transfer, reduced reaction volumes, as well as
improved reagent mixing, with respect to conventional batch
for the direct synthesis of NH-sulfoximines using convenient and
inexpensive nitrogen sources.
transformations, should be promoted.[18] In addition,
a
continuous flow process for the imination of sulfide and/or
sulfoxides holds the potential to significantly increase safety and
to reduce production costs. To date, only a few processes for
the synthesis of sulfoximines have been developed under flow
conditions. Lebel and co-workers reported a photochemical
process for the synthesis of sulfilimines and sulfoximines by
imination of sulfides and sulfoxides respectively. [19] The flow
system required a particular photoreactor, in which the solutions
of sulfide or sulfoxide reacted with trichloroethoxysulfonyl azide
Results and Discussion
The investigation started considering our previous batch
experiments on sulfides and sulfoxides, directly providing NH-
sulfoximines, under mild conditions, employing a suitable source
of ammonia in the presence of phenyliodo diacetate (Scheme 3).
This straightforward metal-free protocol has been tested on
several sulfides and sulfoxides, proving robustness and
functional groups tolerance. As reported in Scheme 3, several
sources of ammonia such as ammonium carbamate, ammonium
acetate, and methanol solution of ammonia were found effective
either starting from sulfides, or sulfoxides. The reactions could
be run in different solvents such as methanol, acetonitrile, and
(
3
TcesN ), in the presence of catalytic Fe(III) acetylacetonate,
producing in good yields and stereoselectivities aromatic and
aliphatic N-Tces substituted sulfilimines or sulfoximines
(
Scheme 2). This photochemical continuous flow process
resulted very efficient, giving protected derivatives within 50-90
min, albeit a quite laborious procedure was employed to remove
the Tces group in order to reveal NH-sulfoximines. In another
toluene but required
a precise stoichiometry and 0.5 M
very recent example, Kappe and co-workers, reported
continuous flow protocol for the preparation of
a
a
concentration in sulfides or sulfoxide (Scheme 3). Mechanistic
study supported the hypothesis that a short-lived iodonitrene or
iminoiodinane species are likely responsible for the N-transfer to
the sulfur atom (Scheme 3, c).[17b, 22]
pharmaceutically relevant target molecule by imination of a
sulfoxide group. [20] The reaction proceeded under severe
3
conditions by using TMSN in a biphasic system, and fuming
2
PhI(OAc) (2.5 equiv)
N source (equiv)
sulfuric acid at 50 °C (Scheme 2). Kappe’s work highlights the
potential of the flow technology to significantly increase the
safety of this synthesis. However, the protocol focused on the
preparation of a single pharmaceutical target rather than on a
systematic study on the imination of sulfoxides, and did not
preserve the stereochemistry of the starting sulfoxide.
O
NH
Me
S
a)
Tol
Me
0.5M)
N-source:
NH COONH
S
Tol
(
MeOH, 25 °C, 3h
99%
2
4
(2 equiv)
MeCOONH4 (2 equiv)
NH /MeOH (6 equiv)
3
O
S
O
NH
PhI(OAc)
N source (equiv)
2
(3 equiv)
S
Lebel, 2016
b)
Tol
Me
Tol
Me
(
0.5M)
N-source:
i) NH COONH
MeOH, time
94-99%
UVA (365 nm)
O
S
S
R
1
R
2
or
TcesN
Fe(acac)
R
1
R
2
/ DCM
(1.5 equiv)
(10 mol %)
NTces
S
O
NTces
O
1
NH
or
S
S
2
4
(4 equiv), 25 °C, 30 min
3
R
1
R
R
1
R
2
R
R
2
2
ii) MeCONH4 (4-8 equiv), 25 °C, 1h
iii) NH /MeOH (4-8 equiv), 25 °C, 1h
3
3
Kappe, 2015
c) H NCO NH
4
+
AcOH
AcONH4
+
CO2
+
NH3
f ast in MeOH
O
2
2
2
H O
TMSN
3
N
N
O
N
PhI(OAc)2
+
NH3
Ph
I
NH or
Ph
I N
O
S
-AcOH
iminoiodinane
iodonitrene
5
0°C
0°C
N
Cl
4
short lived
intermediates
NH
O
N
S
Fuming H
2
SO
N
Cl
Scheme 3.
This work
With the aim to develop a more sustainable and practical
protocol for the synthesis of NH-sulfoximines, we planned the
experiments in a flow reactor considering: a) the nature of the
solvent; b) the most suitable source of ammonia; c) the
stoichiometry of the reaction. We reasoned that methanol would
have been a suitable solvent, while, as source of ammonia, we
considered that the ammonium carbamate would have been
problematic to handle under flow conditions (Scheme 3, c), and
not very practical because of its intrinsic instability. For these
reasons, we focused our attention towards more convenient
alternatives such as ammonium acetate and aqueous solution of
ammonia. As for the stoichiometry, we aimed at reducing the
O
S
S
R
1
R
2
or
R
1
R
2
tR'
O
NH
PhI(OAc)
2
S
R
1
R
2
R'
NH
3
Scheme 2.
Building on our previous contribution on the development of
more sustainable synthesis of NH-sulfoximines, and on our
involvement in the field of flow chemistry, [21] we evaluated the
possibility to transfer the direct imination of sulfides and
sulfoxides in a flow reactor in order to provide a strategy with
more environmental compliance. Herein, we report the
development of such safer, metal-free continuous flow protocol
2
equivalents of PhI(OAc) with respect to batch processing.
From a technical point of view, a Vapourtec R2 system equipped
with a 10mL PTFE reactor, and 2 mL PTFE loops was initially
used for the optimization study (see Supporting Information).
2
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European Journal of Organic Chemistry
10.1002/ejoc.201700850
COMMUNICATION
First, we examined the N- and O-transfer to sulfides. In choosing
the best starting point for the flow process, we considered that
the high concentration of sulfide (0.5 M), used under batch
conditions, would have required high concentrations of both
were achieved using 2 equiv of PhI(OAc)
at 15 min residence time (Table 1, entry 9), or by using higher
amount of PhI(OAc) (Table 1, entries 7, 8). As best compromise,
the use of 2 equiv of PhI(OAc) , 2 equiv of NH3(aq), 15 min of
2
, and 3 equiv of NH3(aq)
2
2
PhI(OAc)
2
, and N-sources with risk for precipitation and clogging. residence time at 0°C furnished sulfoximine 3a in 95% yield
[23]
We found that lowering the molar concentration of
(Table 1, entry 11). It is worth pointing out that such optimized
methylphenyl sulfide 1a up to 0.2 M in methanol avoided
precipitations or handling of slurries. The results of the
optimization study are collected in Table 1.
2
conditions allowed to use a reduced amount of PhI(OAc) with
respect to batch conditions (2 equiv vs 2.5 equiv).
Next, the imination of sulfoxides was considered. Surprisingly,
using sulfoxide 2a as test molecule for the optimization study, it
was found that the reaction performed less well with respect to
sulfide 1a (Table 2).
Table 1. Flow oxo- imination of sulfide 1a: Optimization study.
S
Table 2. Flow imination of sulfoxide 2a: Optimization study.
T °C
Ph
Me
O
1
a, 0.2M
tr
S
T °C
O
NH
Ph
Me
PhI(OAc)
N-source
2
S
2
a, 0.4M
tr
Ph
Me
O
NH
R
PhI(OAc)2
S
3
a
Ph
Me
R
R = reactor
tr = residence time
N-source
3
a
R = reactor
t = residence time
V = 10 mL
r
PhI(OAc)
equiv) [
2
b]
N-source
(equiv)
3a[a]
(%)
entry
T °C
tr (min)
[b]
(
[
a]
PhI(OAc)
(equiv)[b]
2
N-source
(equiv) [b]
tR
(min)
3a
entry
T °C
1
2
3
4
5
6
7
8
9
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.0
2.0
2.0
2.0
AcONH
NH3(aq) (3)
4
(3)
20
20
20
20
20
20
20
20
20
20
0
30
30
30
30
30
15
5
15
15
15
15
5
97
86
99
97
89
99
95
99
96
60
95
58
(%)
[
[
c]
c]
1
2
2.0
3.0
2.0
2.0
2.5
2.5
2.5
2.0
2.0
2.0
2.0
2.0
NH3(aq) (4)
NH3(aq) (4)
NH3(aq) (2)
NH3(aq) (2)
NH3(aq) (3)
NH3(aq) (4)
NH3(aq) (3)
20
20
20
0
20
20
50
0
0
20
0
0
30
30
30
30
30
30
10
15
30
30
30
15
53
50
47
84
58
53
37
65
80
65
58
46
NH
(NH
AcONH
4
COONH
CO (3)
(2)
2
(3)
4
)
2
3
3
4
4
5
6
7
8
9
4
NH3(aq) (3)
NH3(aq) (3)
NH3(aq) (2)
NH3(aq) (3)
NH3(aq) (2)
NH3(aq) (2)
NH3(aq) (2)
AcONH
4
(2)
(2)
(2)
(3)
(3)
1
1
1
0
1
2
AcONH
4
AcONH
AcONH
AcONH
4
0
10
4
1
1
4
[
a] Calculated by 1H NMR of the crude reaction mixture under steady-state
conditions. [b] Solution in MeOH.
[a] Calculated by H NMR of the crude reaction mixture under steady-state
1
conditions. [b] Solution in MeOH. [c] 0.2 M solution of substrate in MeOH.
According to batch procedure, using methanol as the solvent, at
Unfortunately, the use of 0.2M solution of 2a, 2 or 3 equiv of
PhI(OAc) , and 4 equiv of ammonia, resulted in a low yield of the
2
2
0 °C, and 2.5 equiv of PhI(OAc)
were compared (Table 1, entries 1-4).
that the reaction proceeded in all cases furnishing sulfoximine
a in good to excellent yields.[25] For sake of comparison,
2
, several N-sources (3 equiv)
[24]
We were glad to find
corresponding sulfoximine 3a (Table 2, entries 1, 2). According
to batch conditions, a higher concentration of sulfoxide is
mandatory to speed up the reaction and observe full conversion.
Thus, the optimization experiments were executed using a 0.4 M
solution of 2a. Furthermore, in order to handle more concentrate
3
ammonium carbamate and ammonium carbonate were also
evaluated, observing excellent performance (Table 1, entries 4,
5). Nevertheless, handling and dosing of ammonium carbamate
solutions of PhI(OAc)
2
and N-source, a different set-up for the
was not simple because of its tendency to decompose. In the
case of ammonium carbonate, the results proved that this salt
could be a suitable cheap source of ammonia, compatible with
flow reactor was considered. In particular, syringe pumps were
[25]
employed to feed a 10 mL PTFE coil reactor. Both ammonium
acetate and aqueous solution of ammonia were employed as N-
sources. As reported in Table 2, the reaction performed well at
lower temperature (Table 2, compare entries 3, 4 and 6) using 2
4 3 2
the reaction conditions. As drawback, NH (CO ) dissolves
slowly in methanol and the resulting solution need to be filtered
before using under flow conditions. For these reasons, we
decided to focus our attention on the readily available aqueous
solution of ammonia (28%w/w) as suitable, cheap, and practical
2
equiv of PhI(OAc) , and 2 equiv of N-sources (Table 2, entries 4
and 8). The results obtained in the imination of sulfoxide showed
that, under flow conditions, the stoichiometric ratio between the
oxidant and the N-source is an important parameter, as well as
the residence time. As reported in Table 2, the use of higher
4
N-source. However, NH OAc was also found to be a suitable
and convenient N-source but need to be used under the
conditions reported in Table 1 (compare entries 1 and 5). In
order to improve the performance of the reaction, using NH3(aq)
as N-source, the effect of the retention time, the temperature, as
well as the stoichiometry were considered (Table 1, entries 6-12).
2
PhI(OAc) /N-source ratios and shorter residence time were
detrimental for the yields (entries 4-6 and 9-11). In the case of
sulfoxide 2a, conditions of entries 4 and 8 (Table 2) were found
as the best compromise in terms of stoichiometry of reactants,
and yield of the reaction. It is also remarkable that with
sulfoxides, the use of a flow reactor allowed to reduce the
Reducing PhI(OAc)
2
/NH3(aq) molar ratio (2:2), and retention time,
was detrimental for the yield (Table 1, entry 10). Higher yields
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700850
COMMUNICATION
2
amounts of oxidant (PhI(OAc) ) and N-sources, with respect to
O
er: 95:5
Me
the batch processing. Another important point is that convenient
and easy to handle N-sources could be employed. Taken as
whole, the developed flow processes resulted more sustainable
starting either from sulfides or from sulfoxides.
a)
S
0
°C
Me
O
NH
(
R)-2m, 0.4 M
tr
S
Me
PhI(OAc)
2
[
a]
[b]
0.4 M in MeOH
O
S
R
Me
T °C
(R)-3m
S
or
NH3(aq)
0.4 M in MeOH
R
R1
R
R1
70%
tr
R = reactor 10 mL
tr = 30 min
O
NH
R1
er: 95:5
PhI(OAc)
2
S
R
R
NHBoc
NH3(aq)
3a-m
b)
0
°C
MeS
COOMe
1n, 0.2 M
O
NH
O
NH
O
NH
O
S
NH
S
S
S
tr
NHBoc
Me
Me
PhI(OAc)2
Me
Me
N
O
0.4 M in MeOH
NH3(aq)
0.4 M in MeOH
3
a
3b
3c
COOMe
R
3
9
n
From 1a: 95%
From 2a: 84%
productivity test: 1.34 g/h
From 1b: 99%
From 2b: 92%
From 1c: 90%
From 2c: nr
9%
R = reactor 10 mL
r
t = 15 min
CF
3
O
NH
Bn
O
NH
Bn
O
S
S
S
Scheme 5. Further application of the flow synthesis of NH-sulfoximines
.
Me
Bn
S
NH
N
O
3f
3
d
3
e
From 1f: 90%
From 2f: 75%
From 1d: 90%
From 2d: 90%
From 1e: 40%
Conclusions
O
NH
O
NH
Bu
O
NH
O
NH
S
In conclusion a straightforward continuous flow process for the
preparation of NH-sulfoximines has been developed. The flow
process uses a more convenient stoichiometry for PhI(OAc) ,
2
with respect to batch conditions, and aqueous solution of
ammonia as the N-source. The scope of the reaction has been
demonstrated by using several substituted sulfides and
sulfoxides including an enantioenriched sulfoxide, and the
biologically relevant methionine derivative. Both the developed
flow strategies were found more convenient with respect to
conventional batch processing.
S
S
S
Bu
Ph
Ph
Bn
Ph
OMe
3
g
3h
3i
3l
From 1g: 84%
From 1f: 99%
From 2f: 37%
From 1i: 99%
From 2i: 62%
From 1l: 99%
dr = 3:1
Scheme 4. Scope of the reaction. [a] Flow conditions: sulfide (0.2 M), 222
µL/min; PhI(OAc) (0.4 M), 222 µL/min; NH (aq) (0.4 M) 222 µL/min; residence
time: 15 min; solvent: MeOH; reactor volume 10 mL; temperature 0 °C. [b]
Flow conditions: sulfoxide (0.4 M), 67 µL/min; PhI(OAc) (0.4 M), 133 µL/min;
NH (aq) (0.4 M) 133 µL/min; residence time: 30 min; solvent: MeOH; reactor
volume 10 mL; temperature 0 °C.
2
3
2
3
Acknowledgements
The developed flow protocol was applied to representative
examples of sulfides and sulfoxides under optimized conditions,
reported in Table 1, entry 11 and Table 2, entry 4 respectively.
As reported in Scheme 4, sulfoximines 3a-l could be obtained
under continuous flow conditions with good to excellent yields.
According to the optimization study, higher yields were observed
using sulfides rather than sulfoxides. This flow process tolerates
several substituents at the sulfur atom, including alkyls,
cycloalkyls, aryls and heteroaromatics. To further benchmark the
flow methodology, sulfoximine 3a was produced in continuous
flow conditions from sulfide 1a, using a flow system consisting of
syringe pumps and 10 mL PTFE flow reactor, observing a
productivity of 1.34 g/h. Furthermore, we evaluated the imination
of enantioenriched sulfoxide (R)-2m (er: 95:5) obtaining the
corresponding sulfoximine (R)-3m with complete stereocontrol
We are grateful to Dr. James, A. Bull of Imperial College of
London for precious contribute in the discovery of this N-transfer
methodology. We thank the University of Bari, the Politecnico di
Bari, the Regional Project “Reti di Laboratori Pubblici di Ricerca”
Code 20, and Code 67, and Laboratorio SISTEMA, (Code
PONa300369) financed by Italian Miur.
Keywords: NH-Sulfoximines • Flow chemistry • N-Transfer •
Microtube reactors • Sulfur derivatives
References
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(
er: 95:5) in 70% yield (Scheme 5, a). The functional group
tolerance observed with sulfides, was tested with the continuous
flow synthesis of biologically relevant methionine sulfoximine
[
2
2] F. W. Goldberg, J. G. Kettle, J. Xiong, D. Lin, Tetrahedron
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5
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COMMUNICATION
NH-Sulfoximines flow synthesis
Leonardo Degennaro,* Arianna Tota,
Sonia De Angelis, Michael Andresini,
Cosimo Cardellicchio, Maria Annunziata
Capozzi, Giuseppe Romanazzi, and
Renzo Luisi*
We report herein the development of an efficient, convenient, and sustainable
continuous flow strategy for the direct straightforward preparation of NH-sulfoximines
Page No. – Page No.
starting either from sulfides or from sulfoxides. The flow process uses PhI(OAc)
2
as the
A convenient, mild and green
synthesis of NH-sulfoximines in flow
reactors
oxidant and aqueous solutions of ammonia as the N-source. The flow strategy was found
more convenient with respect to conventional batch processing.
6
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