Synthesis of NH-Sulfoximines from Sulfides Using

Ammonium Carbamate and (Diacetoxyiodo)benzene to

Transfer NH and O
Arianna Tota,‡ Mauro Spennacchio, ‡ Edward L. Briggs,† Tsz-Kan
Ma,† Zhenhao Zhong,† Leonardo Degennaro,‡ James A. Bull,†* and
Renzo Luisi*‡
‡
Department of Pharmacy-Drug Sciences, University of Bari “A. Moro” Via
E. Orabona 4, Bari 70125.
†
Department of Chemistry, Imperial College London, Molecular Sciences
Research Hub, White City Campus, Wood Lane, London W12 0BZ, UK.

Checked by Ellie Plachinski and Tehshik Yoon

PhI(OAc)2 O NH
S NH2CO2NH4 S
CH3 CH3

Br MeOH Br
1 2

Procedure (Note 1)

(4-Bromophenyl)(imino)(methyl)-λ6-sulfanone (2). In air, a 250 mL one-

necked, round-bottomed flask (24/40), equipped with a Teflon coated oval-
shaped magnetic stirrer bar (32 mm × 15 mm) is suspended in a water bath
at 25 °C and charged with MeOH (70 mL) (Note 2). Stirring of the solvent
500 rpm is initiated. (4-Bromophenyl)(methyl)sulfane (1) (7.11 g, 35 mmol,
1.0 equiv) (Note 3) and ammonium carbamate (5.47 g, 70 mmol, 2.0 equiv)
(Note 4) are added sequentially as single portions via a powder funnel.
(Diacetoxyiodo)benzene (28.18 g, 87.5 mmol, 2.5 equiv) (Note 5) is then added
in four roughly equal portions (over a period of 5 min), allowing for
controlled decarboxylation (Figure 1a). The reaction mixture is stirred at
25 °C (ambient temperature) for 3 h, during which time the reaction mixture

Org. Synth. 2023, 100, 48–60 48 Published on the Web 01/31/2023

DOI: 10.15227/orgsyn.100.0048 Ó 2023 Organic Syntheses, Inc.
turns from colorless to pale yellow (Figure 1b). The reaction progress can be
monitored by TLC (Note 6).

Figure 1. a) Decarboxylation of ammonium carbamate; b) Reaction

mixture after 3 h; c) Reaction mixture after removal of methanol
(photos provided by checkers)

The organic solvent is evaporated under reduced pressure (25 ºC,

35 mmHg) to give a yellow slurry (Figure 1c), which is diluted with EtOAc
(150 mL) (Note 7) and saturated aqueous NaHCO3 (100 mL) (Note 8), and
then stirred for 30 min to neutralize the acetic acid formed during the
reaction. The resulting biphasic solution is transferred to a 1 L separatory
funnel, rinsing the flask with EtOAc (50 mL). The layers are separated, and
the organic layer is washed with distilled H2O (100 mL) to remove residual
ammonium carbamate. The layers are separated. The combined aqueous
fractions are extracted with EtOAc (3 x 100 mL) and subjected to the
subsequent workup procedure to yield additional product. The organic
fraction is extracted with aqueous 1M HCl (3 x 100 mL) (Figure 2a). The acidic
aqueous layers (pH ≈ 1) are combined, transferred to a clean separatory
funnel, and washed with CH2Cl2 (3 x 100 mL) (Note 9). The aqueous fraction
is then basified to pH ≈ 12 with aqueous 2M NaOH (200 mL) and extracted
with CH2Cl2 (3 x 100 mL). The combined organic fractions are dried over
anhydrous Na2SO4 (ca. 20 g) (Note 10). The solution is filtered through a 7 cm
glass funnel plugged with cotton wool and the Na2SO4 is washed with CH2Cl2
(50 mL) into a 500 mL round-bottomed flask (Figure 2b). The organic solvent
is evaporated under reduced pressure (25 °C, 250 mmHg), and the flask is
then placed under high vacuum (21 °C, 0.11 mmHg) for 18 h to remove any

Org. Synth. 2023, 100, 48–60 49 DOI: 10.15227/orgsyn.100.0048

residual solvent to yield (4-bromophenyl)(imino)(methyl)-λ6-sulfanone (2) as
a white solid (5.22 g, 63%, 98% purity) (Figure 2c) (Notes 11, 12 and 13).

Figure 2. a) Extraction using aqueous HCl (1M); b) Product in CH2Cl2after

work up; c) Final compound 2 (photos provided by checkers)

Notes

1. Prior to performing each reaction, a thorough hazard analysis and risk

assessment should be carried out with regard to each chemical substance
and experimental operation on the scale planned and in the context of the
laboratory where the procedures will be carried out. Guidelines for
carrying out risk assessments and for analyzing the hazards associated
with chemicals can be found in references such as Chapter 4 of “Prudent
Practices in the Laboratory" (The National Academies Press, Washington,
D.C., 2011; the full text can be accessed free of charge at
https://www.nap.edu/catalog/12654/prudent-practices-in-the-
laboratory-handling-and-management-of-chemical. See also
“Identifying and Evaluating Hazards in Research Laboratories”
(American Chemical Society, 2015) which is available via the associated
website “Hazard Assessment in Research Laboratories” at
https://www.acs.org/content/acs/en/about/governance/committees
/chemicalsafety/hazard-assessment.html. In the case of this procedure,
the risk assessment should include (but not necessarily be limited to) an
evaluation of the potential hazards associated with methanol, (4-
bromophenyl)(methyl)sulfane, ammonium carbamate, (diacetoxyiodo)-

Org. Synth. 2023, 100, 48–60 50 DOI: 10.15227/orgsyn.100.0048

 benzene, ethyl acetate, aqueous sodium bicarbonate, ,aqueous 1M
hydrochloric acid, dichloromethane, aqueous 2M sodium hydroxide,
anhydrous sodium sulfate, hexanes, potassium permanganate, CDCl3,
and 1,3,5-trimethoxybenzene.
2. HPLC grade methanol (99.8%) was purchased from Fisher Scientific and
used as received
3. (4-Bromophenyl)(methyl)sulfane 1 (97%) was purchased from Sigma-
Aldrich and used as received.
4. Ammonium carbamate (99%) was purchased from Sigma-Aldrich and
used as received.
5. (Diacetoxyiodo)benzene (98%) was purchased from Fluorochem and
used as received.
6. Reaction progress can be monitored by silica gel TLC analysis performed
with 100% hexanes or 40% EtOAc in hexanes using KMnO4 as a stain.
TLC Silica gel 60 F254 glass backed plates were purchased from Merck,
Inc. The starting material 1 has a Rf = 0.8 and the product 2 has a Rf = 0
using hexanes as eluent (Figure 3a). The starting material 1 has a Rf = 0.95
and the product 2 has a Rf = 0.10 using 40% EtOAc in hexanes as eluent
(Figure 3b).

Figure 3. (a) TLC analysis of reaction using hexaness as the eluent;

(b) TLC analsysis using 40% EtOAc in hexanes as eluent
(photos provided by checkers)

7. Ethyl acetate (99.5%) was purchased from Sigma-Aldrich and used as

received.
8. NaHCO3 (99%) was purchased from Sigma-Aldrich and used as received.
9. Dichloromethane (99.9%) was purchased from Sigma-Aldrich and used
as received.
10. Anhydrous sodium sulfate (99%) was purchased from Fisher Scientific
and used as received.

Org. Synth. 2023, 100, 48–60 51 DOI: 10.15227/orgsyn.100.0048

11. A second run of the reaction on similar scale provided 5.00 g (62%) of the
desired product.
12. The purity of the compound was calculated by quantitative 1H NMR with
a relaxation delay of 30 seconds using 21 mg of 1,3,5-trimethoxybenzene
(purity 99%) and 31 mg of compound 2.
13. Analytical data for (4-bromophenyl)(imino)(methyl)-l6-sulfanone (2):
mp = 89–90 °C. 1H NMR (500 MHz, CDCl3) d: 7.89–7.87 (m, 2H), 7.71–7.69
(m, 2H), 3.10 (s, 3H), 2.72 (s, 1H). 13C NMR (101 MHz, CDCl3) d: 142.7,
132.6, 129.4, 128.3, 46.2. IR (film) 3303, 3274, 3083, 3009, 2928, 1570, 1468,
1215, 1090, 1063, 1020 cm-1.

Working with Hazardous Chemicals

The procedures in Organic Syntheses are intended for use only by persons
with proper training in experimental organic chemistry. All hazardous
materials should be handled using the standard procedures for work with
chemicals described in references such as "Prudent Practices in the
Laboratory" (The National Academies Press, Washington, D.C., 2011; the full
text can be accessed free of charge at
http://www.nap.edu/catalog.php?record_id=12654). All chemical waste
should be disposed of in accordance with local regulations. For general
guidelines for the management of chemical waste, see Chapter 8 of Prudent
Practices.
In some articles in Organic Syntheses, chemical-specific hazards are
highlighted in red “Caution Notes” within a procedure. It is important to
recognize that the absence of a caution note does not imply that no significant
hazards are associated with the chemicals involved in that procedure. Prior
to performing a reaction, a thorough risk assessment should be carried out
that includes a review of the potential hazards associated with each chemical
and experimental operation on the scale that is planned for the procedure.
Guidelines for carrying out a risk assessment and for analyzing the hazards
associated with chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published
and are conducted at one's own risk. Organic Syntheses, Inc., its Editors, and
its Board of Directors do not warrant or guarantee the safety of individuals
using these procedures and hereby disclaim any liability for any injuries or

Org. Synth. 2023, 100, 48–60 52 DOI: 10.15227/orgsyn.100.0048

damages claimed to have resulted from or related in any way to the
procedures herein.

Discussion

Sulfoximines are emerging motifs in the life sciences and have shown
application in asymmetric synthesis as chiral auxiliaries, ligands and
catalysts.2 Their Lewis basic character has also made them interesting
directing groups for C-H functionalization.3 Their most promising
applications are in the pharmaceutical and agrochemical industries as
bioisosteres for sulfones and sulfonamides.4 Recent years have seen broad
uptake in medicinal chemistry and several examples of sulfoximines in
clinical candidates.4b,5 Until relatively recently, uptake in the life sciences had
been limited by the lack of safe and amenable synthetic methods, which have
seen significant recent development.6,7 In 2017 we reported an operationally
simple metal-free protocol for the straightforward preparation of NH-
sulfoximines from sulfides using ammonium carbamate as a convenient
source of ammonia and (diacetoxyiodo)benzene as the oxidant.8 This protocol
was applied by us (and others) for the preparation of NH-sulfoximines and
for the NH- and O-transfer to sulfenamides to access sulfonimidamides.8,9,10
From a mechanistic point of view, it was demonstrated that the process
involves the initial condensation of ammonia with the hypervalent iodine
reagent leading to an iminoiodinane which undergoes oxidation to form a
highly reactive iodonitrene. The iodonitrene reacts directly with the sulfide
to form the corresponding sulfilimine that reacts with the O-donor (the
alcoholic solvent or AcOH) ending up with the formation of a sulfanenitrile
that converts into the corresponding NH-sulfoximine. For mechanistic
evidence see the original report,11 as well as related reports on sulfides8,9a and
sulfenamides.10 The methodology has been widely employed for the direct
one-pot NH and O-transfer to challenging substrates such as fluorinated
sulfides,12 thioglycosides,13 and even to thiols.14 In conclusion, we expect this
metal-free protocol from sulfides to be widely applicable, with the
demonstrated compound presenting an attractive building block for further
derivatization.

Org. Synth. 2023, 100, 48–60 53 DOI: 10.15227/orgsyn.100.0048

References

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Org. Synth. 2023, 100, 48–60 56 DOI: 10.15227/orgsyn.100.0048

 Appendix
Chemical Abstracts Nomenclature (Registry Number)

4-(Bromophenyl)(methyl)sulfane: Benzene, 1-bromo-4-[methylsulfanyl]-;

(104-95-0)
Ammonium carbamate: Carbamic acid, ammonium salt (1:1); (1111-78-0)
(Diacetoxyiodo)benzene: Iodine, bis(acetato-κO)phenyl-; (3240-34-4)
(4-Bromophenyl)(imino)(methyl)-l6-sulfanone: Sulfoximine, (4-
bromophenyl)-S-methyl-; (2258639-09-5)
Methanol; (67-56-1)

Arianna Tota obtained the M.Sci. (summa cum

laude) in Chemistry and Pharmaceutical
Technology at the University of Bari (Italy) in 2015.
In 2020, she obtained the Ph.D. in Chemical and
Molecular Sciences under the supervision of Prof.
Renzo Luisi. Her research activity is focused on the
electrophilic nitrogen transfer to sulfur and the
chemistry of nitrogen-bearing compounds. In
2019, she has been a visiting scholar at the
Department of Synthetic Chemistry and Biological
Chemistry, Kyoto University (Japan), working in
the group of Prof. Aiichiro Nagaki. During this
time, she was involved in the field of flow
microreactor technology applied to organometallic
chemistry.

Mauro Spennacchio obtained the master degree

(summa cum laude) in Pharmacy at the University
of Bari (Italy) in 2019. He is currently at the third
year of his Ph.D. in Pharmaceutical Science under
the supervision of Prof. Renzo Luisi and Prof.
Leonardo Degennaro. His research activity focuses
on the development of new fluorination strategies
exploiting flow microreactor technology and the
electrophilic nitrogen transfer to sulfur.

Org. Synth. 2023, 100, 48–60 57 DOI: 10.15227/orgsyn.100.0048

 Edward Briggs obtained his MChem Chemistry
with six-month placement in 2017 from the
University of Southampton. During this time, he
worked with Professor Bruno Linclau on the
fluorination of glucose and galactose derivatives,
as well as undertaking a placement at Vertex
Pharmaceuticals where he worked simultaneously
on bespoke reagent synthesis and the lead
medicinal chemistry project. Edward started his
Ph.D. with Dr James Bull at Imperial College
London in October 2017 looking at novel synthetic
methods to access sulfoximines and
sulfonimidamides.

Tsz-Kan Ma received his M.Sci. in Chemistry with

Medicinal Chemistry at Imperial College, where he
continued his Ph.D. studies in biomimetic total
synthesis of meroterpenoid natural products
under the supervision of Prof. Anthony G. M.
Barrett. He then moved to UCL as a research fellow
in organic electrosynthetic chemistry, working
with Dr. Jonathan D. Wilden to develop new
electrosynthetic protocols. He is now back at
Imperial College London, working with Dr. James
Bull as a research associate in synthetic chemistry,
focus on developing new synthetic protocols for
transition metal catalyzed C-H activation of
heterocyclic compounds.

Zhenhao Zhong received his B.Sc degree in

chemistry jointly from Nanjing Tech University
and the University of Sheffield in 2019. Then he
obtained his MRes degree in advanced molecular
synthesis at Imperial College London. Zhenhao
continued his Ph.D. studies at the same institution
under the supervision of Dr. James Bull from
October 2020, focusing on developing novel
synthetic methods to synthesize sulfoximines and
sulfonimidamides.

Org. Synth. 2023, 100, 48–60 58 DOI: 10.15227/orgsyn.100.0048

 Leonardo Degennaro obtained the master’s degree
in Chemistry and Pharmaceutical Technology in
1999 and the Ph.D. in Applied Chemical and
Enzymatic Synthesis in 2003. In 2002 he was
"visiting scholar" at the University of Groningen
under the supervision of Prof. B. L. Feringa. In 2006
he was appointed assistant professor in Organic
Chemistry at the Department of Pharmacy of
University of Bari. In 2011 he was "visiting assistant
professor" at the University of Kyoto working in
the group of Prof. J.-i. Yoshida. The research
activity is aimed at developing new
stereocontrolled synthesis by using small
heterocycles and organometallic species, and
microreactor technology

Dr. James Bull is a University Research Fellow at

Imperial College London. His research focuses on
the development of synthetic and catalytic
methods to access medicinally relevant structural
motifs and heterocycles. He obtained his MSci
degree from the University of Cambridge, then
spent a year at GlaxoSmithKline. He returned to
University of Cambridge for his Ph.D. with
Professor Steven Ley. In 2007 he joined Université
de Montréal as a postdoc with Professor André
Charette. He started a Ramsay Memorial
Fellowship at Imperial College in 2009, an EPSRC
Career Acceleration Fellowship in 2011, and in 2016
was awarded a Royal Society URF.

Renzo Luisi is full professor of Organic Chemistry

at the University of Bari (Italy). The research
activity focuses on the chemistry of hetero-
substituted organolithiums, the development of
new synthetic methodologies, and the use of flow
technology. He obtained the Ph.D. in 2000 under
the guidance of Professor Saverio Florio. He has
been visiting student at the Roger Adams Lab at
Urbana Champaign in the group of Prof. Peter
Beak, and visiting professor at the University of
Manchester in the group of Jonathan Clayden. He
is RSC fellow and recipient of the 2014 CINMPIS
award Innovation in Organic Synthesis.

Org. Synth. 2023, 100, 48–60 59 DOI: 10.15227/orgsyn.100.0048

 Ellie Plachinski obtained a B.S. in chemistry in
2020 from the Massachusetts Institute of
Technology, where she conducted research in
the laboratory of Prof. Alison Wendlandt. She
is currently pursuing her Ph.D. in the Yoon
Group in the Department of Chemistry at the
University of Wisconsin–Madison.

Org. Synth. 2023, 100, 48–60 60 DOI: 10.15227/orgsyn.100.0048

 Purity Check
in CDCl3 w/ 0.03% TMS
1,3,5-trimethoxybenzene internal standard

1.95
1.97

2.57

7.79

2.84
0.83
11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0
f1 (ppm)
 1H NMR

7.89
7.89
7.87
7.70
7.70
7.69
7.69

3.10
3.10
2.72
in CDCl3 w/ 0.03% TMS

3.00

0.85
3.2 3.1 3.0 2.9 2.8 2.7 2.6
f1 (ppm)
1.98

2.01

7.9 7.8 7.7 7.6

f1 (ppm)
1.98
2.01

3.00

0.85
11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0
f1 (ppm)
 13 NMR

142.69

132.55
129.36
128.29

46.24
in CDCl3 w/ 0.03% TMS

240 230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30
f1 (ppm)