Increasing Complexity: A Practical Synthetic Approach to Three-Dimensional, Cyclic Sulfoximines and First Insights into Their in Vitro Properties

Article abstract of DOI:10.1002/chem.201905461

A short synthetic approach with broad scope to access five- to seven-membered cyclic sulfoximines in only two to three steps from readily available thiophenols is reported. Thus, simple building blocks were converted to complex molecular structures by a s

Full text of DOI:10.1002/chem.201905461

A Journal of
Accepted Article
Title: Increasing Complexity: A Practical Synthetic Approach to Three-
Dimensional, Cyclic Sulfoximines and First Insights into Their in
vitro Properties
Authors: Ulrich Lücking, Emilie Boulard, Vivien Zibulski, Philip Lienau,
Luisa Oertel, Martina Schaefer, and Ursula Ganzer
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Increasing Complexity: A Practical Synthetic Approach to Three-
Dimensional, Cyclic Sulfoximines and First Insights into Their in
vitro Properties
Emilie Boulard,[b] Vivien Zibulski,[a] Luisa Oertel,[a] Philip Lienau,[a] Martina Schäfer,[a] Ursula Ganzer,[a]
and Ulrich Lücking*[a]
Abstract: A short synthetic approach with broad scope to access five-
to seven-membered cyclic sulfoximines in only 2–3 steps from readily
available thiophenols is reported. Thus, simple building blocks were
converted into complex molecular structures by a sequence of S-
alkylation and one-pot sulfoximine formation, followed by
intramolecular cyclization. 17 structurally diverse cyclic sulfoximines
were prepared in high overall yields. In vitro evaluation of these
underrepresented, three-dimensional, cyclic sulfoximines with respect
to properties relevant to medicinal chemistry did not reveal any
intrinsic flaw for application in drug discovery.
and increased efflux.[2b,2c] In principle, masking of the hydrogen-
bond donor function[7] of the sulfoximine NH (2, R3 = H) by N-
alkylation (2, R3 = alkyl) should be a means to improve membrane
permeability, but there are only scattered reports. However, in a
recent study by Gnamm, Bolm, and co-workers, N-methylation did
not improve permeability properties significantly.[2b] Moreover, N-
methylated sulfoximine analogues 2 (R3 = CH3) can suffer from
reduced metabolic stability and solubility relative to the matched
NH-sulfoximines 2 (R3 = H).[2b] Against this background, we
wondered if cyclic sulfoximines of general structure 3 could
combine high permeability, low efflux, and high metabolic stability
with favorable solubility. Furthermore, we were attracted to these
underrepresented, three-dimensional heterocycles as novel
building blocks for drug discovery efforts, fragment-based
screening, and library syntheses.[8]
Introduction
Sulfoximines 2,[1] the mono-aza analogues of sulfones 1, have
only recently been the subject of growing interest in drug
discovery (Figure 1).[2] Nevertheless, four sulfoximine compounds
(roniciclib,[3] atuveciclib,[4] BAY 1251152,[5] AZD6738[6]) have
entered clinical evaluation for the treatment of cancer of late and
their promising physicochemical and DMPK properties were
important triggers for their selection as clinical candidates.
( )n
1
2
3a, n = 1
3b, n = 2
3c, n = 3
Sulfoximines
2 are isoelectronic with sulfones 1 but the
introduction of the nitrogen atom creates asymmetry at the
tetrahedral sulfur atom in the case where the two carbon
substituents R1 and R2 are not identical. In contrast to sulfones 1,
sulfoximines 2 offer an additional point for substitution, the mildly
basic nitrogen atom, which can also be utilized for the
construction of cyclic sulfoximines 3 (Figure 1), for example by
connecting the substituents R2 and R3. Recent reports have
suggested that the introduction of NH-sulfoximines 2 (R3 = H) into
certain lead structures can result in reduced Caco2 permeability
Figure 1. General structures of sulfones 1, sulfoximines 2, and cyclic
sulfoximines 3.
Currently, only limited literature on the synthesis of cyclic
sulfoximines is available. The first example of a cyclic sulfoximine
3 was reported in 1973 by Johnson and Janiga.[9] The synthetic
approach to their intended target compound 6 started with
alkylation of the sodium salt of p-thiocresol (4) with 1-bromo-3-
chloropropane (Scheme 1). The resulting thioether 5 was
converted into the corresponding sulfoxide, which was followed
by sulfoximine 6 formation using concentrated sulfuric acid and
sodium azide. Upon removal of the volatiles, a partial, ‘slow,
spontaneous cyclization’ of (chloropropyl)sulfoximine 6 to the
undesired cyclic sulfoximine 3aa occurred.[9] No additional
examples of cyclic sulfoximines prepared by this route were
reported in this study.
[a]
[b]
V. Zibulski, L. Oertel, Dr. P. Lienau, Dr. M. Schäfer (0000-0003-
3640-6435), Dr. U. Ganzer, Dr. U. Lücking (0000-0003-2466-5800)
Bayer AG
Pharmaceuticals Division, Drug Discovery Department
Müllerstr. 178, 13353 Berlin (Germany)
E-mail: ulrich.luecking@bayer.com
E. Boulard
CPE Lyon - Campus LyonTech/la Doua
Bâtiment Hubert Curien 43
boulevard du 11 Novembre 1918
69616 Villeurbanne Cedex (France)
Supporting information for this article is given via a link at the end of
the document.
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Possibly, the one-pot sulfoximine formation step could also afford
the direct conversion of thioethers 9 into cyclic sulfoximines 3 in
one step.
a)
4
5
( )n
b-c)
8a–c
a)
( )n
9a–c
7
d)
b)
3aa
6
d)
c)
Scheme 1. Unexpected synthesis of cyclic sulfoximine 3aa by Johnson and
Janiga:[9] a) 1-bromo-3-chloropropane, dioxane, H2O, 86%; b) sodium periodate,
H2O, 99%; c) NaN3, H2SO4, CHCl3, 89%; d) precipitate (insoluble in DCM) was
dissolved in H2O and neutralized with aqueous NaOH, yield not reported.
( )n
( )n
3a–c
10a–c
Some 25 years later, Boßhammer and Gais disclosed a novel
approach for the synthesis of cyclic sulfoximine 3ab (see Table
1).[10] Starting from S-methyl-S-phenylsulfoximine, alkylation of
the NH position with a protected 2-haloethanol led to the
corresponding N-(hydroxyethyl)sulfoximine, which was converted
into the tosylate. Finally, treatment with BuOK/BuLi afforded the
cyclized product 3ab. The six-membered cyclic homologue 3bb
(see Table 1) was prepared in a similar manner. Recently, Bolm
and co-workers reported a novel approach, with broad functional
group tolerance, to five- and six-membered cyclic sulfoximines 3
via intramolecular imidation of azido-containing sulfoxides using
a commercially available iron(II) phthalocyanine as catalyst.[11]
Moreover, Maruoka and co-workers have outlined a novel
procedure for the synthesis of unsaturated five-membered cyclic
sulfoximines from N-propargylsulfinamides via sulfur–carbon
bond formation.[12]
The development of significantly improved methodologies for the
synthesis of sulfoximines 2 has been an important trigger for the
increased interest in this functional group by the drug discovery
community in recent years.[2d] A late example is a novel one-pot
procedure which allows the direct conversion of thioethers into
NH-sulfoximines 2 (R3 = H), first reported by Bull, Luisi, and co-
workers.[13] This reaction is mediated by commercially available
(diacetoxyiodo)benzene and ammonium carbamate in methanol
at room temperature and tolerates a wide range of functional
groups. From our perspective, the major drawback of the early
synthetic route to cyclic sulfoximine 3aa by Johnson and Janiga[9]
is the use of sodium azide and concentrated sulfuric acid, due to
safety concerns.[2a,2d] In this context, we contemplated whether it
would be possible to apply the novel, safe, one-pot methodology
of Bull, Luisi, and co-workers to the synthesis of cyclic
sulfoximines 3. Relying on readily available thiols 7, our strategy
envisaged the preparation of thioethers 9a–c with variable carbon
chain length and a suitable chloro leaving group in place (Scheme
2). One-pot sulfoximine formation would afford the cyclization
precursors 10a–c for the final intramolecular alkylation of the NH
position, resulting in cyclic sulfoximines 3a–c of various ring sizes.
Scheme 2. Novel synthetic approach to cyclic sulfoximines 3: a) NEt3 (2 equiv),
THF, RT; b) PhI(OAc)2 (2.5 equiv), H2NCO2NH4 (2–2.5 equiv), MeOH, RT; c)
aqueous 0.1% NH3, 80 °C; d) PhI(OAc)2 (2.5 equiv), H2NCO2NH4 (2 equiv),
MeOH, RT until full conversion of 9 into 10, then stirring of the mixture in a
closed vial at 80 °C; a: n = 1, b: n = 2, c: n = 3.
Results and Discussion
To evaluate the feasibility, the planned synthetic steps were
tested for the synthesis of model compound 3ab. Using standard
S-alkylation conditions,[14] the reaction of thiophenol (7a) with
commercial 1-bromo-3-chloropropane (8a) in the presence of
triethylamine gave thioether 9ab in 78% yield. One-pot
sulfoximine formation with (diacetoxyiodo)benzene and
ammonium carbamate in methanol[13a] afforded acyclic
sulfoximine 10ab in a clean reaction with no sign of cyclized
product 3ab, as indicated by TLC and UPLC-MS analysis.
However, initial attempts to isolate the novel product 10ab by
preparative HPLC resulted in a mixture of acyclic sulfoximine
10ab and cyclized 3ab in a ca. 2:1 ratio. Further analysis revealed
that this mixture of products was formed in a clean reaction during
rotary evaporation, at elevated temperatures, of the HPLC solvent
(water + 0.1% NH3) from the relevant fractions after preparative
HPLC separation. This unexpected result led to the idea of
employing similar conditions for the desired intramolecular
cyclization reaction. Thus, a stirred solution of cyclization
precursor 10ab in aqueous 0.1% NH3 at 80 °C in a closed
microwave vial for 1 hour afforded the desired product 3ab in a
very clean reaction and 77% isolated yield (Table 1). The
originally intended use of KOH in DMSO[15] for the final
intramolecular alkylation also gave the cyclization product 3ab in
good yield (63%). Moreover, the reaction of 10ab with NaH in
DMF also provided product 3ab in comparable yield (68%). The
isolated yields using the last two methods did not reflect the very
clean reactions indicated by UPLC-MS; product 3ab was also
found in the aqueous phase from the corresponding workup
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procedures, probably due to its high aqueous solubility. However,
since the use of aqueous 0.1% NH3 gave the best isolated yield
of 3ab and was also most attractive from an environmental[16] and
economic point of view, we elected to use these unusual
conditions for the final cyclization step when evaluating the scope
of our novel synthetic approach to the three-dimensional, cyclic
sulfoximines 3. In the series of five-membered cyclic sulfoximines
3aa–ao, a wide range of substituents at the aryl ortho, meta,
and/or para position was tolerated and generally good to excellent
yields were recorded for all three synthetic steps a) to c) (Table
1).
Table 1. Yields of steps a)–d) in the synthesis of cyclic sulfoximines according to Scheme 2 and comparison of the in vitro properties of compounds 3aa–3cb
with acyclic sulfoximines 2a and 2b.
[a]
[b]
[b]
Compound
Yield [%]
steps a), b), c), unless
otherwise indicated
Sw
Fmax
[%]
Fmax
[%]
Papp A–B[c]
[nm/s]
Efflux
ratio[c]
logD
pH 7.5[d]
[mg/L]
pH 6.5
(h/r/m)LMs
rHep
78
80
77
100 (h)
99 (r)
100 (m)
492
510
>195
148
100
256
345
284
363
0.77
0.69
0.62
0.45
0.60
1.00
1.05
0.95
91 (step d)
3ab
quantitative
90
73
100 (h)
98 (r)
100 (m)
100
100
99
3aa
88
72
94
100 (h)
100 (r)
100 (m)
3ac
76
71
78
100 (h)
95 (r)
99 (m)
3ad
84
80
65
100 (h)
100 (r)
100 (m)
>199
>199
100
100
305
417
0.57
0.58
0.70
0.70
3ae
88
61
80
100 (h)
84 (r)
91 (m)
3af
–
97
89
100 (h)
100 (r)
100 (m)
>226
207
79
80
201
462
0.72
0.57
0.75
1.20
3ag
83
95
55
82 (h)
93 (r)
100 (m)
3ah
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82
40
98
94 (h)
100 (r)
92 (m)
279
159
84
369
514
0.74
0.53
1.30
0.50
3ai
89
66
71
100 (h)
97 (r)
87 (m)
100
3aj
95
65
81
99 (h)
28 (r)
99 (m)
229
26
125
0.4
0.90
3ak
87
95
80
86 (h)
98 (r)
95 (m)
>225
126
21
79
390
405
0.64
0.65
0.60
0.90
3al
40
61
73
100 (h)
97 (r)
81 (m)
3am
97
88
73
51 (h)
47 (r)
49 (m)
142
41
382
0.65
2.20
3an
69
80 (h)
99 (r)
97 (m)
not determined
not determined
77 (step d)
[e]
–
97
89
422
373
0.63
0.65
0.95
0.85
3ao
89
53
83
78 (h)
93 (r)
84 (m)
128
3bb
95
96
76[f]
94 (h)
93 (r)
100 (m)
[e]
–
57
84
479
374
0.58
0.60
1.35
0.80
3cb
100 (h)
100 (r)
100 (m)
not applicable
135
2a
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71 (h)
70 (r)
[e]
not applicable
–
100
467
0.55
0.70
98 (m)
2b
[a] Determined by a high-throughput screening method using 1 mM DMSO stock solutions.[17] [b] Predicted hepatic metabolic first pass given as the maximum
oral bioavailability Fmax based on a metabolic stability assay using (i) pooled human liver microsomes (hLMs), (ii) pooled rat liver microsomes (rLMs), (iii) pooled
mouse liver microsomes (mLMs), and (iv) freshly harvested rat hepatocytes (rHep).[18] [c] Papp A–B (apical to basolateral) and efflux ratio (ER) data were
generated in a bidirectionally performed Caco2 permeability assay in a 24-well format; ER was calculated as Papp B–A/Papp A–B.[18] [d] Determined by reversed-
phase HPLC.[19] [e] No valid results were obtained. [f] Cyclization of 10cb using NaH in DMF at 50 °C overnight.
The majority of the final sulfoximine products were isolated as oils,
but in the case of nitro derivative 3ag crystals were obtained and
the cyclic structure was confirmed by X-ray diffraction analysis
(Figure 2, see the Supporting Information for details).
mixture of diastereomers in 77% isolated yield. Moreover,
thioether 9ab was first reacted with (diacetoxyiodo)benzene and
ammonium carbamate on a gram scale to give cyclization
precursor 10ab, as indicated by UPLC-MS. Subsequent heating
of the reaction mixture at 80 °C in a closed vessel for 5 hours led
to the formation of the cyclic product 3ab, which was isolated in
91% yield.
Using the standard three-step procedure, the six-membered
cyclic sulfoximine 3bb was also synthesized, in comparable yield
to the five-membered homologue 3ab (Table 1). To our surprise,
the attempted cyclization of acyclic sulfoximine 10cb to the seven-
membered product 3cb in aqueous 0.1% NH3 at 80 °C resulted in
a very low yield. Full conversion of the acyclic precursor 10cb was
only recorded after 4 days at 80 °C with stirring, and resulted in
the formation of cyclic product 3cb and an acyclic alcohol,
resulting from hydrolysis at the chloro position, in a ca. 1:1 ratio.
The separation of these two products by flash chromatography
proved to be difficult, but was finally achieved by preparative
HPLC. The formation of the alcohol side product and the repeated
isolation attempts contributed to the low, unoptimized yield of 11%
for sulfoximine 3cb by this method. In contrast, cyclization of 10cb
with NaH in DMF at 50 °C gave the cyclized product 3cb in a good
yield of 76%. Moreover, the use of KOH in DMSO[15] for the final
intramolecular alkylation also provided seven-membered cyclic
sulfoximine 3cb in 53% isolated yield.
To gain further knowledge of the medicinal chemistry properties
of the cyclic sulfoximines synthesized in this study, the behavior
of compounds 3aa–cb was compared to acyclic sulfoximines 2a
and 2b in selected in vitro assays (Table 1). The majority of the
cyclic sulfoximines 3 displayed high aqueous solubility at pH 6.5,
including the drug-like, steroidal product 3an (Sw = 142 mg/L).
There was no significant difference in aqueous solubility of the
cyclic sulfoximines relative to acyclic NH-sulfoximine 2a (Sw = 135
mg/L); unfortunately, a valid solubility measurement could not be
obtained in the case of N-methylated sulfoximine 2b. It should be
taken into account, however, that most products were isolated as
oils and that aqueous solubility was determined by a high-
throughput screening method using 1 mM DMSO stock solutions
of test compounds. Ring size and the nature of substituents
significantly influence the lipophilicity of the cyclic compounds
(Table 1). The most polar compound of this study was the cyano-
substituted sulfoximine 3aj, with a logD value of 0.5. Five-
membered cyclic sulfoximine 3ab revealed a logD value of 0.6,
surprisingly slightly lower than that of acyclic NH-sulfoximine 2a
(logD = 0.8) and of N-methylated sulfoximine 2b (logD = 0.7).[23]
Figure 2. X-ray structure of the five-membered cyclic sulfoximine 3ag.
The synthetic applicability of bromo-substituted products like 3ah
for metal-catalyzed cross-coupling reactions has already been
demonstrated by Bolm and co-workers.[11] ortho-Iodo derivative
3ai was envisaged to allow access to a novel class of P,N-
ligands[20] by cross-coupling with suitable phosphines.[21]
Preparation of the matched pyridyl analogues of phenyl derivative
3ab proved to be difficult due to very high polarity and solubility of
the corresponding products, which hampered preparative
isolation. However, the feasibility of heterocyclic substituents R1
is displayed in products 3al and 3am. Moreover, starting from 3-
sulfanylestra-1(10),2,4-trien-17-one,[22] the applicability of the
three-step procedure for complex, drug-like molecules is
demonstrated by the formation of 3an (1:1 mixture of
diastereomers), in high overall yield.
In the attempted synthesis of methyl-substituted analogue 3ao,
one-pot sulfoximine formation from 9ao using (diacetoxyiodo)-
benzene and ammonium carbamate gave the desired cyclization
precursor 10ao in a clean reaction, as indicated by UPLC-MS
analysis. However, upon removal of solvent (hexane/EtOAc) from
the isolated fractions after flash chromatography, we noted partial
cyclization of the acyclic precursor 10ao to the cyclic sulfoximine
3ao. This result rekindled our idea of achieving sulfoximine
formation and intramolecular cyclization in one step. We repeated
the conversion of [(3-chloro-2-methylpropyl)sulfanyl]benzene
(9ao) into the corresponding acyclic sulfoximine 10ao under the
standard conditions. After full conversion of the starting material,
as indicated by UPLC-MS, the mixture was heated to 80 °C in a
closed vessel overnight. To our delight, there was full conversion
of 10ao in a clean reaction which gave cyclic product 3ao as a 1:1
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Synthesis of thioethers 9: General procedure A
Depending on the nature of the substituent, logD values in the
range of 0.50 (3aj) to 1.35 (3cb) were recorded for the fragment-
like compounds, while drug-like molecule 3an displayed a logD
value of 2.2. All compounds were tested in a Caco2 screening
assay and demonstrated high permeability coefficients (Papp A–B)
and no evidence of drug efflux (Table 1). These results can be
attributed to the low molecular weight and the good solubility of
these small and fragment-like compounds. However, steroid
derivative 3an also exhibited high permeability (382 nm/s) and no
efflux (ER = 0.65).
A mixture of thiol 7 (1.0 equiv), the corresponding bromochloroalkane 8
(1.1 equiv), and NEt3 (2.0 equiv) in THF was stirred at RT overnight. Then,
the reaction mixture was diluted with H2O. The organic layer was
separated and the aqueous layer was extracted with DCM (3 ×). The
combined organic layers were filtered through water-repellent filter paper.
The volatiles were removed under reduced pressure and the crude product
was purified by flash column chromatography to afford the desired
thioether 9.
In vitro pharmacokinetic studies in liver microsomes of human, rat,
and mouse origin with the cyclic sulfoximines of this study usually
[(3-Chloropropyl)sulfanyl]benzene (9ab)
demonstrated very high stability, assessed as maximum oral
Prepared according to general procedure A, by reacting benzenethiol
(1.00 g, 9.08 mmol) with 1-bromo-3-chloropropane (0.99 mL, 9.98 mmol)
and NEt3 (2.53 mL, 18.15 mmol) in THF (20 mL); crude purified by flash
column chromatography (0–10% EtOAc in hexane) to give 9ab as a
colorless oil (1.32 g, 7.07 mmol, 78%): 1H NMR (400 MHz, [D6]DMSO): 
= 7.30–7.37 (m, 4H; Ar-H), 7.17–7.24 (m, 1H; Ar-H), 3.73 (t, J = 6.34 Hz,
[24]
bioavailability Fmax
(Table 1). One exception is steroidal
compound 3an which displayed moderate metabolic stability in
human, rat, and mouse liver microsomes. Furthermore, ester 3ak
also exhibited low metabolic stability in rat liver microsomes.
However, it is noteworthy that the main sites of metabolism and
the involved metabolic enzymes were not determined for any of
the test compounds. In the in vitro studies with rat hepatocytes,
very high metabolic stabilities were observed for the majority of
the tested cyclic sulfoximines, again with compounds 3an and 3ak,
along with acetal 3al, being exceptions. In comparison to acyclic
compounds 2a and 2b, five-membered cyclic model compound
3ab shows a trend for increased metabolic stability in vitro in rat
hepatocytes [Fmax: 100% (3ab) vs 84% (2a)] and human and rat
2H; CH2), 3.07 (t, J = 7.10 Hz, 2H; CH2), 1.94–2.02 ppm (m, 2H; CH2); 13
C
NMR (101 MHz, [D6]DMSO):  = 135.5, 129.1, 128.3, 125.9, 43.8, 31.5,
29.2 ppm.
1-[(3-Chloropropyl)sulfanyl]-4-methylbenzene (9aa)
Prepared according to general procedure A, by reacting 4-methyl-
benzenethiol (1.00 g, 8.05 mmol) with 1-bromo-3-chloropropane (0.88 mL,
8.86 mmol) and NEt3 (2.24 mL, 16.1 mmol) in THF (15 mL); crude purified
by flash column chromatography (0–10% EtOAc in hexane) to give 9aa as
a colorless liquid (1.62 g, 8.08 mmol, quantitative): 1H NMR (400 MHz,
[D6]DMSO):  = 7.24–7.28 (m, 2H; Ar-H), 7.15 (d, J = 7.86 Hz, 2H; Ar-H),
3.72 (t, J = 6.34 Hz, 2H; CH2), 3.01 (t, J = 7.10 Hz, 2H; CH2), 2.27 (s, 3H;
CH3), 1.91–1.98 ppm (m, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  =
135.6, 131.6, 129.8, 129.2, 43.8, 31.5, 29.9, 20.6 ppm.
liver microsomes [human Fmax: 100% (3ab) vs 71% (2b); rat Fmax
:
99% (3ab) vs 70% (2b)]. Moreover, the homologous cyclic
sulfoximines 3ab, 3bb, and 3cb show a trend for decreased
metabolic stability in rat hepatocytes with increased ring size, with
Fmax values of 100% (3ab), 89% (3bb), and 57% (3cb). However,
this trend can also be correlated with increased lipophilicity of
these compounds.
1-[(3-Chloropropyl)sulfanyl]-3-methylbenzene (9ac)
Prepared according to general procedure A, by reacting 3-methyl-
benzenethiol (1.00 g, 8.05 mmol) with 1-bromo-3-chloropropane (0.88 mL,
8.86 mmol) and NEt3 (2.24 mL, 16.1 mmol) in THF (15 mL); crude purified
by flash column chromatography (0–10% EtOAc in hexane) to give 9ac as
a colorless liquid (1.43 g, 7.12 mmol, 88%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.10–7.33 (m, 3H; Ar-H), 7.01 (d, J = 7.35 Hz; Ar-H), 3.73
(t, J = 6.34 Hz, 2H; CH2), 3.06 (t, J = 7.10 Hz, 2H; CH2), 2.28 (s, 3H; CH3),
1.94–2.01 ppm (m, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  = 138.5,
135.3, 129.0, 128.8, 126.7, 125.3, 43.9, 31.5, 29.1, 20.9 ppm.
Conclusions
In summary, we have developed a practical, safe approach for the
synthesis of five- to seven-membered cyclic sulfoximines 3, which
are currently underrepresented in drug discovery, to broaden the
chemical repertoire in small molecule drug discovery. Starting
from readily available thiophenols 7, a sequence of S-alkylation
(9), one-pot sulfoximine formation (10), and intramolecular
cyclization afforded 17 cyclized products 3 in high yields and
broad scope. The intramolecular cyclization of acyclic
sulfoximines 10 to five- and seven-membered cyclic products 3
can be achieved with a variety of methods. Moreover, the direct
conversion of thioethers 9 into cyclic sulfoximines 3 in high yields
has also been demonstrated. In vitro evaluation of the compounds
prepared in this study has not revealed any intrinsic flaw of the
five- to seven-membered cyclic sulfoximines 3 with respect to
their application as versatile building blocks for drug discovery.
1-[(3-Chloropropyl)sulfanyl]-2-methylbenzene (9ad)
Prepared according to general procedure A, by reacting 2-methyl-
benzenethiol (1.00 g, 8.05 mmol) with 1-bromo-3-chloropropane (0.88 mL,
8.86 mmol) and NEt3 (2.24 mL, 16.1 mmol) in THF (15 mL); crude purified
by flash column chromatography (0–10% EtOAc in hexane) to give 9ad as
a colorless liquid (1.23 g, 6.13 mmol, 76%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.09–7.35 (m, 4H; Ar-H), 3.75 (t, J = 6.34 Hz, 2H; CH2),
3.05 (t, J = 7.35 Hz, 2H; CH2), 2.28 (s, 3H; CH3), 1.96–2.03 ppm (m, 2H;
CH2); 13C NMR (101 MHz, [D6]DMSO):  = 136.4, 134.8, 130.1, 127.0,
126.7, 125.5, 43.9, 31.4, 28.6, 19.9 ppm.
1-[(3-Chloropropyl)sulfanyl]-4-fluorobenzene (9ae)
Experimental Section
For general methods and materials, see the Supporting Information.
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Prepared according to general procedure A, by reacting 4-fluoro-
benzenethiol (1.00 g, 7.80 mmol) with 1-bromo-3-chloropropane (0.85 mL,
8.58 mmol) and NEt3 (2.18 mL, 15.6 mmol) in THF (25 mL); crude purified
by flash column chromatography (0–10% EtOAc in hexane) to give 9ae as
a colorless liquid (1.34 g, 6.56 mmol, 84%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.42 (t, J = 6.41 Hz, 2H; Ar-H), 7.19 (t, J = 8.28 Hz, 2H;
Ar-H), 3.72 (t, J = 6.46 Hz, 2H; CH2), 3.04 (t, J = 7.1 Hz, 2H; CH2), 1.91–
1.98 ppm (m, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  = 162.2, 159.8,
131.5, 131.4, 130.8, 130.8, 116.3, 116.1, 43.7, 31.4, 30.3 ppm.
Prepared according to general procedure A, by reacting methyl 4-
sulfanylbenzoate (500 mg, 2.97 mmol) with 1-bromo-3-chloropropane
(0.32 mL, 3.27 mmol) and NEt3 (0.83 mL, 5.94 mmol) in THF (10 mL);
crude purified by flash column chromatography (0–10% EtOAc in hexane)
to give 9ak as a colorless liquid (690 mg, 2.82 mmol, 95%): 1H NMR (400
MHz, [D6]DMSO):  = 7.80–7.96 (m, 2H; Ar-H), 7.36–7.47 (m, 2H; Ar-H),
3.83 (s, 3H; OMe), 3.72–3.81 (m, 2H; CH2), 3.15–3.21 (m, 2H; CH2), 1.86–
2.08 ppm (m, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  = 165.9, 143.3,
129.7, 126.3, 126.2, 52.1, 43.8, 31.2, 27.9 ppm.
1-[(3-Chloropropyl)sulfanyl]-2-fluorobenzene (9af)
5-[(3-Chloropropyl)sulfanyl]-1,3-benzodioxole (9al)
Prepared according to general procedure A, by reacting 2-fluoro-
benzenethiol (1.00 g, 7.80 mmol) with 1-bromo-3-chloropropane (0.85 mL,
8.58 mmol) and NEt3 (2.18 mL, 15.6 mmol) in THF (25 mL); crude purified
by flash column chromatography (0–10% EtOAc in hexane) to give 9af as
a colorless liquid (1.40 g, 6.86 mmol, 88%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.48 (td, J = 7.79, 1.65 Hz, 1H; Ar-H), 7.19–7.33 (m, 3H;
Ar-H), 3.74 (t, J = 6.34 Hz, 2H; CH2), 3.07 (t, J = 7.10 Hz, 2H; CH2), 1.97
ppm (quin, J = 6.78 Hz, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  =
161.4, 159.0, 130.7, 130.7, 128.4, 128.3, 125.2, 125.2, 122.3, 122.2, 115.7,
115.5, 43.7, 31.5, 28.8, 28.8 ppm.
Prepared according to general procedure A, by reacting 1,3-benzodioxole-
5-thiol (1.00 g, 6.48 mmol) with 1-bromo-3-chloropropane (0.71 mL, 7.13
mmol) and NEt3 (1.81 mL, 12.97 mmol) in THF (20 mL); crude purified by
flash column chromatography (0–10% EtOAc in hexane) to give 9al as a
colorless oil (1.30 g, 5.63 mmol, 87%): 1H NMR (400 MHz, [D6]DMSO): 
= 7.02 (t, J = 1.01 Hz, 1H; Ar-H), 6.88 (d, J = 1.01 Hz, 2H; Ar-H), 6.02 (s,
2H; OCH2O), 3.71 (t, J = 6.34 Hz, 2H; CH2), 2.96 (t, J = 7.10 Hz, 2H; CH2),
1.87–1.99 ppm (m, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  = 147.9,
146.6, 126.9, 124.4, 111.0, 108.8, 101.4, 43.7, 31.5, 31.3 ppm.
8-[(3-Chloropropyl)sulfanyl]quinoline (9am)
1-Bromo-3-[(3-chloropropyl)sulfanyl]benzene (9ah)
Prepared according to general procedure A, by reacting quinoline-8-thiol
hydrochloride (1:1) (1.00 g, 5.06 mmol) with 1-bromo-3-chloropropane
(0.55 mL, 5.56 mmol) and NEt3 (1.41 mL, 10.12 mmol) in THF (16 mL);
crude purified by flash column chromatography (0–10% EtOAc in hexane)
to give 9am as a colorless oil (480 mg, 2.02 mmol, 40%): 1H NMR (400
MHz, [D6]DMSO):  = 8.89 (dd, J = 1.77, 4.06 Hz, 1H; Ar-H), 8.36 (dd,
J = 1.65, 8.24 Hz, 1H; Ar-H), 7.73 (dd, J = 2.15, 7.22 Hz, 1H; Ar-H), 7.53–
7.60 (m, 3H; Ar-H), 3.82 (t, J = 6.34 Hz, 2H; CH2), 3.17 (t, J = 7.22 Hz, 2H;
CH2), 2.14 ppm (quin, J = 6.84 Hz, 2H; CH2); 13C NMR (101 MHz,
[D6]DMSO):  = 149.3, 144.7, 137.7, 136.5, 127.9, 126.8, 123.9, 123.7,
122.1, 44.2, 31.0, 26.6 ppm.
Prepared according to general procedure A, by reacting 3-bromo-
benzenethiol (1.00 g, 5.29 mmol) with 1-bromo-3-chloropropane (0.58 mL,
5.82 mmol) and NEt3 (1.34 mL, 9.62 mmol) in THF (15 mL); crude purified
by flash column chromatography (0–10% EtOAc in hexane) to give 9ah as
a colorless liquid (1.17 g, 4.41 mmol, 83%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.52 (t, J = 1.77 Hz, 1H; Ar-H), 7.25–7.40 (m, 3H; Ar-H),
3.73 (t, J = 6.34 Hz, 2H; CH2), 3.12 (t, J = 7.22 Hz, 2H; CH2), 1.99 ppm
(quin, J = 6.78 Hz, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  = 138.6,
130.9, 129.7, 128.5, 126.8, 122.3, 43.7, 31.3, 28.8 ppm.
1-[(3-Chloropropyl)sulfanyl]-2-iodobenzene (9ai)
3-[(3-Chloropropyl)sulfanyl]estra-1(10),2,4-trien-17-one (9an)
Prepared according to general procedure A, by reacting 2-iodo-
benzenethiol (250 mg, 1.06 mmol) with 1-bromo-3-chloropropane (0.12
mL, 1.16 mmol) and NEt3 (0.30 mL, 2.11 mmol) in THF (3.4 mL); crude
purified by flash column chromatography (0–10% EtOAc in hexane) to give
9ai as a colorless liquid (270 mg, 0.86 mmol, 82%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.84 (dd, J = 1.39, 7.73 Hz, 1H; Ar-H), 7.29–7.54 (m, 2H;
Ar-H), 6.93 (dt, J = 1.65, 7.54 Hz, 1H; Ar-H), 3.70–3.78 (m, 2H; CH2), 3.04–
3.15 (m, 2H; CH2), 1.95–2.07 ppm (m, 2H; CH2); 13C NMR (101 MHz,
[D6]DMSO):  = 140.6, 139.3, 129.0, 126.9, 126.6, 99.0, 44.0, 30.9, 29.8
ppm.
Prepared according to general procedure A, by reacting 3-sulfanylestra-
1(10),2,4-trien-17-one (500 mg, 1.75 mmol) with 1-bromo-3-chloropropane
(0.19 mL, 1.92 mmol) and NEt3 (0.49 mL, 3.49 mmol) in THF (6 mL); crude
purified by flash column chromatography (0–10% EtOAc in hexane) to give
9an as a colorless oil (615 mg, 1.70 mmol, 97%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.24 (d, J = 8.11 Hz, 1H), 7.11 (d, J = 8.50 Hz, 1H), 7.06
(s, 1H), 3.73 (t, J = 6.34 Hz, 2H), 3.02 (t, J = 7.10 Hz, 2H), 2.83 (br dd,
J = 3.68, 8.49 Hz, 2H), 2.32–2.48 (m, 2H), 2.22 (br s, 1H), 1.91–2.11 (m,
5H), 1.72–1.81 (m, 1H), 1.33–1.62 (m, 6H), 0.83 ppm (s, 3H); 13C NMR
(101 MHz, [D6]DMSO):  = 219.6, 137.8, 137.3, 131.9, 129.1, 126.2, 126.2,
49.6, 47.3, 43.9, 43.7, 37.5, 35.4, 31.6, 29.5, 28.8, 25.9, 25.2, 21.2, 13.5
ppm.
4-[(3-Chloropropyl)sulfanyl]benzonitrile (9aj)
Prepared according to general procedure A, by reacting 4-sulfanyl-
benzonitrile (1.00 g, 7.40 mmol) with 1-bromo-3-chloropropane (0.81 mL,
8.14 mmol) and NEt3 (2.06 mL, 14.79 mmol) in THF (24 mL); crude purified
by flash column chromatography (0–10% EtOAc in hexane) to give 9aj as
a colorless liquid (1.40 g, 6.61 mmol, 89%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.71–7.78 (m, 2H; Ar-H), 7.43–7.54 (m, 2H; Ar-H), 3.75 (t,
J = 6.46 Hz, 2H; CH2), 3.16–3.20 (m, 2H; CH2), 1.99–2.08 ppm (m, 2H;
CH2); 13C NMR (101 MHz, [D6]DMSO):  = 143.9, 132.6, 126.8, 118.9,
107.2, 43.8, 31.1, 27.7 ppm.
[(3-Chloro-2-methylpropyl)sulfanyl]benzene (9ao)
Prepared according to general procedure A, by reacting benzenethiol
(1.00 g, 9.08 mmol) with 1-bromo-3-chloro-2-methylpropane (1.59 mL,
13.61 mmol) and NEt3 (2.53 mL, 18.15 mmol) in THF (15 mL); crude
purified by flash column chromatography (0–10% EtOAc in hexane) to give
9ao as a colorless oil (1.25 g, 6.23 mmol, 69%): 1H NMR (400 MHz,
[D6]DMSO):  = 7.28–7.42 (m, 4H; Ar-H), 7.15–7.24 (m, 1H; Ar-H), 3.70
(dd, J = 1.65, 5.45 Hz, 2H; CH2), 3.07 (dd, J = 6.46, 13.31 Hz, 1H), 2.91
(dd, J = 7.10, 13.43 Hz, 1H), 1.96–2.07 (m, 1H), 1.06 ppm (d, J = 6.84 Hz,
3H; CH3); 13C NMR (101 MHz, [D6]DMSO):  = 135.9, 129.2, 128.3, 125.9,
49.7, 36.0, 34.7, 16.9 ppm.
Methyl 4-[(3-chloropropyl)sulfanyl]benzoate (9ak)
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[(4-Chlorobutyl)sulfanyl]benzene (9bb)
1-[S-(3-Chloropropyl)sulfonimidoyl]-3-methylbenzene (10ac)
Prepared according to general procedure A, by reacting benzenethiol
(1.00 g, 9.08 mmol) with 1-bromo-4-chlorobutane (1.15 mL, 9.98 mmol)
and NEt3 (2.53 mL, 18.15 mmol) in THF (15 mL); crude purified by flash
column chromatography (0–10% EtOAc in hexane) to give 9bb as a
colorless oil (1.63 g, 8.12 mmol, 89%): 1H NMR (400 MHz, [D6]DMSO): 
= 7.29–7.34 (m, 4H; Ar-H), 7.11–7.21 (m, 1H; Ar-H), 3.66 (t, J = 6.46 Hz,
2H; CH2), 2.99 (t, J = 7.35 Hz, 2H; CH2), 1.80–1.88 (m, 2H; CH2), 1.63–
1.74 ppm (m, 2H; CH2); 13C NMR (101 MHz, [D6]DMSO):  = 136.1, 129.1,
128.0, 125.6, 44.9, 31.1, 31.1, 25.9 ppm.
Prepared according to general procedure B, by reacting thioether 9ac (500
mg, 2.49 mmol) with PhI(OAc)2 (2.01 g, 6.23 mmol) and H2NCO2NH4 (486
mg, 6.23 mmol) in MeOH (4.0 mL); crude purified by flash column
chromatography (0–50% EtOAc in hexane) to give 10ac as a colorless oil
(418 mg, 1.80 mmol, 72%): 1H NMR (400 MHz, [D6]DMSO):  = 7.66–7.74
(m, 2H), 7.47–7.58 (m, 2H), 4.46 (br s, 1H), 3.67 (t, J = 6.59 Hz, 2H), 3.16–
3.32 (m, 2H), 2.41 (s, 3H), 1.90–2.01 ppm (m, 2H); 13C NMR (101 MHz,
[D6]DMSO):  = 141.7, 138.9, 133.5, 129.0, 128.2, 125.2, 54.2, 43.4, 26.7,
20.9 ppm; LC-MS (+ESI) m/z: 232.1 [M+H]+.
[(5-Chloropentyl)sulfanyl]benzene (9cb)
1-[S-(3-Chloropropyl)sulfonimidoyl]-2-methylbenzene (10ad)
Prepared according to general procedure A, by reacting benzenethiol
(1.00 g, 9.08 mmol) with 1-bromo-5-chloropentane (1.32 mL, 9.98 mmol)
and NEt3 (2.53 mL, 18.15 mmol) in THF (15 mL); crude purified by flash
column chromatography (0–10% EtOAc in hexane) to give 9cb as a
colorless oil (1.85 g, 8.67 mmol, 95%): 1H NMR (400 MHz, [D6]DMSO): 
= 7.28–7.41 (m, 4H; Ar-H), 7.10–7.20 (m, 1H; Ar-H), 3.58–3.66 (m, 2H;
CH2), 2.96 (t, J = 7.10 Hz, 2H; CH2), 1.68–1.86 (m, 2H; CH2), 1.46–1.63
ppm (m, 4H; 2×CH2); 13C NMR (101 MHz, [D6]DMSO):  = 136.4, 129.0,
127.9, 125.5, 45.3, 31.8, 31.6, 27.8, 25.5 ppm.
Prepared according to general procedure B, by reacting thioether 9ad (500
mg, 2.49 mmol) with PhI(OAc)2 (2.01 g, 6.23 mmol) and H2NCO2NH4 (486
mg, 6.23 mmol) in MeOH (4.0 mL); crude purified by flash column
chromatography (0–50% EtOAc in hexane) to give 10ad as a yellow oil
(409 mg, 1.77 mmol, 71%): 1H NMR (400 MHz, [D6]DMSO):  = 7.93–7.95
(m, 1H), 7.50–7.58 (m, 1H), 7.38–7.47 (m, 2H), 3.69 (t, J = 6.59 Hz, 2H),
3.23–3.30 (m, 2H), 2.67 (s, 3H), 1.91–1.99 ppm (m, 2H); 13C NMR (101
MHz, [D6]DMSO):  = 139.7, 137.6, 133.0, 132.9, 129.9, 126.5, 52.4, 43.4,
26.6, 20.3 ppm; LC-MS (+ESI) m/z: 232.1 [M+H]+.
Synthesis of acyclic sulfoximines 10 from thioethers 9: General
procedure B
1-[S-(3-Chloropropyl)sulfonimidoyl]-4-fluorobenzene (10ae)
Prepared according to general procedure B, by reacting thioether 9ae (500
mg, 2.44 mmol) with PhI(OAc)2 (1.97 g, 6.11 mmol) and H2NCO2NH4 (479
mg, 6.11 mmol) in MeOH (4.0 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10ae as a yellow oil (460
mg, 1.95 mmol, 80%): 1H NMR (400 MHz, [D6]DMSO):  = 7.93–7.99 (m,
2H), 7.43–7.50 (m, 2H), 3.62–3.71 (m, 2H), 3.21–3.37 (m, 2H), 1.91–2.02
ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  = 165.9, 163.4, 137.8,
131.3, 131.2, 116.4, 116.2, 54.2, 43.3, 26.7 ppm; LC-MS (+ESI) m/z: 236.1
[M+H]+.
In an open flask, MeOH was added to thioether
9 (1.0 equiv),
(diacetoxyiodo)benzene [PhI(OAc)2] (2.5 equiv), and ammonium
carbamate (H2NCO2NH4) (2.0–2.5 equiv). The mixture was stirred at RT
for 2 h. When all starting material had been consumed (monitored by TLC
and UPLC-MS), saturated aqueous NaHCO3 and EtOAc were added, and
the mixture was stirred for 5 min. The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 ×). The organic phases were
combined and dried by filtration through water-repellent filter paper. The
volatiles were removed under reduced pressure and the crude product was
purified by flash column chromatography to afford the desired acyclic
sulfoximine 10.
1-[S-(3-Chloropropyl)sulfonimidoyl]-2-fluorobenzene (10af)
Prepared according to general procedure B, by reacting thioether 9af (500
mg, 2.44 mmol) with PhI(OAc)2 (1.97 g, 6.11 mmol) and H2NCO2NH4 (479
mg, 6.11 mmol) in MeOH (4.00 mL); crude purified by flash column
chromatography (0–50% EtOAc in hexane) to give 10af as a colorless oil
(352 mg, 1.49 mmol, 61%): 1H NMR (400 MHz, [D6]DMSO):  = 7.85 (t,
J = 7.69 Hz, 1H), 7.69–7.78 (m, 1H), 7.40–7.50 (m, 2H), 4.90 (br s, 1H),
[S-(3-Chloropropyl)sulfonimidoyl]benzene (10ab)
Prepared according to general procedure B, by reacting thioether 9ab (500
mg, 2.68 mmol) with PhI(OAc)2 (2.16 g, 6.70 mmol) and H2NCO2NH4 (418
mg, 5.36 mmol) in MeOH (4.3 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10ab as a yellow oil (468
mg, 2.15 mmol, 80%): 1H NMR (400 MHz, [D6]DMSO):  = 7.84–7.91 (m,
2H), 7.60–7.73 (m, 3H), 3.78–3.82 (m, 1H), 3.58–3.70 (m, 1H), 3.35–3.43
(m, 2H), 2.15–2.33 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  =
140.3, 133.3, 129.3, 128.9, 55.9, 55.4, 25.7 ppm; LC-MS (+ESI) m/z: 218.1
[M+H]+.
3.71 (t, J = 6.59 Hz, 2H), 3.30–3.45 (m, 2H), 1.95–2.05 ppm (m, 2H); 13
C
NMR (101 MHz, [D6]DMSO):  = 160.0, 157.5, 135.8, 135.7, 130.5, 130.0,
129.9, 125.0, 124.9, 117.4, 117.2, 53.1, 53.1, 43.3, 26.5 ppm; LC-MS
(+ESI) m/z: 236.1 [M+H]+.
1-[S-(3-Chloropropyl)sulfonimidoyl]-4-nitrobenzene (10ag)
1-[S-(3-Chloropropyl)sulfonimidoyl]-4-methylbenzene (10aa)
Prepared according to general procedure B, by reacting commercially
available 1-[(3-chloropropyl)sulfanyl]-4-nitrobenzene (9ag; 2.00 g, 8.63
mmol) with PhI(OAc)2 (6.95 g, 21.58 mmol) and H2NCO2NH4 (1.35 g,
17.26 mmol) in MeOH (17.2 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10ag as a yellow solid
(2.20 g, 8.37 mmol, 97%): 1H NMR (400 MHz, [D6]DMSO):  = 8.36–8.52
(m, 2H), 8.04–8.24 (m, 2H), 4.80 (br s, 1H), 3.68 (t, J = 6.59 Hz, 2H), 3.28–
3.40 (m, 2H), 1.91–2.07 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO): 
= 150.0, 147.8, 129.7, 124.4, 53.8, 43.2, 26.6 ppm; LC-MS (+ESI) m/z:
263.1 [M+H]+.
Prepared according to general procedure B, by reacting thioether 9aa (500
mg, 2.49 mmol) with PhI(OAc)2 (2.01 g, 6.23 mmol) and H2NCO2NH4 (389
mg, 4.98 mmol) in MeOH (4.0 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10aa as an orange oil (521
mg, 2.25 mmol, 90%): 1H NMR (400 MHz, [D6]DMSO):  = 7.69–7.84 (m,
2H), 7.35–7.57 (m, 2H), 4.45 (br s, 1H), 3.58–3.71 (m, 2H), 3.14–3.27 (m,
2H), 2.40 (s, 3H), 1.89–2.02 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):
 = 143.3, 138.8, 129.7, 129.3, 128.1, 54.3, 43.3, 26.9, 21.0 ppm; HRMS
(+ESI): m/z calcd for C10H15ClNOS [M+H]+: 232.0563, found: 232.0565.
1-Bromo-3-[S-(3-chloropropyl)sulfonimidoyl]benzene (10ah)
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Prepared according to general procedure B, by reacting thioether 9ah (500
mg, 1.88 mmol) with PhI(OAc)2 (1.52 g, 4.71 mmol) and H2NCO2NH4 (294
mg, 3.77 mmol) in MeOH (3.2 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10ah as a yellow oil (531
mg, 1.80 mmol, 95%): 1H NMR (400 MHz, [D6]DMSO):  = 8.02 (t, J = 1.77
Hz, 1H), 7.85–7.93 (m, 2H), 7.59 (t, J = 7.86 Hz, 1H), 4.60 (br s, 1H), 3.68
(t, J = 6.59 Hz, 2H), 3.25–3.33 (m, 2H), 1.90–2.03 ppm (m, 2H); 13C NMR
(101 MHz, [D6]DMSO):  = 144.3, 135.7, 131.4, 130.5, 127.1, 122.1, 53.8,
43.3, 26.6 ppm; LC-MS (+ESI) m/z: 297.9 [M+H]+.
chromatography (0–10% EtOH in DCM) to give 10am as a yellow oil (331
mg, 1.23 mmol, 61%): 1H NMR (400 MHz, [D6]DMSO):  = 9.08 (dd,
J = 1.77, 4.06 Hz, 1H), 8.56 (dd, J = 1.77, 8.36 Hz, 1H), 8.41 (dd, J = 1.52,
7.35 Hz, 1H), 8.31 (dd, J = 1.39, 8.24 Hz, 1H), 7.80 (t, J = 7.73 Hz, 1H),
7.69–7.74 (m, 1H), 4.52 (s, 1H), 3.92 (t, J = 7.60 Hz, 2H), 3.67 (t, J = 6.46
Hz, 2H), 1.90–2.08 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  =
151.3, 143.2, 138.3, 137.2, 134.1, 130.9, 128.7, 125.8, 122.5, 53.1, 43.6,
26.5 ppm; LC-MS (+ESI) m/z: 269.0 [M+H]+.
3-[S-(3-Chloropropyl)sulfonimidoyl]estra-1(10),2,4-trien-17-one (1:1
1-[S-(3-Chloropropyl)sulfonimidoyl]-2-iodobenzene (10ai)
mixture of diastereomers) (10an)
Prepared according to general procedure B, by reacting thioether 9ai (270
mg, 0.86 mmol) with PhI(OAc)2 (696 mg, 2.16 mmol) and H2NCO2NH4
(135 mg, 1.73 mmol) in MeOH (1.5 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10ai as a yellow oil (120
mg, 0.35 mmol, 40%): 1H NMR (400 MHz, [D6]DMSO):  = 8.10–8.21 (m,
2H), 7.64 (dt, J = 1.14, 7.67 Hz, 1H), 7.33 (dt, J = 1.65, 7.54 Hz, 1H), 3.70
(t, J = 6.34 Hz, 2H), 3.44–3.58 (m, 2H), 1.91–2.01 ppm (m, 2H); 13C NMR
(101 MHz, [D6]DMSO):  = 143.7, 142.8, 133.9, 131.0, 128.8, 95.0, 50.3,
43.5, 26.4 ppm; LC-MS (+ESI) m/z: 344.0 [M+H]+.
Prepared according to general procedure B, by reacting thioether 9an (660
mg, 1.82 mmol) with PhI(OAc)2 (1.46 g, 4.55 mmol) and H2NCO2NH4 (284
mg, 3.64 mmol) in MeOH (3.1 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give a 1:1 diastereomeric
mixture of 10an as a yellow solid (630 mg, 1.60 mmol, 88%): 1H NMR (400
MHz, [D6]DMSO):  = 7.58–7.65 (m, 2H), 7.50–7.55 (m, 1H), 3.68 (t,
J = 6.59 Hz, 2H), 3.22–3.30 (m, 2H), 2.91–2.99 (m, 2H), 2.30–2.47 (m, 3H),
1.90–2.12 (m, 5H), 1.71–1.88 (m, 1H), 1.36–1.64 (m, 6H), 0.84 ppm (s,
3H); 13C NMR (101 MHz, [D6]DMSO):  = 219.5, 145.1, 138.6, 137.6, 128.3,
126.2, 125.3, 54.1, 49.6, 47.3, 44.0, 43.4, 37.1, 35.4, 31.3, 28.9, 26.7, 25.6,
25.2, 21.2, 13.5 ppm; LC-MS (+ESI) m/z: 394.2 [M+H]+.
4-[S-(3-Chloropropyl)sulfonimidoyl]benzonitrile (10aj)
[S-(4-Chlorobutyl)sulfonimidoyl]benzene (10bb)
Prepared according to general procedure B, by reacting thioether 9aj (500
mg, 2.36 mmol) with PhI(OAc)2 (1.90 g, 5.90 mmol) and H2NCO2NH4 (369
mg, 4.72 mmol) in MeOH (4.0 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10aj as a yellow oil (370
mg, 1.55 mmol, 66%): 1H NMR (400 MHz, [D6]DMSO):  = 8.04–8.18 (m,
4H), 3.59–3.71 (m, 2H), 3.29–3.43 (m, 2H), 1.91–2.01 ppm (m, 2H); 13C
NMR (101 MHz, [D6]DMSO):  = 146.3, 133.3, 128.9, 117.9, 115.3, 53.6,
43.2, 26.5 ppm; LC-MS (+ESI) m/z: 243.1 [M+H]+.
Prepared according to general procedure B, by reacting thioether 9bb (500
mg, 2.49 mmol) with PhI(OAc)2 (2.00 g, 6.23 mmol) and H2NCO2NH4 (486
mg, 6.23 mmol) in MeOH (4.3 mL); crude purified by flash column
chromatography (0–50% EtOAc in hexane) to give 10bb as a yellow oil
(305 mg, 1.32 mmol, 53%): 1H NMR (400 MHz, [D6]DMSO):  = 7.89 (d,
J = 7.70 Hz, 2H), 7.58–7.69 (m, 3H), 4.24 (br s, 1H), 3.60 (t, J = 6.34 Hz,
2H), 3.13–3.22 (m, 2H), 1.59–1.77 ppm (m, 4H); 13C NMR (101 MHz,
[D6]DMSO):  = 142.2, 132.7, 129.1, 128.0, 55.7, 44.8, 30.3, 20.6 ppm;
LC-MS (+ESI) m/z: 232.1 [M+H]+.
Methyl 4-[S-(3-chloropropyl)sulfonimidoyl]benzoate (10ak)
Prepared according to general procedure B, by reacting thioether 9ak (500
mg, 2.04 mmol) with PhI(OAc)2 (1.75 g, 5.42 mmol) and H2NCO2NH4 (338
mg, 4.33 mmol) in MeOH (3.6 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10ak as a yellow oil (390
mg, 1.41 mmol, 69%): 1H NMR (400 MHz, [D6]DMSO):  = 8.12–8.20 (m,
2H), 8.02–8.07 (m, 2H), 4.60 (br s, 1H), 3.83–3.91 (s, 3H), 3.67 (t, J = 6.59
Hz, 2H), 3.20–3.34 (m, 2H), 1.91–2.02 ppm (m, 2H); 13C NMR (101 MHz,
[D6]DMSO):  = 165.3, 146.0, 133.3, 129.9, 128.6, 53.9, 52.7, 43.3, 26.6
ppm; LC-MS (+ESI) m/z: 276.0 [M+H]+.
[S-(5-Chloropentyl)sulfonimidoyl]benzene (10cb)
Prepared according to general procedure B, by reacting thioether 9cb
(1.00 g, 4.66 mmol) with PhI(OAc)2 (3.75 g, 11.64 mmol) and H2NCO2NH4
(727 mg, 9.31 mmol) in MeOH (7.5 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10cb as a yellow oil (1.10
g, 4.48 mmol, 96%): 1H NMR (400 MHz, [D6]DMSO):  = 7.89 (d, J = 7.33
Hz, 2H), 7.58–7.69 (m, 3H), 4.20 (s, 1H), 3.55 (t, J = 6.59 Hz, 2H), 3.10–
3.17 (m, 2H), 1.48–1.68 (m, 4H), 1.33–1.43 ppm (m, 2H); 13C NMR (101
MHz, [D6]DMSO):  = 142.2, 132.6, 129.0, 128.0, 56.4, 45.1, 31.5, 24.9,
22.4 ppm; LC-MS (+ESI) m/z: 246.1 [M+H]+.
5-[S-(3-Chloropropyl)sulfonimidoyl]-1,3-benzodioxole (10al)
Prepared according to general procedure B, by reacting thioether 9al (500
mg, 2.17 mmol) with PhI(OAc)2 (1.75 g, 5.42 mmol) and H2NCO2NH4 (338
mg, 4.33 mmol) in MeOH (3.6 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 10al as a yellow oil (540
mg, 2.06 mmol, 95%): 1H NMR (400 MHz, [D6]DMSO):  = 7.42 (dd,
J = 1.77, 8.11 Hz, 1H), 7.33 (d, J = 1.77 Hz, 1H), 7.11 (d, J = 8.11 Hz, 1H),
6.18 (s, 2H), 4.28 (s, 1H), 3.67 (t, J = 6.59 Hz, 2H), 3.17–3.26 (m, 2H),
1.90–1.99 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  = 152.4, 148.3,
130.6, 124.9, 108.7, 108.2, 103.0, 53.4, 43.0, 26.3 ppm; LC-MS (+ESI)
m/z: 262.0 [M+H]+.
Synthesis of cyclic sulfoximines 3 by the cyclization of acyclic
sulfoximines 10 in aqueous NH3: General procedure C
The acyclic sulfoximine 10 was dissolved in aqueous 0.1% NH3. The
mixture was stirred for 1–2 h at 80 °C in a sealed microwave vial. The
cooled reaction mixture was neutralized by the addition of saturated
aqueous NaHCO3 and then concentrated to dryness under reduced
pressure. The residue was purified by flash column chromatography to
afford the desired cyclic sulfoximine 3.
8-[S-(3-Chloropropyl)sulfonimidoyl]quinoline (10am)
1-Phenyl-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ab)
Prepared according to general procedure B, by reacting thioether 9am
(480 mg, 2.02 mmol) with PhI(OAc)2 (1.63 g, 5.05 mmol) and H2NCO2NH4
(315 mg, 4.04 mmol) in MeOH (3.4 mL); crude purified by flash column
Prepared according to general procedure C, from acyclic sulfoximine 10ab
(100 mg, 0.46 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ab as a yellow oil
This article is protected by copyright. All rights reserved.

10.1002/chem.201905461
Chemistry - A European Journal
FULL PAPER
(64 mg, 0.35 mmol, 77%): 1H NMR (400 MHz, [D6]DMSO):  = 7.84–7.88
(m, 2H), 7.59–7.74 (m, 3H), 3.78–3.84 (m, 1H), 3.65–3.69 (m, 1H), 3.35–
3.43 (m, 2H), 2.16–2.33 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO): 
= 140.4, 133.3, 129.3, 128.8, 55.9, 55.5, 25.8 ppm; IR (ATR):  = 3062,
2937, 2860, 1447, 1332, 1205, 1105, 902 cm–1; HRMS (+ESI): m/z calcd
for C9H12NOS [M+H]+: 182.0640, found: 182.0638.
(68 mg, 0.34 mmol, 80%): 1H NMR (400 MHz, [D6]DMSO):  = 7.88 (dt,
J = 1.77, 7.60 Hz, 1H), 7.75 (dddd, J = 1.90, 5.32, 7.32, 8.27 Hz, 1H),
7.25–7.57 (m, 2H), 3.73–3.90 (m, 1H), 3.58 (br d, J = 1.27 Hz, 1H), 3.38–
3.51 (m, 2H), 2.10–2.29 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO): 
= 160.1, 157.6, 135.9, 135.8, 129.9, 129.3, 129.1, 124.9, 124.9, 117.4,
117.2, 54.5, 54.5, 25.2 ppm; IR (ATR):  = 2922, 2862, 1597, 1469, 1205,
1095, 761 cm–1 HRMS (+ESI): m/z calcd for C9H11FNOS [M+H]+:
;
1-(4-Methylphenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3aa)
200.0545, found: 200.0545.
1-(4-Nitrophenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ag)
Prepared according to general procedure C, from acyclic sulfoximine 10aa
(100 mg, 0.43 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3aa as a yellow oil
(61 mg, 0.31 mmol, 73%): 1H NMR (400 MHz, [D6]DMSO):  = 7.73 (d,
J = 7.84 Hz, 2H), 7.43 (d, J = 7.77 Hz, 2H), 3.78 (ddd, J = 5.32, 6.65, 10.33
Hz, 1H), 3.60–3.71 (m, 1H), 3.31–3.40 (m, 2H), 2.41 (s, 3H), 2.13–2.30
ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  = 143.7, 137.4, 129.7,
128.9, 56.0, 55.4, 25.8, 21.0 ppm; IR (ATR):  = 3572, 3060, 2923, 2854,
1595, 1201, 1101, 900, 812 cm–1; HRMS (+ESI): m/z calcd for C10H14NOS
[M+H]+: 196.0796, found: 196.0793.
Prepared according to general procedure C, from acyclic sulfoximine 10ag
(100 mg, 0.38 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ag as a colorless
solid (77 mg, 0.34 mmol, 89%): 1H NMR (400 MHz, [D6]DMSO):  = 8.35–
8.48 (m, 2H), 8.12 (d, J = 9.12 Hz, 2H), 3.78–3.95 (m, 1H), 3.62–3.74 (m,
1H), 3.41–3.59 (m, 2H), 2.14–2.39 ppm (m, 2H); 13C NMR (101 MHz,
[D6]DMSO):  = 150.3, 146.6, 130.4, 124.4, 55.7, 55.6, 25.7 ppm; IR
(ATR):  = 3099, 2934, 2874, 1514, 1339, 1204, 1097, 905 cm–1; HRMS
(+ESI): m/z calcd for C9H11N2O3S [M+H]+: 227.0490, found: 227.0487.
1-(3-Methylphenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ac)
1-(3-Bromophenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ah)
Prepared according to general procedure C, from acyclic sulfoximine 10ac
(100 mg, 0.43 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ac as a yellow oil
(80 mg, 0.41 mmol, 94%): 1H NMR (400 MHz, [D6]DMSO):  = 7.63–7.72
(m, 2H), 7.49–7.53 (m, 2H), 3.80 (ddd, J = 5.20, 6.59, 10.27 Hz, 1H), 3.66
(td, J = 6.56, 10.20 Hz, 1H), 3.31–3.39 (m, 2H), 2.41 (s, 3H), 2.14–2.34
ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  = 140.3, 139.0, 133.9,
129.1, 129.0, 126.0, 55.9, 55.4, 25.7, 20.8 ppm; IR (ATR):  = 3666, 2773,
1595, 1197, 1095, 900, 707 cm–1; HRMS (+ESI): m/z calcd for C10H14NOS
[M+H]+: 196.0796, found: 196.0791.
Prepared according to general procedure C, from acyclic sulfoximine 10ah
(520 mg, 1.75 mmol) in aqueous 0.1% NH3 (8 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ah as a yellow oil
(250 mg, 0.96 mmol, 55%): 1H NMR (400 MHz, [D6]DMSO):  = 7.79–8.06
(m, 3H), 7.51–7.66 (m, 1H), 3.76–3.90 (m, 1H), 3.59–3.72 (m, 1H), 3.34–
3.57 (m, 2H), 2.02–2.30 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO): 
= 142.8, 136.1, 131.4, 131.1, 128.0, 122.1, 55.7, 55.5, 25.6 ppm; IR (ATR):
 = 2933, 2854, 1568, 1402, 1203, 1103, 902, 765 cm–1; HRMS (+ESI):
m/z calcd for C9H11BrNOS [M+H]+: 259.9745, found: 259.9757.
1-(2-Methylphenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ad)
1-(2-Iodophenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ai)
Prepared according to general procedure C, from acyclic sulfoximine 10ad
(100 mg, 0.43 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ad as a yellow oil
(66 mg, 0.34 mmol, 78%): 1H NMR (400 MHz, [D6]DMSO):  = 7.86–8.01
(m, 1H), 7.50–7.64 (m, 1H), 7.43 (s, 2H), 3.76–3.91 (m, 1H), 3.42 (s, 3H),
2.59 (s, 3H), 1.96–2.35 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  =
139.4, 137.7, 133.0, 132.5, 128.6, 126.3, 54.2, 54.0, 25.3, 20.1 ppm; IR
(ATR):  = 2927, 2852, 1458, 1205, 1095, 904, 763 cm–1; HRMS (+ESI):
m/z calcd for C10H14NOS [M+H]+: 196.0796, found: 196.0791.
Prepared according to general procedure C, from acyclic sulfoximine 10ai
(120 mg, 0.35 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ai as a yellow oil
(105 mg, 0.34 mmol, 98%): 1H NMR (400 MHz, [D6]DMSO):  = 8.14 (ddd,
J = 1.39, 7.79, 15.91 Hz, 2H), 7.54–7.70 (m, 1H), 7.26–7.43 (m, 1H), 3.86–
3.99 (m, 1H), 3.44–3.64 (m, 3H), 2.10–2.37 ppm (m, 2H); 13C NMR (101
MHz, [D6]DMSO):  = 143.3, 142.2, 134.1, 130.5, 128.6, 95.7, 54.3, 53.1,
25.1 ppm; IR (ATR):  = 2922, 2866, 1562, 1201, 1095, 904, 763 cm–1
;
HRMS (+ESI): m/z calcd for C9H11INOS [M+H]+: 307.9606, found:
307.9602.
1-(4-Fluorophenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ae)
4-(1-Oxido-4,5-dihydro-3H-14,2-thiazol-1-yl)benzonitrile (3aj)
Prepared according to general procedure C, from acyclic sulfoximine 10ae
(100 mg, 0.42 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ae as a yellow oil
(55 mg, 0.28 mmol, 65%): 1H NMR (400 MHz, [D6]DMSO):  = 7.82–8.04
(m, 2H), 7.46 (t, J = 8.87 Hz, 2H), 3.73–3.89 (m, 1H), 3.58–3.71 (m, 1H),
3.34–3.48 (m, 2H), 2.11–2.33 ppm (m, 2H); 13C NMR (101 MHz,
[D6]DMSO):  = 166.2, 163.7, 136.6, 136.5, 132.1, 132.0, 116.5, 116.3,
55.9, 55.3, 25.7 ppm; IR (ATR):  = 2814, 1575, 1479, 1199, 1101, 808,
682 cm–1; HRMS (+ESI): m/z calcd for C9H11FNOS [M+H]+: 200.0545,
found: 200.0542.
Prepared according to general procedure C, from acyclic sulfoximine 10aj
(100 mg, 0.41 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3aj as a colorless
oil (60 mg, 0.29 mmol, 71%): 1H NMR (400 MHz, [D6]DMSO):  = 7.81–
8.04 (m, 3H), 7.59 (t, J = 7.86 Hz, 1H), 3.75–3.90 (m, 1H), 3.59–3.73 (m,
1H), 3.37–3.54 (m, 2H), 2.06–2.32 ppm (m, 2H); 13C NMR (101 MHz,
[D6]DMSO):  = 145.3, 133.3, 129.5, 117.8, 115.6, 55.6, 55.5, 25.7 ppm;
IR (ATR):  = 2853, 2233, 1201, 1097, 929, 692 cm–1; HRMS (+ESI): m/z
calcd for C10H11N2OS [M+H]+: 207.0592, found: 207.0597.
1-(2-Fluorophenyl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3af)
Methyl 4-(1-oxido-4,5-dihydro-3H-14,2-thiazol-1-yl)benzoate (3ak)
Prepared according to general procedure C, from acyclic sulfoximine 10af
(100 mg, 0.42 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3af as a yellow oil
Prepared according to general procedure C, from acyclic sulfoximine 10ak
(100 mg, 0.36 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3ak as a yellow oil
This article is protected by copyright. All rights reserved.

10.1002/chem.201905461
Chemistry - A European Journal
FULL PAPER
(70 mg, 0.29 mmol, 81%): 1H NMR (400 MHz, [D6]DMSO):  = 8.10–8.24
(m, 2H), 7.87–8.05 (m, 2H), 3.90 (s, 3H), 3.79–3.88 (m, 1H), 3.59–3.74 (m,
1H), 3.36–3.56 (m, 2H), 2.16–2.36 ppm (m, 2H); 13C NMR (101 MHz,
[D6]DMSO):  = 165.3, 144.9, 133.6, 129.9, 129.2, 55.7, 55.6, 52.7, 25.7
ppm; IR (ATR):  = 2949, 2860, 1720, 1434, 1274, 1203, 902 cm–1; HRMS
(+ESI): m/z calcd for C11H14NO3S [M+H]+: 240.0694, found: 240.0696.
Synthesis of cyclic sulfoximines
method): General procedure D
3 from thioethers 9 (one-pot
In an open flask, MeOH was added to thioether 9 (1.0 equiv), PhI(OAc)2
(2.5 equiv), and H2NCO2NH4 (2.0 equiv). The mixture was stirred at RT for
2 h. When all starting material had been consumed (monitored by TLC and
UPLC-MS), the reaction mixture was stirred at 80 °C in a closed
microwave vial. After full conversion of the intermediate acyclic sulfoximine
10 (monitored by TLC and UPLC-MS), the reaction mixture was cooled to
RT and saturated aqueous NaHCO3 and EtOAc were added. The mixture
was stirred for 5 min. The organic layer was separated and the aqueous
layer was extracted with EtOAc (3 ×). The organic phases were combined
and dried by filtration through water-repellent filter paper. The volatiles
were removed under reduced pressure and the crude product was purified
by flash column chromatography to afford the desired cyclic sulfoximine 3.
1-(1,3-Benzodioxol-5-yl)-4,5-dihydro-3H-14,2-thiazole 1-oxide (3al)
Prepared according to general procedure C, from acyclic sulfoximine 10al
(190 mg, 0.73 mmol) in aqueous 0.1% NH3 (4 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3al as a colorless
oil (130 mg, 0.58 mmol, 80%): 1H NMR (400 MHz, [D6]DMSO):  = 7.41
(dd, J = 1.90, 8.24 Hz, 1H), 7.27 (d, J = 1.77 Hz, 1H), 7.11 (d, J = 8.36 Hz,
1H), 6.18 (s, 2H), 3.70–3.83 (m, 1H), 3.58–3.68 (m, 1H), 3.22–3.42 (m,
2H), 2.07–2.34 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  = 151.6,
148.0, 133.3, 124.8, 108.5, 108.3, 102.7, 56.0, 55.2, 25.7 ppm; IR (ATR):
 = 2841, 1477, 1190, 1068, 1039, 858, 730 cm–1; HRMS (+ESI): m/z calcd
for C10H12NO3S [M+H]+: 226.0538, found: 226.0537.
4-Methyl-1-phenyl-4,5-dihydro-3H-14,2-thiazole 1-oxide (1:1 mixture
of diastereomers) (3ao)
Prepared according to general procedure D, by reacting thioether 9ao (200
mg, 1.00 mmol) with PhI(OAc)2 (802 mg, 2.49 mmol) and H2NCO2NH4
(156 mg, 1.99 mmol) in MeOH (2 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give a 1:1 diastereomeric
mixture of 3ao as a yellow oil (150 mg, 0.77 mmol, 77%): 1H NMR (400
MHz, [D6]DMSO):  = 7.80–7.95 (m, 4H), 7.54–7.77 (m, 6H), 3.85–3.98 (m,
1H), 3.72–3.85 (m, 1H), 3.60–3.71 (m, 1H), 3.46–3.60 (m, 1H), 3.37–3.46
(m, 1H), 3.16–3.27 (m, 1H), 2.98–3.14 (m, 2H), 2.66–2.83 (m, 1H), 2.54–
2.66 (m, 1H), 1.04–1.20 ppm (m, 6H); 13C NMR (101 MHz, [D6]DMSO): 
= 141.0, 140.5, 133.2, 129.3, 129.2, 128.8, 128.7, 62.8, 62.6, 62.3, 62.2,
35.6, 33.7, 17.3, 17.0 ppm; IR (ATR):  = 2960, 2850, 1446, 1211, 1105,
893, 734, 628 cm–1; HRMS (+ESI): m/z calcd for C10H14NOS [M+H]+:
196.0796, found: 196.0795.
8-(1-Oxido-4,5-dihydro-3H-14,2-thiazol-1-yl)quinoline (3am)
Prepared according to general procedure C, from acyclic sulfoximine
10am (110 mg, 0.41 mmol) in aqueous 0.1% NH3 (2 mL); crude purified
by flash column chromatography (0–10% EtOH in DCM) to give 3am as a
yellow oil (70 mg, 0.30 mmol, 73%): 1H NMR (400 MHz, [D6]DMSO):  =
9.07 (dd, J = 1.65, 4.18 Hz, 1H), 8.55 (dd, J = 1.52, 8.36 Hz, 1H), 8.43 (dd,
J = 1.27, 7.35 Hz, 1H), 8.31 (dd, J = 1.14, 8.24 Hz, 1H), 7.78 (t, J = 7.68
Hz, 1H), 7.69–7.74 (m, 1H), 3.83–3.93 (m, 2H), 3.46–3.62 (m, 2H), 2.17–
2.42 ppm (m, 2H); 13C NMR (101 MHz, [D6]DMSO):  = 151.3, 143.3, 138.8,
137.0, 133.7, 130.4, 128.8, 125.8, 122.5, 54.7, 54.1, 25.1 ppm; IR (ATR):
 = 3572, 2937, 2862, 1490, 1191, 1085, 902, 786 cm–1; HRMS (+ESI):
m/z calcd for C12H13N2OS [M+H]+: 233.0749, found: 233.0750.
1-Phenyl-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ab)
3-(1-Oxido-4,5-dihydro-3H-14,2-thiazol-1-yl)estra-1(10),2,4-trien-17-
one (1:1 mixture of diastereomers) (3an)
Prepared according to general procedure D, by reacting thioether 9ab
(1.32 g, 7.07 mmol) with PhI(OAc)2 (5.69 g, 17.67 mmol) and H2NCO2NH4
(1.10 g, 14.14 mmol) in MeOH (11.4 mL); crude purified by flash column
chromatography (0–10% EtOH in DCM) to give 3ab as a yellow oil (1.17
g, 6.43 mmol, 91%). NMR data consistent with the data listed for 3ab
prepared from 10ab according to general procedure C.
Prepared according to general procedure C, from acyclic sulfoximine 10an
(130 mg, 0.33 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give
a 1:1
diastereomeric mixture of 3an as a colorless solid (87 mg, 0.24 mmol,
73%): 1H NMR (400 MHz, [D6]DMSO):  = 7.51–7.63 (m, 3H), 3.74–3.81
(m, 1H), 3.62–3.70 (m, 1H), 3.15–3.31 (m, 2H), 2.91–2.99 (m, 2H), 2.40–
2.48 (m, 2H), 2.30–2.38 (m, 1H), 2.03–2.28 (m, 3H), 1.94–2.01 (m, 2H),
1.71–1.86 (m, 1H), 1.23–1.63 (m, 6H), 0.83 ppm (s, 3H); 13C NMR (101
MHz, [D6]DMSO):  = 219.6, 145.5, 145.5, 137.8, 137.3, 129.1, 129.1,
128.4, 126.1, 126.1, 56.0, 55.4, 49.6, 47.3, 44.0, 37.1, 35.4, 31.3, 28.8,
25.8, 25.6, 25.2, 25.2, 21.2, 13.5 ppm; IR (ATR):  = 2926, 2856, 1732,
1404, 1203, 1082, 902 cm–1; HRMS (+ESI): m/z calcd for C21H28NO2S
[M+H]+: 358.1841, found: 358.1845.
Synthesis of cyclic sulfoximines 3 by the cyclization of acyclic
sulfoximines 10: Alternative procedures
1-Phenyl-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ab)
Under argon, NaH (13 mg, 0.55 mmol) was added to a solution of acyclic
sulfoximine 10ab (100 mg, 0.46 mmol) in DMF (1.9 mL) at RT. The reaction
mixture was stirred at RT for 2 h, then quenched with H2O and extracted
with EtOAc (3 ×). The organic phases were combined and dried by
filtration through water-repellent filter paper. The volatiles were removed
under reduced pressure and the crude product was purified by flash
column chromatography (0–10% EtOH in DCM) to afford 3ab as a yellow
oil (57 mg, 0.32 mmol, 68%). NMR data consistent with the data listed for
3ab prepared from 10ab according to general procedure C.
1-Phenyl-3,4,5,6-tetrahydro-14,2-thiazine 1-oxide (3bb)
Prepared according to general procedure C, from acyclic sulfoximine 10bb
(100 mg, 0.43 mmol) in aqueous 0.1% NH3 (2 mL); crude purified by flash
column chromatography (0–10% EtOH in DCM) to give 3bb as a yellow oil
(70 mg, 0.36 mmol, 83%): 1H NMR (400 MHz, [D6]DMSO):  = 7.93–8.03
(m, 2H), 7.68–7.76 (m, 1H), 7.58–7.66 (m, 2H), 3.37–3.48 (m, 1H), 3.24–
3.32 (m, 1H), 3.11–3.21 (m, 1H), 2.99–3.10 (m, 1H), 2.19–2.37 (m, 1H),
2.05–2.17 (m, 1H), 1.57–1.75 ppm (m, 2H); 13C NMR (101 MHz,
[D6]DMSO):  = 139.8, 133.2, 129.2, 127.8, 50.6, 43.2, 23.1, 21.2 ppm; IR
(ATR):  = 2925, 2862, 1440, 1217, 1116, 730, 599 cm–1; HRMS (+ESI):
m/z calcd for C10H14NOS [M+H]+: 196.0796, found: 196.0794.
1-Phenyl-4,5-dihydro-3H-14,2-thiazole 1-oxide (3ab)
Under argon, KOH (52 mg, 0.92 mmol) was added to a solution of acyclic
sulfoximine 10ab (100 mg, 0.46 mmol) in DMSO (1.9 mL) at RT. The
reaction mixture was stirred at RT for 2 h, then diluted with H2O and
extracted with EtOAc (3 ×). The organic phases were combined and dried
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by filtration through water-repellent filter paper. The volatiles were
removed under reduced pressure and the crude product was purified by
flash column chromatography (0–10% EtOH in DCM) to afford 3ab as a
yellow oil (52 mg, 0.29 mmol, 63%). NMR data consistent with the data
listed for 3ab prepared from 10ab according to general procedure C.
[3]
[4]
U. Lücking, R. Jautelat, M. Krüger, T. Brumby, P. Lienau, M. Schäfer, H.
Briem, J. Schulze, A. Hillisch, A. Reichel, A. M. Wengner, G. Siemeister,
ChemMedChem 2013, 8, 1067.
U. Lücking, A. Scholz, P. Lienau, G. Siemeister, D. Kosemund, R.
Bohlmann, H. Briem, I. Terebesi, K. Meyer, K. Prelle, K. Denner, U.
Bömer, M. Schäfer, K. Eis, R. Valencia, S. Ince, F. von Nussbaum, D.
Mumberg, K. Ziegelbauer, B. Klebl, A. Choidas, P. Nussbaumer, M.
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1-Phenyl-4,5,6,7-tetrahydro-3H-14,2-thiazepine 1-oxide (3cb)
Under argon, NaH (23 mg, 0.98 mmol) was added to a solution of acyclic
sulfoximine 10cb (200 mg, 0.81 mmol) in DMF (4 mL) at RT. The reaction
mixture was stirred at 50 °C overnight. After cooling, the reaction mixture
was quenched with H2O and extracted with EtOAc (3 ×). The organic
phases were combined and dried by filtration through water-repellent filter
paper. The volatiles were removed under reduced pressure and the crude
product was purified by flash column chromatography (0–5% EtOH in
DCM) to afford 3cb as a yellow oil (130 mg, 0.62 mmol, 76%): 1H NMR
(400 MHz, [D6]DMSO):  = 7.93–8.07 (m, 2H), 7.55–7.74 (m, 3H), 3.44–
3.60 (m, 2H), 3.35–3.43 (m, 1H), 3.09–3.28 (m, 1H), 1.76–1.92 (m, 2H),
1.38–1.76 ppm (m, 4H); 13C NMR (101 MHz, [D6]DMSO):  = 139.9, 132.8,
129.1, 128.4, 58.8, 44.1, 32.4, 29.9, 22.5 ppm; IR (ATR):  = 2916, 2844,
1444, 1276, 1126, 908, 752, 688 cm–1; HRMS (+ESI): m/z calcd for
C11H16NOS [M+H]+: 210.0953, found: 210.0952.
[5]
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U. T. Luecking, A. Scholz, D. Kosemund, R. Bohlmann, H. Briem, P.
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Under argon, KOH (91 mg, 1.63 mmol) was added to a solution of acyclic
sulfoximine 10cb (200 mg, 0.81 mmol) in DMSO (3.8 mL) at RT. The
reaction mixture was stirred at RT overnight, then diluted with H2O and
extracted with EtOAc (3 ×). The organic phases were combined and dried
by filtration through water-repellent filter paper. The volatiles were
removed under reduced pressure and the crude product was purified by
flash column chromatography (0–5% EtOH in DCM) to afford 3cb as a
yellow oil (90 mg, 0.43 mmol, 53%). NMR data consistent with the data
listed above for 3cb prepared from 10cb with NaH in DMF.
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Acknowledgements
We thank M. Bergmann and K. Greenfield for valuable technical
support with the manuscript and S. Gründemann for support with
analytical data.
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Corporation Application Note AN1731EN00, 2003.
Conflict of interest
[18] For the assay description, see: U. Lücking, P. Wasnaire, A. Scholz, P.
Lienau, G. Siemeister, C. Stegmann, U. Bömer, K. Zheng, P. Gao, G.
Chen, J. Xi (Bayer Schering Pharma Aktiengesellschaft), WO
2015155197, 2015.
The authors declare no conflict of interest.
[19] For the assay description, see: D. J. Minick, J. H. Frenz, M. A. Patrick, D.
A. Brent, J. Med. Chem. 1988, 31, 1923.
Keywords: cyclic sulfoximines • cyclization • drug design •
medicinal chemistry • structure diversity
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[21] See, for example: C. Korff, G. Helmchen, Chem. Commun. 2004, 530.
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10.1002/chem.201905461
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FULL PAPER
Emilie Boulard, Vivien Zibulski, Luisa
Oertel, Philip Lienau, Martina Schäfer,
Ursula Ganzer, Ulrich Lücking*
Page No. – Page No.
Increasing Complexity: A Practical
Synthetic Approach to Three-
Dimensional, Cyclic Sulfoximines and
First Insights into Their in vitro
Properties
Text for Table of Contents
An underrepresented structural motive in the life sciences is now accessible by a practical and safe synthetic approach. Five- to
seven-membered cyclic sulfoximines were prepared in 2–3 steps in high yields and broad scope (17 examples). In vitro evaluation of
properties relevant to medicinal chemistry of these three-dimensional, cyclic sulfoximines did not reveal any intrinsic flaw for drug
discovery.
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