Sulfoximines with α-Ketoester Functionalities at Nitrogen from Cyanoacetates and Air

Article abstract of DOI:10.1002/adsc.202001264

Sulfoximines with nitrogen-bound α-ketoester units are efficiently prepared by an operationally simple one-pot reaction sequence in air starting from methoxy(mesyloxy)iodobenzene, NH-sulfoximines, and cyanoacetates. Key of the process is the in-situ forma

Full text of DOI:10.1002/adsc.202001264

Title: Sulfoximines with alpha-Ketoester Functionalities at Nitrogen
from Cyanoacetates and Air
Authors: Chenyang Wang, Han Wang, and Carsten Bolm
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: Adv. Synth. Catal. 10.1002/adsc.202001264
Link to VoR: https://doi.org/10.1002/adsc.202001264

10.1002/adsc.202001264
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202
Sulfoximines with -Ketoester Functionalities at Nitrogen from
Cyanoacetates and Air
Chenyang Wang,+a Han Wang,+a and Carsten Bolm*a
a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
Phone: (+49)-241-8094675; e-mail: Carsten.Bolm@oc.RWTH-Aachen.de
+ These authors contributed equally
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
cyanoacetate (3a) hoping to obtain -substituted
product 4aa via hypervalent iodine reagent 5aa
(Scheme 2). However, with K3PO4 as base in DCE at
ambient temperature in air, the result was very
different. Instead of 4aa, 23% of unexpected-
ketoester -imide-type molecule 6aa was formed.[3]
Considering the importance of both sulfoximines and
-ketoamides in medicinal chemistry,[4,5] we decided
to optimize the process and to examine the scope of
this unusual transformation. The results are described
here.
Abstract: Sulfoximines with nitrogen-bound -
ketoester units are efficiently prepared by an
operationally simple one-pot reaction sequence in air
starting from methoxy(mesyloxy)iodobenzene, NH-
sulfoximines, and cyanoacetates. Key of the process is
the in-situ formation of hypervalent iodine reagents,
which serve as electrophilic sulfoximidoyl sources.
Keywords: electrophilic sulfoximidation; hypervalent
iodine reagent; -ketoester; sulfoximine
Initial design
O
Ph
N
S
Recently, we started exploiting hypervalent iodine
reagents 1 and 2 (Scheme 1).[1,2] Depending on the
activation mode, they react either via sulfoximidoyl
radicals or as electrophilic sulfoximidoyl source.
While the former reactivity requires an activation of
by light,[2a-d] the latter is provoked by the addition of
simple bases allowing N-alkynylations and N-
sulfenylation of sulfoximines on unprecedented
pathways.[2e,f]
I
OMs
Me
O
Ph
N
O
CO2tBu
S
1a Ph
CN
Me
O
base
CN
4aa
3a
O
Ph
CO2tBu
S
N
Me
I
CN
Ph
5aa
Unexpected result
O
O
R
N
O
S
1a, K3PO4
DCE, in air
N
O
CN
O
I
X
R’
R
S
photocatalytic
C–H insertions
O
S
•
O
N
Ph Me
O
and addition reactions
R’’
R’
3a
6aa: 23%
sulfoximidoyl
radicals
1
X = OMs, OTs, F
Scheme 2. Reaction design and experimental result.
Ar
or
O
R
N
S
R
S
R
R
S
In order to raise the yield of 6aa from the initial 23%,
various modifications of the original protocol were
tested (Table 1). The first ones focused on the
hypervalent iodine reagent serving as electrophilic
sulfoximidoyl source. To our surprise, neither the use
of I-tosyl analog 1b nor cyclic derivative 2a led to 6aa
revealing the very special role of 1a and its mesyl
group (Table 1, entries 1-3). When DCE was
substituted as solvent by toluene, THF, or acetonitrile
(Table 1, entries 1, 4-6), the latter showed a beneficial
SR
R’
I
O
O
N
and
O
O
S
N
N
O
R’
R’
R’
R’’
N-alkynylations N-sulfenylations
electrophilic
sulfoximidoyl
source
2
Scheme 1. Hypervalent iodine reagents 1 and 2 and
their reactivity.
With the intention to extend this chemistry, we now
reacted hypervalent iodine reagent 1a with tert-butyl
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001264
Advanced Synthesis & Catalysis
effect leading to 6aa in 38% yield. Screening bases
absence of 7 was performed. Light generated by blue
LEDs was used to potentially generate radicals. Under
those conditions, however, no product formation
occurred (Table 1, entry 14).
revealed that NaH2PO4 was better than K3PO4, KOH,
Table 1. Optimization of the reaction conditions.[a]
With the optimized reaction conditions in hand, the
substrate scope was investigated. In this context, the
-ketoester functionality of the targeted products 6
was particularly important, because despite the fact
that several strategies towards compounds with 1,2-
dicarbonyl groups at the sulfoximine nitrogen are
known,[6,7] to the best of our knowledge, none of them
was applied in preparing molecules with terminal ester
groups. Until now, all products had aryl groups at the
terminal position. In contrast, using the optimized
protocol developed here, allowed accessing a wide
range of -ketoester -imide-type molecule 6 varying
at both the ester site as well as the sulfoximine core.
Scheme 3 shows the results from reactions with
iodine reagent 7, NH-sulfoximine 8a, and a number of
cyanoacetates 3. In general, all reactions proceeded
well affording the corresponding products 6aa-ia in
yields of 78-81%. Apparently, the ester group had only
a minor effect on the coupling quality.
O
O
iodine reagent, base
solvent, air, r.t.
N
Ph
CN
O
S
O
Me
O
O
3a
6aa
Ph
Ph
MsO
I
OMe
TsO
I
N
O
I
N
Ph
S
S
HN
Me
Me
O
S
O
O
Me
O
1b
2a
7
8a
entry iodine reagent base
solvent yield (%)
1
2
3
4
5
6
7
8
K3PO4
DCE
DCE
DCE
23
--
--
1a
1b
2a
1a
1a
1a
1a
1a
1a
1a
1a
1a
7, 8a
8a
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KOH
toluene 31
THF --
MeCN 38
MeCN 27
MeCN trace
MeCN 49
O
K2CO3
Na3PO4
air
Na2HPO4
OMs
I
O
N
Ph
N
Ph
9
+
Ph
+
H
S
RO
S
CN
RO
MeCN, r.t.
sealed tube
Me
Me
10
11[b]
12[c]
13[d]
14[e]
NaH2PO4 MeCN 60
NaH2PO4 MeCN 80
NaH2PO4 MeCN 91
NaH2PO4 MeCN 81
NaH2PO4 MeCN --
O
O
OMe
O
3
6
8a
7
81%
80%
78%
81%
78%
80%
6aa: R = tBu 81%
6ba: R = iBu 80%
6ca: R = nBu 78%
6da: R = iPr
6ea: R = Et
6fa: R = Me
6ga: R = nOctyl
6ha: R = Allyl
6ia: R = Bn
[a]
Reaction conditions: 1a (0.2 mmol), 3 (0.2 mmol), base
(0.2 mmol), solvent (2 mL), room temperature, open to
the air, 30 h.
Scheme 3. Products obtained from reacting 7 and 8a
with various cyanoacetates 3.
[b] Use of 2 equiv. of 1a (0.4 mmol).
[c] Use of 2 equiv. (0.4 mmol) of both 1a and NaH2PO4.
[d] Use of 2 equiv. (0.4 mmol) of each 7, 8a, and NaH2PO4.
[e] Under light (blue LED).
Next, the sulfoximine structure was varied, and the
results are shown in Figure 1.
F
OMe
O
O
O
O
O
Ph
K2CO3, and Na3PO4 (Table 1, entries 6-10). Finally,
the reagent ratio was varied, and by using a
combination of 2 equiv. of each 1a and NaH2PO4, 6aa
was obtained in a yield of 91% (Table 1, entries 11 and
12).
N
tBuO
S
RO
S
tBuO
S
N
N
Me
nOctyl
O
O
O
O
43%
48%
45%
49%
46%
6ab: R = tBu
6bb: R = iBu
6cb: R = nBu
6db: R = iPr
6ib: R = Bn
6ac: 81%
6ad: 62%
O
O
O
O
Realizing that reagent 1a was easily accessible by
simple and rapid ligand exchange starting from
methoxy(mesyloxy)iodobenzene (7) and NH-sulfox-
imine 8a,[2] the development of a reaction protocol
with an in-situ prepared reagent 1a was envisaged. The
aforementioned observations led us assume that the
presence of the 1 equiv. of methanol resulting from the
first step of the targeted reaction sequence should only
have a minor influence on the subsequent coupling of
in-situ generated 1a with 3a. Confirming this
hypothesis, 6aa was obtained in 81% yield by
following the new reaction protocol (Table 1, entry 13).
Although this yield was slightly lower than the one
obtained in the experiment with preformed 1a, the one-
pot procedure was convincing by its experimental
simplicity and practicability avoiding any initial
preparation and isolation of the applied iodine reagent.
In order to ensure that an iodine reagent was needed
for the coupling, a reaction with 3a and 8a in the
Ph
Ph
tBuO
S
tBuO
S
N
N
O
O
O
O
Me
tBuO
S
N
6af: 78%
6ae: 81%
Me
O
6ag: 80%
Figure 1. Products obtained by reacting cyanoacetates
3 and iodine reagent 7 with various NH-sulfoximines
8.
Combinations of cyanoacetates 3a-d and 3i with S-
4-fluorophenyl-S-methyl-substituted NH-sulfoximine
8b afforded the corresponding products 6ab-db and
6ib in yield ranging from 43% to 49%. Thus,
compared to the reactions with S-phenyl analog 8a, all
yields were significantly lower revealing a negative
impact of the fluoro substituent on the product
formation. Also in this series, the product yields
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001264
Advanced Synthesis & Catalysis
remained largely unaffected by the ester group.
Enlarging the S-alkyl substituent from methyl to octyl
had no effect as shown by the comparison between 6aa
and 6ac, which both were obtained in 81% yield.
Using S-aryl-S-benzyl-substituted sulfoximine 8d in
the reaction with 3a and 7 gave 6ad in 62% yield. This
slightly lower yield compared, for example, to the one
for S-methyl-S-phenyl-containing 6aa (81%) might be
due to a general sensitivity of sulfoximines with S-
benzyl substituents as previously also observed for
analogous heteroyclic derivatives.[8] As indicated by
the yield of 81% for product 6ae, S,S-diphenyl
sulfoximine (8e) reacted well too. The same was true
for dibenzosulfoximine (8f), which gave 6af in 78%
yield. This result is noteworthy because 8f revealed a
rather unusual reaction behavior in previous studies.[9]
Finally, 6ag was obtained in 80% yield showing that
also S,S-dimethyl sulfoximine (8g) could be applied.
This result is important because 8g was used in a
medicinal chemistry study, where it was found to
affect to ADME properties of target molecules.[10]
For analyzing the reaction pathway, several process
modifications were studied using a mixture of
preformed 1a and cyanoacetate 3a as representative
substrate combination (Scheme 4). As noted before,
the standard conditions involving the use of NaH2PO4
in a sealed tube under an atmosphere of air at room
temperature for 30 h gave 6aa in 91% yield (Table 1,
entry 12). Under argon, no product was formed.
Substituting air by dioxygen led to 6aa in 92% yield.
The critical need of an iodine reagent had already been
demonstrated in the attempt to couple 3a with 8a under
blue LED light in the absence of 7 (Table 1, entry 14).
There, no 6aa was formed.
Scheme 5. Plausible mechanistic pathway.
deprotonated cyanoacetate generates a new iodine-
centered species A, which forms intermediate B by
expulsion of phenyliodide.[12] Under the aerobic
reaction conditions, B reacts with dioxygen providing
unstable intermediate C, which loses isocyanic acid
(HNCO)[13] to provide the observed product 6.[14]
In summary, we developed a protocol for the
preparation of sulfoximines with nitrogen-bound -
ketoester units. In an operationally simple one-pot
room temperature transformation, NH-sulfoximines
react with methoxy(mesyloxy)iodobenzene to give
hypervalent iodine reagents which are capable of
transferring sulfoximidoyl units to deprotonated
cyanoacetates. Subsequent aerobic oxidation then
leads to the observed products in good yields.
Experimental Section
General procedure for preparation of -keto-N-acyl-
sulfoximines 6 exemplified by the synthesis of compound
6aa. Under air atmosphere, a 10 mL sealed tube was
charged with tert-butyl 2-cyanoacetate (3a, 0.2 mmol),
methoxy(mesyloxy)iodobenzene (7, 0.4 mmol), sulfox-
imine (8a, 0.4 mmol), NaH2PO4 (0.4 mmol) and MeCN (2
mL). Then, the reaction mixture was stirred at room
temperature for 30 h. The product was purified by column
chromatography using silica gel as stationary phase and
mixtures of pentane/ethyl acetate.
Acknowledgements
C. W and H. W. are thankful to the Chinese Scholarship Council
(CSC) for pre-doctoral stipends.
O
air
Na2HPO4
O
Ph
Ph
N
N
I
OMs
+
OtBu
S
NC
S
OtBu
MeCN, r.t.
sealed tube
Me
Me
Ph
O
O
O
1a
6aa
3a
References
standard conditions as depicted:
91% yield of 6aa
Modifications:
- under Ar instead of air: no product formation
- under O2 instead of air: 92% of 6aa
- use of 8a instead of 1a;
[1] For selected reviews on (hypervalent) iodine reagents,
see: a) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002,
102, 2523–2584; b) F. V. Singh, T. Wirth, Chem. Asian
J. 2014, 9, 950–971; c) M. Ochiai, Chem. Rec. 2007, 7,
12-23; d) M. Uyanik, K. Ishihara, ChemCatChem 2012,
4, 177–185; e) V. V. Zhdankin, P. J. Stang, Chem. Rev.
2008, 108, 5299–5358; f) A. Yoshimura, V. V.
Zhdankin, Chem. Rev. 2016, 116, 3328–3435; g) V. V.
Zhdankin, Hypervalent Iodine Chemistry: Preparation,
Structure and Synthetic Application of Polyvalent Iodine
Compounds, Wiley, New York, 2013; h) D. P. Hari, P.
Caramenti, J. Waser, Acc. Chem. Res. 2018, 51, 3212–
3225; i) A. Flores, E. Cots, J. Bergès, K. Muñiz, Adv.
Synth. Catal. 2019, 361, 2–25; j) Hypervalent Iodine
Chemistry, Top. Curr. Chem. Vol. 373 (Ed. T. Wirth),
Springer, Switzerland, 2015; g) A. Flores, E. Cots, J.
Bergès, K. Muñiz, Adv. Synth. Catal. 2019, 361, 2–25.
under blue LED light:
no product formation
Scheme 4. Control experiments.
In light of those results and on the basis of previous
mechanistic interpretations of related reactions by
others,[1,11] a tentative mechanism for the formation of
-ketoester -imide-type molecule 6 as shown in
Scheme 5 was devised. Initial ligand exchange of (in
situ formed) hypervalent iodine reagent 1 with the
CN
O
O
O
S
NH
N
OMs
7
3
N
S
CO2R3
S
I
I
R1
R1
R1
R2
– PhI
R2
base
R2
Ph
Ph
A
8
1
CN
OH
CN
O
O
S
O
O2
base
[2] a) H. Wang, Y. Cheng, P. Becker, G. Raabe, C. Bolm,
Angew. Chem. 2016, 128, 12845–12848; Angew. Chem.
Int. Ed. 2016, 55, 12655–12658; b) H. Wang, D. Zhang,
H. Sheng, C. Bolm, J. Org. Chem. 2017, 82, 11854–
CO2R3
N
O
CO2R3
N
N
S
S
CO2R3
R1
R1
R1
– HNCO
R2
R2
R2
O
6
C
B
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001264
Advanced Synthesis & Catalysis
11858; c) H. Wang, D. Zhang, C. Bolm, Chem. Eur. J.
[7] For a light-promoted radical coupling of reagents 1 with
aryl alkynes leading to sulfoximines with aryl-
substituted 1,2-dicarbonyl substituents, see: C. Wang, D.
Ma, Y. Tu, C. Bolm, Org. Lett. 2020, 22, 8937–8940.
2018, 24, 14942–14945; d) H. Wang, D. Zhang, C. Bolm,
Angew. Chem. 2018, 130, 5965–5968; Angew. Chem. Int.
Ed. 2018, 57, 5863–5866; e) H. Wang, D. Zhang, M.
Cao, C. Bolm, Synthesis 2019, 51, 271–275; f) C. Wang,
Y. Tu, D. Ma, C. Bolm, Angew. Chem. 2020, 132,
14238–14241; Angew. Chem. Int. Ed. 2020, 59, 14134–
14137.
[8] O. Garcìa Mancheño, J. Dallimore, A. Plant, C. Bolm,
Adv. Synth. Catal. 2010, 352, 309–316.
[9] Z. Li, H. Yu, C. Bolm, Angew. Chem. 2017, 129, 9660–
9663; Angew. Chem. Int. Ed. 2017, 56, 9532–9535.
[3] Products of this type can also be obtained by reacting the
corresponding NH-sulfoximine with either dialkyl
oxalate at elevated temperature (150 °C) or with the half
ester of oxalyl chloride in pyridine. For the first two
examples, see: R. R. Williams, D. J. Cram, J. Org. Chem.
1973, 38, 20–26.
[10] F. W. Goldberg, J. G. Kettle, J. Xiong, D. Lin,
Tetrahedron 2014, 70, 6613–6622.
[11] a) G. F. Koser, A. G. Relenyi, A. N. Kalos, L. Rebrovic,
R. H. Wettach, J. Org. Chem. 1982, 47, 2487–2489; b)
J. S. Lodaya, G. F. Koser, J. Org. Chem. 1988, 53, 210-
212; c) D. F. González, J. P. Brand, J. Waser, Chem. Eur.
J. 2010, 16, 9457–9461.
[4] For recent overviews highlighting the importance of
sulfoximines in medicinal chemistry, see: a) U. Lücking,
Angew. Chem. 2013, 125, 9570–9580; Angew. Chem. Int.
Ed. 2013, 52, 9399–9408; b) U. Lücking, Org. Chem.
Front. 2019, 6, 1319–1324; c) M. Frings, C. Bolm, A.
Blum, C. Gnamm, Eur. J. Med. Chem. 2017, 126, 225–
245; d) J. A. Bull, L. Degennaro, R. Luisi, Synlett 2017,
28, 2525–2538; e) P. Ghosh, B. Ganguly, S. Das, Asian
J. Org. Chem. 2020, DOI: 10.1002/ajoc.202000320; f) P.
Mäder, L. Kattner, J. Med. Chem. 2020, DOI:
10.1021/acs.jmedchem.0c00960; g) Y. Han, K. Xing, J.
Zhang, T. Tong, Y. Shi, H. Cao, H. Yu, Y. Zhang, D.
Liu, L. Zhao, Eur. J. Med. Chem. 2020, DOI:
10.1016/j.ejmech.2020.112885.
[12] We consider it unlikely that the process starts with an
oxidation of 3a by 7, because in a control experiment
with the two reagents we did not find any oxidation
product stemming from 3a (as analyzed by NMR
spectroscopy).
[13] For related transformation with air mediated by CuI,
see: a) S. H. Kim, K. H. Kim, J. N. Kim, Adv. Synth.
Catal. 2011, 353, 3335–3339; b) S. H. Kim, S. H. Kim,
H. J. Lee, J. N. Kim, Bull. Korean Chem. Soc. 2012, 33,
2079–2082; c) N. Rabjohn, C. A. Harbert, J. Org. Chem.
1970, 35, 3240–3243; d) Y. Matsubara, T. Matsuda, A.
Kato, Y. Yamagushi, Z.-i. Yoshida, Tetrahedron Lett.
2000, 41, 7901–7904; D. T. Breslin, M. A. Fox, J. Am.
Chem. Soc. 1993, 115, 11716–11721.
[5] For selected recent work illustrating the relevance of -
ketoamides, see: a) C. De Risi, G. P. Pollini, V. Zanirato,
V. Chem. Rev. 2016, 116, 3241–3305; b) Y. J. Yoo, H.
Kim, S. R. Park, Y. J. Yoon, J. Ind. Microbiol.
Biotechnol. 2017, 44, 537–553; c) J. Zhou, E. D. Mock,
A. Martella, V. Kantae, X. Di, L. Burggraaff, M. P.
Baggelaar, K. Al-Ayed, A. Bakker, B. I. Florea, S. H.
Grimm, H. den Dulk, C. T. Li, L. Mulder, H. S.
Overkleeft, T. Hankemeier, G. J. P. van Westen, M. van
der Stelt, ACS Chem Biol. 2019, 14, 164–169; d) L.
Zhang, D. Lin, Y. Kusov, Y. Nian, Q. Ma, J. Wang, A.
Brunn, P. Leyssen, K. Lanko, J. Neyts, A. Wilde, E. J.
Snijder, H. Liu, F. Hilgenfeld, J. Med. Chem. 2020, 63,
4562–4578
[14] For visible light-promoted reactions of cyanoacetates
with alcohols under dioxygen to give organyl 2-cyano-
2-oxoacetates, see: C. Xu, N.-N. Zhang, X.-J. Ji, Y.-Q.
Ge, P.-H. Diao, C. Guo, Synlett 2018, 29, 1065–1070.
We exclude an analogous pathway with 8a as
nucleophile here because no product formation was
observed in the absence of a hypervalent iodine reagent
confirming its central role in the newly reported reaction
process.
[6] a) L. Wang, D. L. Priebbenow, L.-H. Zou, C. Bolm, Adv.
Synth. Catal. 2013, 355, 1490–1494; b) Y. Zou, Z. Peng,
W. Dong, D. An, Eur. J. Org. Chem. 2015, 4913–4921;
c) H. Cheng, C. Bolm, Synlett 2016, 27, 769–772; d) X.
Y. Chen, L. Wang, M. Frings, C. Bolm, Org. Lett. 2014,
16, 3796–3799.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001264
Advanced Synthesis & Catalysis
COMMUNICATION
Sulfoximines with a-Ketoester Functionalities at
Nitrogen from Cyanoacetates and Air
O
air
Na2HPO4
OMs
I
O
Adv. Synth. Catal. Year, Volume, Page – Page
R1
R2
R1
R2
N
N
+
Ph
+
S
RO
H
S
CN
RO
MeCN, r.t.
O
O
OMe
O
Chenyang Wang, Han Wang and Carsten Bolm*
5
This article is protected by copyright. All rights reserved.