Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-amino-λ6-sulfanenitrile Intermediate

Article abstract of DOI:10.1002/anie.201906001

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH-sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disulfides. A highly chemoselective and one-pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source, and in the presence of 1 equivalent of acetic acid. A wide range of functional groups are tolerated under the developed reaction conditions, which also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel S≡N sulfanenitrile species as intermediates. Several alkoxy-amino-λ⁶-sulfanenitriles are prepared with different alcohols, and shown to be alkylating agents to a range of nucleophiles.

Full text of DOI:10.1002/anie.201906001

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-
amino-λ6-sulfanenitrile Intermediate
Authors: Edward L. Briggs, Arianna Tota, Marco Colella, Leonardo
Degennaro, Renzo Luisi, and James Adam Bull
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906001
Angew. Chem. 10.1002/ange.201906001
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10.1002/anie.201906001
Angewandte Chemie International Edition
RESEARCH ARTICLE
Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-
l6
amino- -sulfanenitrile Intermediate
Edward L. Briggs,[a] Arianna Tota,[b] Marco Colella,[b] Leonardo Degennaro,[b] Renzo Luisi*[b] and
James A. Bull*[a]
Abstract: Sulfonimidamides are intriguing new motifs for medicinal
a) Emerging sulfur(VI) aza-analogues
and agrochemistry, and provide attractive bioisosteres for
O
S
O
O
S
NH
O
S
O
O
S
NH
N
sulfonamides. However, there remain few operationally simple
methods for their preparation. Here, for the first time the synthesis of
NH-sulfonimidamides is achieved directly from sulfenamides,
themselves readily formed in 1 step from amines and disulfides. A
highly chemoselective and one-pot NH and O transfer is developed,
mediated by PhIO in iPrOH, using ammonium carbamate as the NH
source, and in the presence of 1 equivalent of acetic acid. A wide
range of functional groups are tolerated under the developed reaction
conditions, including the functionalization of anti-depressants
desipramine and fluoxetine. Additionally, the methodology is applied
to the preparation of an aza-analogue of the drug probenecid, with
further N-functionalization reactions exemplified on this scaffold. The
reaction is shown to proceed via different and concurrent mechanistic
pathways, including the formation of novel S≡N sulfanenitrile species
as intermediates. Several alkoxy-amino-l6-sulfanenitriles are
prepared with different alcohols, and shown to be alkylating agents to
a range of nucleophiles. Detailed mechanistic studies demonstrate
the iPrOH as one source of the sulfonimidamide oxygen atom, in
addition to water and acetate.
N
Sulfone
b) New aza-bioisosteres
NH
Sulfoximine
Sulfonamide
Sulfonimidamide
O
S
F
O
O
NH2
NH2
S
N
N
N
Cl
O
CF3
O
O
H2N
S
N
S
Cl
Cl
Cl
Br
celecoxib analogue
tasisulam analogue
sodium channel inhibitor
c) Methods for the synthesis of sulfonimidamides
Ph3PCl2
1)
1)
2)
NH2
Li
O
S
O
O
2)
Imidazole then MeOTf
F
F
S
Sharpless 2018[10]
Grygorenko 2019[13b]
X = Imid.
N
F
F
H
X = F
= TBS
MgBr
Ph3PCl2
Chen 2015[13a]
X = Cl
O
O
N
O
N
S
S
Willis 2017[6]
X
X = Cl
= Tr
= TBS
H
N
H2NCO2NH4
PhIO
H2NCO2NH4
PhI(OAc)2
O
N
AcOH
Introduction
S
S
S
N
N
N
Stockman, Lücking 2017[15]
This work
= H
= H
The adoption of unusual functional groups into medicinal and
agrochemical research programs provides enhanced coverage of
both chemical and intellectual property space.[1] Sulfoximines and
sulfonimidamides, the mono-aza analogues of sulfones and
sulfonamides respectively are receiving considerable attention in
this context as bioisosteres in drug design (Scheme 1a).[2,3] High
metabolic and chemical stability, along with hydrogen bond
donor/acceptor capabilities can impart improved physicochemical
properties to these aza-derivatives.[2] Sulfoximines have recently
received extensive examination in clinical drug candidates from
Bayer,[4] and AstraZeneca.[5] The sulfonimidamide group on the
OBz
N
H
N
O
O
S
NH
CuTC (20 mol%), O2
CuBr (20 mol%)
Bolm 2018[11]
S
N
Bolm 2016[12]
H
CH3
= Ar
= H
Scheme 1. Examples of bioactive sulfonimidamides, and strategies for the
synthesis of sulfoximines and sulfonimidamides via NH and O transfer to sulfur
functional groups.
other hand has been less developed, but presents similar
opportunities. Biologically active examples of sulfonimidamides
include the aza-analogues of sulfonamides celecoxib[6] and
tasisulam,[7] as well as a sodium channel inhibitor published by
Genentech in a patent application (Scheme 1b).[8] This interest
has prompted several recent synthetic advances (Scheme 1c).[9]
Selected examples include Willis’ use of N-sulfinyltritylamine as a
linchpin for the addition of Grignard reagents and amines, via
sulfonimidoyl chlorides.[6] Sharpless described the use of thionyl
tetrafluoride (SOF4) as a useful reagent for sulfur fluoride
exchange (SuFEx) click chemistry, using sulfonimidoyl fluorides
[a]
[b]
E. L. Briggs and Dr J. A. Bull
Department of Chemistry, Imperial College London, Molecular
Sciences Research Hub, White City Campus, Wood Lane W12 0BZ,
UK
E-mail: j.bull@imperial.ac.uk
Homepage: http://www3.imperial.ac.uk/people/j.bull
A. Tota, M. Colella, Dr. L. Degennaro and Prof. Dr. R. Luisi
Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”
Via E. Orabona 4, Bari 70125. Italy.
E-mail: renzo.luisi@uniba.it
Homepage:http://www.farmchim.uniba.it/chimica_organica/Luisi2.html
as
precursors
to
sulfoximines,
sulfonimidates
and
sulfonimidamides.[10] Bolm has reported copper catalyzed
methods to form sulfonimidamides involving a cross coupling of
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906001
Angewandte Chemie International Edition
RESEARCH ARTICLE
sulfinamides[11] and the oxidation of methyl sulfoximines.[12]
Sulfonamides have also been converted to sulfonimidamides with
this approach being recently extended by Grygorenko to form
imidazolium salts as precursors to sulfonimidamides and
imidosulfuric diamides.[13]
In 2016 we reported a facile metal-free protocol for the direct
synthesis of NH-sulfoximines from sulfoxides in high yields and
functional group compatibility.[14] The NH-transfer occurred with
sources of ammonia, with ammonium carbamate preferred, in the
presence of bisacetoxyiodobenzene as the oxidant. Our approach
has been recently extended by Stockman and Lϋcking to form
sulfonimidamides, using closely related conditions to effect NH-
transfer to sulfinamides (Scheme 1c).[15] We, and others, recently
reported related conditions for the conversion of sulfides to
sulfoximines in one-pot through a highly chemoselective NH and
O transfer.[16-18]
Here we report the development of a new strategy for the
direct synthesis of NH-sulfonimidamides from sulfenamides as
simple, readily available, and previously unexplored substrates. A
highly selective one-pot NH and O transfer is achieved using
operationally simple conditions. This provides a new and efficient
disconnection of sulfonimidamides, allowing their preparation
from functionalized amines and disulfides. Furthermore, we
present detailed mechanistic studies on the reaction. Key
intermediate alkoxy-amino-l6-sulfanenitriles have been isolated
and characterised, providing insight to the reaction mechanism.
The reactivity of these new l6-sulfanenitriles with nucleophiles is
demonstrated. Overall, this strategy provides a short, 2-step
synthetic sequence for the preparation of NH-sulfonimidamides
that is applicable to late-stage diversification.
Results and Discussion
Bench-stable sulfenamides used in this study, were readily
prepared starting from disulfides and a suitable amine.[19,20] As a
model substrate for optimization, sulfenamide 1a was prepared
from Ph2S2 and piperidine in the presence of silver nitrate (Table
1), using a procedure modified from that developed by Davis.[21,22]
We started investigations by applying our previously reported
reaction conditions using PhI(OAc)2 and ammonium
carbamate.[14] Pleasingly, the expected sulfonimidamide 2a was
observed as the main product. Sulfonimidate 3 and sulfonamide
4 were also formed, with the loss of the piperidine moiety (Table
1, entry 1). The equivalents of oxidant and ammonium carbamate
could be reduced to 2.5 and 2 respectively without affecting the
reaction yield (entry 2), while further reduction of the equivalents
of the oxidant resulted in incomplete conversion. Changing the
solvent to iPrOH gave an improved yield of 2a (entry 3). We
noticed that excess acid, derived from the oxidant, was
responsible for degradation of the sulfenamide and formation of
side products. In fact, the use of a base such as NaOH as an
additive (entry 4), resulted in a slightly improved yield of 2a. In
order to reduce the amount of acidic species, we investigated
iodosylbenzene as the oxidant, which is known to dissolve in
MeOH to form PhI(OMe)2, without the formation of acid.
Remarkably, the use of this reagent led to a lower yield of 2a
(entry 5) but a 47% yield of a new product, identified as an
unprecedented alkoxy-amino-l6-sulfanenitrile (5a). Optimized
conditions, leading to a 90% yield of sulfonimidamide 2a, were
achieved using iPrOH as the solvent, PhIO as the oxidant (2.5
equiv), and only 1 equiv of added acetic acid (entry 8).
Table 1. Selected results in the development and optimization of NH and O transfer to sulfenamides.
iodine (III) reagent
O
S
NH
N
O
S
NH
O
S
O
RO
N
NH2CO2NH4
S
S
S
AgNO3
MeOH
additive
HN
N
OMe
NH2
N
2
+
+
+
+
solvent (0.2 M)
25 °C, 0.5-3 h
3 equiv
1.5 equiv
96%
60%
1a
2a
3
4
5
Yield[a]
NH2CO2NH4
(equiv)
PhI(OAc)2
(equiv)
PhIO
(equiv)
Additive
(equiv)
Entry
Solvent
2a
56
56
60
64
11
52
51
90
27
3
4
5
-
Total
73
1
2
3
4
5
6
7
8
9
4
2
2
2
2
2
2
2
2
3
-
-
MeOH
MeOH
iPrOH
MeOH
MeOH
MeOH
MeOH
iPrOH
iPrOH
11
11
6
6
2.5
-
-
3
-
70
2.5
-
-
10
11
3
-
76
2.5
-
NaOH (6)
-
6
-
81
-
-
-
-
-
2.5
2.5
2.5
2.5
2.5
2
47 (R = Me, 5a)
63
AcOH (1)
AcOH (5)
AcOH (1)
-
5
3
-
60
11
2
8
-
70
1
-
93
1
1
53 (R = iPr, 5b)
82
[a] Determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as internal standard.
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10.1002/anie.201906001
Angewandte Chemie International Edition
RESEARCH ARTICLE
PhIO (2.5 equiv)
NH2CO2NH4 (2 equiv)
AcOH (1 equiv)
O
S
NH
N
The use of iPrOH reduced alternative unproductive pathways and
afforded very high chemoselectivity for the heteroatom transfers.
Increasing or decreasing the amount of acid gave unsatisfactory
results. Interestingly, running the reaction under the optimized
conditions but without the acid, produced the alkoxy-amino-l6-
sulfanenitrile 5b in a 53% yield, while 2a was formed in only 27%
yield (entry 9).
S
N
1a-ad
2a-ad
iPrOH (0.2 M)
25 °C, 1 h
(0.4-1.2 mmol)
X =
O
NH
N
O
S
NH
N
O
S
NH
H
2a
75%
tBu
S
OMe 2b
Ph 2c
72%
89%
85%
66%
48%
N
F
Cl
2d
2e
X
X
2m
69%
2n
79%
Using these optimized conditions, the scope of the reaction
was assessed with different sulfenamides, varying substituents
on both sides of the functional group (Scheme 2). It is worth noting
the facile and rapid preparation of sulfenamides as
sulfonimidamide precursors,[22] in comparison to sulfinamides for
example, which often require extra steps and/or formation of
sulfinylchlorides. First, piperidine-substituted sulfenamides 1a-1r
bearing several aromatics, heteroaromatics and alkyl substituents
were evaluated. Sulfonimidamides 2a-2r were obtained in yields
ranging from 45% to 89%. Sulfonimidamide 2a was isolated in
75% yield on a 0.5 mmol scale, and the reaction could be scaled
to 9 mmol to provide 1.3 g of 2a in 64% yield. Several substituted
aromatics were compatible with the protocol, regardless of the
position of the substituents (i.e. ortho-, meta- or para-) providing
sulfonimidamides 2b-2l (Scheme 2). Aromatic groups with varied
electronic properties were tolerated, though the presence of
electron-donating groups generally gave slightly higher yields
when compared to aromatics bearing electron-withdrawing
groups. Disubstituted phenyl and 2-naphtyl substituents furnished
the corresponding NH-sulfonimidamides 2m and 2n respectively.
Pyridine containing sulfenamides 1o and 1p substituted at the 2-
and 4-positions were well tolerated (2o and 2p), as were an alkyl
(cyclohexyl, 2q) and benzyl substituents (2r).
CF3 2f
O
NH
O
NH
O
O
NH
N
S
S
X =
OMe 2g 85%
Cl 2h 75%
N
N
S
N
N
2o
61%
2p
51%
(+ 14% NAc)
X =
Me 2i 45%
Br 2j 70%
NH
N
O
S
NH
O
S
NH
N
S
Ph
N
CF3 2k 67%
NO2 2l 41%
X
2q
65%
2r
75%
O
S
NH
N
O
S
NH
N
O
NH
O
NH
S
S
N
N
O
NBoc
Ph
2s
82%
2t
60%
2u
63%
2v
61%
O
NH
O
NH
O
S
NH
O
NH
S
S
S
Ph
N
N
N
N
Me
Me
Cl
2w
90%
2x
45%
2y
94%
2z
95%
O
S
NH CO2Me
N
O
S
NH
N
Ph
2aa
2ab
The variation of the amino moiety of the sulfenamide was then
evaluated (Scheme 2). Cyclic amino substituents, including those
bearing additional heteroatoms, furnished good to excellent yields
of the corresponding NH-sulfonimidamides 2s-2v (Scheme 2).
Acyclic secondary amines, bearing diethyl (2w), methylphenyl
(2x) and allyl substituents (2y and 2z) were similarly successful.
Using sulfenamides 1aa and 1ab prepared from chiral amines
provided NH-sulfonimidamides 2aa and 2ab in good yields as a
1:1 mixture of diastereoisomers, with complete retention of the
enantiomeric excess of the chiral starting amines.[22,23]
Sulfenamides 1ac and 1ad derived from anti-depressant drugs
desipramine and fluoxetine yielded sulfonimidamide analogues
2ac and 2ad (dr 1:1) in 48% and 79% yields respectively,
illustrating the potential of the method for late stage
functionalization.
71%
62%
CF3
Ph
O
S
NH
N
O
NH
S
N
N
O
2ac
48%
2ad
79%
Scheme 2. Reaction scope varying the sulfenamide substrate to form NH
sulfonimidamides by NH and O transfer.
PhIO
NH2CO2NH4
AcOH
O
NH
O
NH2
N
S
S
S
N
N
N
N
H
NH
S
S
S
iPrOH (0.2 M)
25 °C, 1 h
7a
30%
6a
Secondary sulfenamide substrates containing an NH were
then evaluated, affording interesting results. Benzothiazole
containing sulfenamide 6a gave sulfonimidamide 7a in 30%
isolated yield, along with the corresponding sulfinamide as the
major side product. In comparison, t-butylphenylsulfenamide 6b
unexpectedly gave product 9, incorporating 2 molecules of 6b in
high yield. This was presumably formed through activation of the
expected sulfonimidamide 7b with excess oxidant, leading to
iminoiodinane intermediate 8 and subsequent imination of 6b
(Scheme 3).[24] Application of these conditions to phenyl methyl
sulfide yielded the corresponding NH-sulfoximine in 83% isolated
yield,[22] providing an alternative for the formation of sulfoximines
from sulfides.[16,17]
H
N
PhIO (2.5 equiv)
NH2CO2NH4 (2 equiv)
AcOH (1 equiv)
Ph
S
tBu
S
tBu
Ph
N
H
O
N
9
77%
S
tBu
6b
iPrOH (0.2 M)
25 °C, 1 h
Ph
N
6b
Ph
O
O
O
N I
NH
NH
NH2
PhIO
S
S
S
Ph
NH
tBu
Ph
Ph
N
tBu
tBu
7b
8
Scheme 3. Reactivity of secondary sulfenamides 6 under NH and O transfer
conditions.
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10.1002/anie.201906001
Angewandte Chemie International Edition
RESEARCH ARTICLE
To further demonstrate the utility of this method for the
preparation of drug-like compounds, a sulfonimidamide analogue
of probenecid was prepared (Scheme 4). Probenecid is a
sulfonamide containing drug on the market for the treatment of
hyperuricemia. Synthesis of the aza-analogue was achieved in 3
steps, in an overall yield of 45% from known disulfide 10.[25]
Disulfide 10 was readily converted to sulfenamide 11 using silver
nitrate and dipropylamine. Applying the developed conditions for
NH and O transfer furnished sulfonimidamide 12 in 76% yield.
Finally, hydrolysis of the ester using TFA/H2O at 90 °C gave the
aza-analogue of the drug compound 13 and demonstrated
stability of the sulfonimidamide functional group to acid.
alkoxy-l6-sulfanenitrile 17 (Figure 1). This was a powerful
alkylating agent, readily converting to the corresponding
sulfoximine by transfer of the R group.[28] In 2017, Reboul
described alkoxy-l6-sulfanenitrile 18 in the mechanistic
investigation on the NH, and O transfer to sulfides to form
sulfoximines.[17a] Compounds 5a and 5b isolated here represent
a new class of l6-sulfanenitrile, and have been fully characterized
1
(IR, H and 13C NMR and HRMS) along with small quantities of
the corresponding sulfonimidamide. The calculated S≡N IR
stretch (DFT) was consistent with that observed for 5b, and for
17.[22] In situ IR experiments in the absence of acid also indicated
formation of an intermediate ascribed as 5b (1387 cm–1).[22]
Compounds 5a and 5b readily converted to the sulfonimidamide
on silica, and were not observed in the presence of added AcOH.
HN(nPr)2 (3.0 equiv)
SH
S
1
2
AgNO3 (2.0 equiv)
ref 25
In situ H NMR studies corroborated that the breakdown of the
alkoxy-amino-l6-sulfanenitrile to the sulfonimidamide is rapid in
the presence of acid, or slow in the absence of acid in MeOD
solution.[22]
MeOH, 25 °C, 1 h
74%
HO2C
MeO2C
70%
10
PhIO (2.5 equiv)
NH2CO2NH4 (2 equiv)
AcOH (1 equiv)
O
S
NH
N
nPr
S
nPr
N
iPrOH (0.2 M)
25 °C, 1 h
76%
nPr
nPr
H3C
D3C
iPr
O
MeO2C
MeO2C
O
S
N
O
S
N
N
11
12
Ph
S
N
O
S
NH
N
O O
TFA:H2O (1:1)
17
Yoshimura 1989 [27]
18
5b
This work
S
N
Reboul 2017 [17a]
90 ºC, 24 h
80%
HO2C
HO2C
Identified by NMR studies
as intermediate
in sulfoximine synthesis
Isolated as major component
under acid free conditions.
Characterised by HRMS;
1H and 13C NMR
13
probenecid
3-bromopyridine
Pd(OAc)2 (5 mol%)
IR
S
N 1340 cm–1 [27]
IR
(calculated 1368 cm-1
S
N 1363 cm–1
N
O
S
N
(calculated 1332 cm-1
)
)
Xantphos (10 mol%)
Cs2CO3
nPr
N
nPr
Figure 1. Prior reports of alkoxy-l6-sulfanenitriles, and comparison of key data
obtained for alkoxy-amino-l6-sulfanenitrile 5b.
toluene, 100 °C, 18 h
88%
MeO2C
14
O
S
N
propargyl bromide
O
S
NH
N
nPr
nPr
N
NaH, (nBu)4NBr (5 mol%)
Studies were undertaken to elucidate the mechanism of
nPr
nPr
DME, 55 °C, 16 h
65%
MeO2C
conversion
of
alkoxy-amino-l6-sulfanenitriles
5b
to
MeO2C
15
12
sulfonimidamide 2a. Firstly, other acids were included in the
standard reaction of sulfenamide 1a (Table 2). When benzoic acid
was used in place of AcOH a similarly high yield of 2a was
obtained (entries 1 & 2). Pleasingly, the less volatile isopropyl
benzoate was detected in a 48% yield. This was presumed to be
protonation of the S≡N group promoting alkylation of either the
conjugate base or another nucleophile (e.g. solvent). In the
presence of pTsOH a reduced yield of 2a was achieved but with
the same amount of pTsOiPr formed, indicating all of the formed
2a was derived from attack of the sulfonate anion at the isopropyl
group of 5b (entry 3).
O
Cl
O
S
N
chloroacetyl chloride
Et3N, DMAP (10 mol%)
nPr
N
nPr
CH2Cl2, 0 to 25 °C, 2 h
80%
MeO2C
16
Scheme 4. Synthesis of probenecid analogue 13 and NH functionalization to
enhance coverage of chemical space.
To display the potential of the sulfonimidamide group to
explore broader chemical space than their oxo-analogues, N-
functionalization of intermediate 12 was undertaken (Scheme
4).[26] Pd catalyzed cross-coupling introduced a pyridyl group,
installing further medicinally relevant functionality.[26a] Alkylation
with propargyl bromide and acylation with chloroacetyl chloride
gave 15 and 16 respectively, introducing functionality commonly
employed in chemical biology, as a click handle or in covalent
probes respectively.
The isolation of the unusual alkoxy-amino-l6-sulfanenitriles
5a and 5b (Table 1) presented intriguing structures that were
likely to be immediate precursors to the sulfonimidamide in the
mechanism. There are very few reports of related S≡N containing
compounds. In 1989, Yoshimura[27] reported an example of an
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10.1002/anie.201906001
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RESEARCH ARTICLE
a) Ratios 5:2a with different alcohols
Table 2. Role of different acids in formation of 2a and in breakdown of
intermediate alkoxy-amino-λ6-sulfanenitrile.
PhIO (2.5 equiv)
R
O
S
N
O
S
NH
N
NH2CO2NH4 (2 equiv)
S
PhIO (2.5 equiv)
no acid
N
N
+
NH2CO2NH4 (2 equiv)
O
S
NH
N
(0.2 M)
R
OH
A-H (1 equiv)
S
25 °C, 1 h
1a
5
2a
CF3
N
+
A-iPr
iPrOH (0.2 M)
25 °C, 1 h
=
R
iPr
5b
R
= Me
84:16
R
=
Et
R
=
1a
2a
86:14
88:12
5a
5c
5d
74:26
Yield[a]
73:27 (aqueous workup)
60:40 (with 5 equiv H2O)
Entry
A-H
tBu
Additive 5 : 2a : 1a
R
=
R
=
2a
A–iPr
61:39 (in 1:1 iPrOH:PhMe)
65:35 in toluene (1:1)
5e
0 : 18 : 82
0 : 88 : 12
0 : 82 : 18
-
[b]
1
2
3
AcOH
90
89
-
AcOH
AcONa
PhCOOH
pTsOH
48
29
b) 18O incorporation study
PhIO (2.5 equiv)
30[c]
NH2CO2NH4 (2 equiv)
18OH2 (10 equiv)
AcOH (1 equiv)
18O
S
O
S
NH
N
NH
N
S
[a] Determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-
trimethoxybenzene as internal standard. [b] Observed during in-situ 1H NMR
experiments. See SI for further details. [c] Remaining starting material
decomposed.
N
+
iPrOH (0.2 M)
25 °C, 1 h
1a
2a
2a'
ratio
68:32
c) BnOH: fast O to N Bn transfer
Next, reactions were performed in the absence of added
acetic acid to allow examination of the stability of the l6-
sulfanenitrile species 5 (Scheme 5a). Using iPrOH as the reaction
solvent gave a 74:26 ratio of 5b:2a on evaporation of the reaction
mixture as determined by 1H NMR. The same result was obtained
with an aqueous work up indicating the stability of 5b to water.
Doping the reaction with water (5 equiv) led to increased
conversion to 2a, suggesting an alternative possible pathway that
incorporated H2O directly. To further confirm this, 18OH2 was
added to the reaction (with acetic acid), and mass spectrometry
of the obtained sulfonimidamide product indicated incorporation
of 18O in the in a roughly 1:2 ratio to the 16O isotope (Scheme 5b).
Different alcohols were employed to form derivatives of the
alkoxy-amino-l6-sulfanenitrile species 5, examining the extent of
conversion to the sulfonimidamide under the reaction conditions
(Scheme 5a). In each case, the corresponding l6-sulfanenitrile
was observed. Various primary alcohols gave increased amounts
of 5. To enable a broader range of solid alcohols, a mixture of
alcohol in toluene was tested; as a reference iPrOH gave a 60:40
ratio of 5b:2a. Neopentyl alcohol (in toluene), gave similar results
to iPrOH. As a poor electrophile for SN1 and SN2 reactions, this
is consistent with an alternative H2O mediated pathway being
operative to form 2a in these examples. Using tBuOH was
unsuccessful in forming the corresponding l6-sulfanenitrile,
instead returning mainly 1a and a small amount of 2a. It is notable
that PhIO has poor solubility in tBuOH, however, when one equiv.
of either AcOH or AcONa were used in the reaction a good
conversion to 2a was observed, suggesting a crucial role of the
acetate beyond just solubility. When benzyl alcohol was used as
the reaction solvent, the l6-sulfanenitrile was not observed, with
2a as the major product. Interestingly, rearrangement product 19
was also isolated, presumably by intermolecular benzylation due
to the l6-sulfanenitrile being a highly reactive benzylating agent.
Finally, 2-trimethylsilylethanol was investigated expecting to
further destabilize the intermediate to allow conversion to the
sulfonimidamide through silyl promoted elimination. This was
indeed the case, providing an increased ratio of sulfonimidamide
2a to l6-sulfanenitrile (15:85) which allowed for isolation of 2a
under acid free conditions in a 62% yield.
PhIO (2.5 equiv)
NH2CO2NH4 (2 equiv)
Bn
Bn
N
O
S
N
N
O
S
O to N
no acid
S
N
N
BnOH (0.2 M)
25 °C, 1 h
1a
putative intermediate
not observed
19
20% from 1a
d) β-Silyl group promotes elimination
PhIO (2.5 equiv)
NH2CO2NH4 (2 equiv)
O
S
NH
N
no acid
S
N
2-(TMS)ethanol:toluene
(1:1) (0.2 M)
1a
2a
25 °C, 1 h
62% from 1a
Scheme 5. Formation of various alkoxy-amino-λ6-sulfanenitriles 5.
The reactivity of alkoxy-amino-l6-sulfanenitriles 5b, 5d and 5e
with acidic nucleophiles was then investigated (Scheme 6).
Treating l6-sulfanenitrile 5b with benzoic acid in anhydrous
CH2Cl2 gave high yields of 2a and the corresponding alkylated
product. Thiophenol and phenol were also suitable nucleophiles.
Intriguingly, AcONa did not convert any of the l6-sulfanenitrile to
2a showing the need for a prior protonation before alkylation can
take place. The 2,2,2-trifluoroethyl group of 5d was transferred to
thiophenol in 75% yield, with overall activation of trifluoroethanol.
Furthermore, stirring 5e containing the highly sterically hindered
neopentyl group with thiophenol led to alkylation in low yield with
a slight improvement in yield when the reaction time was
extended to 3 days. More strongly acidic conditions using benzoic
acid led to a good yield (63%) of the neopentyl ester product.
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10.1002/anie.201906001
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RESEARCH ARTICLE
R
Table 3. Product distribution when using carboxylate salts.
O
S
N
O
S
NH
N
NuH (1 equiv)
PhIO (2.5 equiv)
NH2CO2NH4 (2 equiv)
additive
N
R
Nu
+
=
O
S
N
O
S
NH
N
CH2Cl2 (0.2 M)
25 °C, 1 h
S
+
5
2a
N
N
iPrOH (0.2 M)
Product yields (2a and
) with various nucleophiles:[a,b]
Nu
R
25 °C, 1 h
1a
5b
2a
F3C
=
R
iPr
5b
R
=
5d
5e
R
Yield[a]
2a
NuH
2a
R
Nu
NuH
2a
R
Nu
75
NuH
2a
R
Nu
Entry
Additive
PhCO2H
quant
93
PhSH
74
PhSH
PhSH[c] 42
PhCO2H
34
26
5b
9
1a
10
13
12
PhSH
92
quant
84
63
0
38
63
PhOH
AcONa[d]
69
1
2
3
AcONa
73
0
AcONBu4
PhCO2Na
7
74
Scheme 6. Formation of various alkoxy-amino-l6-sulfanenitriles 5 and their
reactivity with different nucleophiles. [a] Determined by 1H NMR analysis of the
crude reaction mixture using 1,3,5-trimethoxybenzene as internal standard. [b]
The amount of 2a corresponds to the amount of 2a formed in the reaction after
subtraction of that already present in the mixture deriving from the synthesis of
5 (37% with 5b, 13% 5d and 35% 5e). [c] Reaction time extended to 72 h. [d]
iPrOH used as a co-solvent to solubilize AcONa (1:1).
55
36
[a] Determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-
trimethoxybenzene as internal standard.
diastereotopic
protons
H
H
PhIO (2.5 equiv)
NH2CO2NH4 (2 equiv)
It is apparent from intermediate alkoxy-amino-l6-
sulfanenitriles that the O atom originates from the solvent through
this pathway. The protonated alkoxy-amino-l6-sulfanenitriles are
powerful electrophiles. These results are suggestive of a
combination of SN1 and SN2 pathways being operative, and that
the conjugate base is likely to be the nucleophile. The use of
isopropanol provides a cleaner overall reaction than other
solvents, which may be due to the balance it offers of higher
nucleophilicity (cf tBuOH), as well as effective substitution
pathways.
S
O
O
S
N
aq
CH3CH2CO2H (1 equiv)
N
2a
N
CH2Cl2 (0.2 M)
25 °C, 1 h
(82% from 1a)
1a
20 (18%) + 2a
observed by 1H NMR
and HRMS
Scheme 7. Identification of an acyl-amino-l6-sulfanenitrile as
a putative
intermediate.
Finally, we considered potential differences in the reaction
mechanism in the presence of the acetic acid. The influence of
sodium acetate on the reaction in tBuOH (Scheme 5), and the
inability of NaOAc to break down the sulfanenitrile (Scheme 6),
suggested an additional role for acetate in the reaction
mechanism. When sodium acetate was used as an additive under
the full reaction conditions, in place of acetic acid, 2a was formed
in a 73% yield (Table 3, entry 1). When using tetrabutylammonium
acetate essentially the same product distribution was seen
indicating that there is no effect from the sodium counterion on
the l6-sulfanenitrile (entry 2). Importantly, the alkoxy-amino-l6-
sulfanenitrile 5b was also observed in both cases. This suggested
Therefore, mechanistically we propose the following, as
shown in Scheme 8. Initial solubilization of PhIO occurs through
condensation with iPrOH. A highly reactive iodonitrene species is
then formed from the oxidant and ammonia. We have previously
detected this short-lived intermediate via HRMS studies with 15N
labelled ammonia.[14] The iodonitrene rapidly reacts with the
sulfenamide to form a sulfinamidine salt. The elimination of
iodobenzene from this species to form the S≡N triple bond may
occur before or at the same time as attack of a suitable
nucleophile. Under the reaction conditions,
3
possible
nucleophiles can attack at the sulfur centre. Addition of the
abundant alcohol solvent forms the alkoxy-amino-l6-sulfanenitrile.
This is relatively stable under neutral conditions, but becomes a
powerful alkylating agent in mild acidic conditions. Alternatively,
attack of acetate provides an unstable intermediate that readily
converts to the sulfonimidamide through the action of solvent.
Finally, the addition of water, present in the solvent or generated
from the solubilization of iodosylbenzene can lead directly to the
sulfonimidamide. It is notable that each possible pathway leads to
the same product, conferring the remarkably high
chemoselectivity to the reaction.
a
third pathway where an intermediate acetoxy-amino-l6-
sulfanenitrile is formed, such a species could break down rapidly
via attack of the alcohol solvent to form 2a. Interestingly, sodium
benzoate afforded an increased amount of the alkoxy-amino-l6-
sulfanenitrile 5b perhaps due to its reduced nucleophilicity (entry
3). Performing the standard reaction using AcOH, but in CH2Cl2
rather than iPrOH gave intermediate products that could be
1
putatively assigned as an acetoxy-amino-l6-sulfanenitrile by H
NMR of the crude reaction mixture following evaporation.
Exposure of the sample to water led to immediate breakdown to
sulfonimidamide 2a. Using propionic acid in place of AcOH gave
further support for this unstable intermediate, with the observation
of diastereotopic methylene protons derived from the propionate
in the l6-sulfanenitrile, which was also characterized by high
resolution mass spectrometry (Scheme 7).[22]
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10.1002/anie.201906001
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RESEARCH ARTICLE
Formation of iodonitrene:[14]
[1]
a) F. W. Goldberg, J. G. Kettle, T. Kogej, M. W. D. Perry, N. P.
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Synlett 2017, 28, 2525; h) U. Lücking, Org. Chem. Front. 2019, 6, 1319.
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Buendia, G. Grelier, B. Darses, A. G. Jarvis, F. Taran, P. Dauban, Angew.
Chem. Int. Ed. 2016, 55, 7530; Angew. Chem. 2016, 128, 7656; b) J.
Buendia, B. Darses, P. Dauban, Angew. Chem. Int. Ed. 2015, 54, 5697;
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2010, 75, 3301; d) C. Worch, C. Bolm, Synlett 2009, 2009, 2425.
a) U. Lücking, R. Jautelat, M. Krüger, T. Brumby, P. Lienau, M. Schäfer,
H. Briem, J. Schulze, A. Hillisch, A. Reichel, et al., ChemMedChem 2013,
8, 1067; b) U. Lücking, A. Scholz, P. Lienau, G. Siemeister, D. Kosemund,
R. Bohlmann, H. Briem, I. Terebesi, K. Meyer, K. Prelle, et al.,
ChemMedChem 2017, 12, 1776.
[O]
iPrOH
NH3
PhIO
PhI(OiPr)2
PhI=NH
Ph
I N
-H2O
-iPrOH
Formation of sulfonimidamides:
R
O
S
N
R
OH
N
RCO H
P
P
2
ArSH
ArOH
IPh
[2]
Ph
I
N
N
S
AcO
HO
N
P
O
O
AcOH
or
AcO
S
S
N
N
N
ROH
AcO
H2O
ROH
P
P
N
O
S
NH
H2O
S
N
N
Scheme 8. Proposed mechanism of sulfonimidamide formation.
[3]
Conclusion
In summary, we have developed an efficient method for the
preparation of NH-sulfonimidamides from sulfenamides. A highly
selective one-pot NH and O transfer is achieved, using a simple
ammonia source and a hypervalent iodine reagent. The use of
iodosylbenzene allows for control over the acidity of the reaction,
with one equivalent of acetic acid optimal for formation of the
desired sulfonimidamide. In the absence of added acid, an
unprecedented alkoxy-amino-l6-sulfanenitrile is isolated as a
reaction intermediate. The isolation and characterization of
several examples of this novel species provides insight into the
reaction mechanism, and identifies the solvent as one source of
the oxygen atom in the product. These newly formed alkoxy-
amino-l6-sulfanenitriles act as alkylating agents to a range of
acidic nucleophiles. Other pathways through the addition of water
or acetate are also operative. The sulfenamide to
sulfonimidamide transformation is tolerant of a range of functional
[4]
[5]
a) K. M. Foote, J. W. M. Nissink, T. McGuire, P. Turner, S. Guichard, J.
W. T. Yates, A. Lau, K. Blades, D. Heathcote, R. Odedra, et al., J. Med.
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14937; Angew. Chem. 2017, 129, 15133.
[6]
[7]
[8]
A. D. Steinkamp, L. Schmitt, X. Chen, K. Fietkau, R. Heise, J. M. Baron,
C. Bolm, Skin Pharmacol. Physiol. 2017, 29, 281.
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Hemeon, S. McKerrall, D. Sutherlin (Genentech, Inc.), WO 2017172802,
2017.
groups, displaying
a wide substrate scope, including the
[9]
For a review: G. C. Nandi, P. I. Arvidsson, Adv. Synth. Catal. 2018, 360,
2976.
functionalization of anti-depressants desipramine and fluoxetine.
The method was used in the synthesis of an aza-analogue of the
sulfonamide drug probenecid, as well as displaying possible
useful N-functionalization reactions on this scaffold,
demonstrating the utility of the methodology for medicinal
chemistry.
[10] B. Gao, S. Li, P. Wu, J. E. Moses, K. B. Sharpless, Angew. Chem. Int.
Ed. 2018, 57, 1939; Angew. Chem. 2018; 130, 1957.
[11] H. Yu, Z. Li, C. Bolm, Angew. Chem. Int. Ed. 2018, 57, 15602; Angew.
Chem. 2018; 130, 15828.
[12] J. Wen, H. Cheng, S. Dong, C. Bolm, Chem. Eur. J. 2016, 22, 5547.
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Aurell, A. Pettersen, E. Zamaratski, P. I. Arvidsson, Y. Chen, A.
Sandström, Eur. J. Org. Chem. 2019, 2019, 1045. b) S. V. Zasukha, V.
M. Timoshenko, A. A. Tolmachev, V. O. Pivnytska, O. Gavrylenko, S.
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Acknowledgements
We gratefully acknowledge The Royal Society [University
Research Fellowship, UF140161 (to J. A. B.) and URF appointed
grant RG150444, and URF enhancement grant, RGF\EA\180031],
and EPSRC [CAF to J.A.B. (EP/J001538/1), Impact Acceleration
Account (EP/K503733/1), DTA Studentship (to E.L.B.)]. This
research was supported by the project MISE, Horizon 2020 –
PON 2014/2020 FARMIDIAB “code 338”, the University of Bari.
[14] M. Zenzola, R. Doran, L. Degennaro, R. Luisi, J. A. Bull, Angew. Chem.
Int. Ed. 2016, 55, 7203; Angew. Chem. 2016, 128, 7319.
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53, 348.
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Marzag, A.-C. Gaumont, V. Reboul, Chem. Commun. 2017, 53, 2064; b)
Y. Xie, B. Zhou, S. Zhou, S. Zhou, W. Wei, J. Liu, Y. Zhan, D. Cheng, M.
Chen, Y. Li, et al., ChemistrySelect 2017, 2, 1620; Also see: c) S.
Keywords: hypervalent iodine • reactive intermediates • sulfur •
sulfonimidamides • synthetic methods
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10.1002/anie.201906001
Angewandte Chemie International Edition
RESEARCH ARTICLE
Chaabouni, J.-F. Lohier, A.-L. Barthelemy, T. Glachet, E. Anselmi, G.
Dagousset, P. Diter, B. Pégot, E. Magnier, V. Reboul, Chem. Eur. J. 2018,
24, 17006.
2aa converted preferentially on neutral alumina during purification to give
a cyclic N-acyl sulfonimidamide, which was isolated in 74% yield from
the reactive diastereoisomer. Both diastereoisomers could be slowly
converted to the same cyclized product on stirring with alumina, due to
epimerisation. See reference 13a and also SI for further details.
[24] For an example of NsNH2 transfer to sulfoxides in the presence of
PhI(OAc)2, see: G. Y. Cho, C. Bolm, Tetrahedron Lett. 2005, 46, 8007.
[25] E. Carbonnel, T. Besset, T. Poisson, D. Labar, X. Pannecoucke, P.
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Campbell, E. L. Briggs, G. O. Estévez, M. Afonso, L. Degennaro, R. Luisi,
J. A. Bull, Org. Lett. 2018, 20, 2599; b) For synthesis of sulfoximine
carbamates using Rh-catalysis, see: M. Zenzola, R. Doran, R. Luisi, J. A.
Bull, J. Org. Chem. 2015, 80, 6391.
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F. Izzo, M. Schäfer, P. Lienau, U. Ganzer, R. A. Stockman, U. Lücking,
Chem. Eur. J. 2018, 24, 9295. See SI for further examples of N-arylation
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Kruger, P. I. Arvidsson, Tetrahedron 2014, 70, 5428.
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[22] See SI for further details.
[28] W. Hao, T. Fujii, T. Dong, Y. Wakai, T. Yoshimura, Heteroat. Chem. 2004,
15, 193.
[23] Typically the sulfonimidamides were purified on neutral alumina,
whereas compound 2aa was purified on silica. One diastereoisomer of
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RESEARCH ARTICLE
Layout 2:
RESEARCH ARTICLE
E. L. Briggs, A. Tota, M. Colella,
L. Degennaro, R. Luisi* and J. A. Bull*
PhIO, NH2CO2NH4
AcOH (1 equiv)
R
O
S
NH
N
Isolation of key
intermediate -
a novel
O
S
N
S
N
N
iPrOH
25 °C, 1 h
functional group!
Page No. – Page No.
>30 examples
Synthesis of Sulfonimidamides from
Sulfenamides via an Alkoxy-amino-l6
sulfanenitrile Intermediate
Highly chemoselective
Yields up to 95%
Drug analogues
Mechanistic studies
-
NH and O transfer: Convenient reagents for NH and O transfer allow the direct
preparation of NH sulfonimidamides from sulfenamides. A wide range of diversely
functionalized sulfonimidamides are prepared in high yields using mild reagents in
just two steps from commercial starting material. Novel alkoxy-amino-l6-
sulfanenitriles are isolated and their reactivity demonstrated for the first time.
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