Copper-Catalyzed Transsulfinamidation of Sulfinamides as a Key Step in the Preparation of Sulfonamides and Sulfonimidamides

Article abstract of DOI:10.1002/anie.201810548

Secondary or tertiary sulfinamides are prepared by copper-catalyzed transsulfinamidation of primary sulfinamides with O-benzoyl hydroxylamines. Subsequent oxidations of the resulting products lead to the corresponding sulfonamides. Treatment of N-aryl sulfinamides with O-benzoyl hydroxylamines under copper catalysis provides N-aryl sulfonimidamides.

Full text of DOI:10.1002/anie.201810548

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Accepted Article
Title: Copper-Catalyzed Transsulfinamidation of Sulfinamides as a Key
Step in the Preparation of Sulfonamides and Sulfonimidamides
Authors: Hao Yu, Zhen Li, and Carsten Bolm
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10.1002/anie.201810548
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed Transsulfinamidation of Sulfinamides as a Key
Step in the Preparation of Sulfonamides and Sulfonimidamides
Hao Yu,+ Zhen Li,+ and Carsten Bolm*
O
S
O
S
CuBr2 (20 mol %)
R’
PPh3 (20 mol %)
Abstract: Secondary or tertiary sulfinamides are prepared by
copper-catalyzed transsulfinamidation of primary sulfinamides with
O-benzoyl hydroxylamines. Subsequent oxidations of the resulting
products lead to the corresponding sulfonamides. Treatment of N-
aryl sulfinamides with O-benzoyl hydroxylamines under copper
catalysis provides N-aryl sulfonimidamides.
BzO
R’
N
NH2
+
N
R
R
R’’
DCE, 60 °C
argon, 12 h
R’’
1 (2 equiv)
2 (R’, R’’ ≠ H)
Me
3
O
S
O
S
O
S
N
Ar
N
N
O
S
O
O
Me
Me
Transamidations are synthetically highly valuable reactions for
the preparation of amides.[1] Whereas significant progress has
been made in transamidations of primary amides (Scheme 1),[2]
analogous conversions of sulfinamides[3] have remained
unknown. Considering the importance of such sulfur reagents as
chiral auxiliaries,[4] ligands,[5] and intermediates in the
preparation of sulfonamides,[6,7] this synthetic gap comes as a
surprise. Here, we report on the development of trans-
sulfinamidation reactions and the extension of those studies
leading to the discovery of a novel approach towards N-arylated
sulfonimidamides.
3ga: 78%
3aa (Ar = pTol): 82%
3fa: 61%
O
S
3ba (Ar = pCl-C6H4): 76%
3ca (Ar = pF-C6H4): 79%
3da (Ar = Ph): 83%
N
O
3ea (Ar = pMeO-C6H4): 75%
3ha: 63%
O
S
O
S
O
S
pTol
N
pTol
N
pTol
N
X
( )n
3ab (n = 1): 41%
3ac (n = 2): 73%
3ad (n = 3): 75%
3af (X = S): 72%
3ae: 60%
3ag (X = N-Bz): 67%
3ah (X = N-Boc): 80%
O
S
O
S
pTol
N
O
pTol
N
Transamidation of primary amides
O
N
N
O
many
examples
S
O
H
R’
N
O
R’
+
O
R
N
R
NH2
R''
Br
3ai: 70%
3aj: 76%
R''
O
S
O
S
Transsulfinamidation of primary sulfinamides
O
S
pTol
N
N
pTol
Ph
O
N
O
S
H
R’
pTol
NR’R’’
unknown
N
N
N
S
R’
+
R
N
R
NH2
R''
3am (R’ = R’’ = Et): 66%
3an (R’ = R’’ = Allyl): 58%
3ao (R’ = R’’ = Bn): 75%
N
R''
BzO
R’
3ak: 50%
3al: 68%
N
R''
copper catalysis
reported here
O
S
O
S
Me
Ph
O
iPr
S
Me
pTol
N
pTol
N
pTol
N
Bn
Bn
Bn
Scheme 1. Transamidations of primary amides (top) and analogous reactions
3aq: 52%
(S,R)-3ar and (R,R)-3ar
(1:1 dr): 46%
3ap: 73%
starting from primary sulfinamides (bottom).
Scheme 2. Substrate scope of transsulfinamidations with O-benzoyl
For the initial experiments, para-tolylsulfinamide (1a) was
selected as representative starting material. Being guided by
literature,[8] O-benzoyl hydroxylmorpholine (2a) was chosen as
amino transfer agent.[9] After an extensive screening and
optimization,[10] product 3aa could be obtained in 82% yield. A
combination of CuBr2 (20 mol %) and PPh3 (20 mol %) served
as catalyst, which as applied in 1,2-dichloroethane (DCE) at
60 °C for 12 h under an argon atmosphere. The scope of this
unprecedented reaction is depicted in Scheme 2.
hydroxylamines of secondary amines (on a 0.2 mmol scale).
First, the sulfinamide component was varied, and for
products 3aa-3ha, O-benzoyl hydroxylmorpholine (2a) served as
amino source. In general, the transsulfinamidations worked well,
and the products were obtained in yields ranging from 61-83%.
While electronic factors appeared to be irrelevant for the
reaction efficiency (as reflected by the results for variously para-
substituted benzenesulfinamides 3aa-3ea), steric crowding (as
in 3fa, 61% yield) and the presence of a heteroatom in the arene
(as in 3ha, 63% yield) seemed to hamper the reaction leading to
lower product yields.
Subsequently, a range of O-benzoyl hydroxylamines 2 were
examined in reactions with para-tolylsulfinamide (1a) as coupling
partner (Scheme 2). Substrates derived from pyrrolidine,
piperidine, azepane, tetrahydroisoquinoline and thiomorpholine
provided the corresponding sulfinamides 3ab-3af in yields of 41-
75%. Various protected piperazine derivatives reacted well too,
leading to products 3ag-3ak in moderate to high yields (50-80%).
[*]
H. Yu, Dr. Z. Li, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.
Homepage: http://bolm.oc.rwth-aachen.de/
[+] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201810548
Angewandte Chemie International Edition
COMMUNICATION
Product 3al was obtained from O-benzoylhydroxyl N-phenyl-
imidazolidine (2l) in 68% yield. Besides cyclic O-benzoylhydroxyl
amines, acyclic derivatives could be applied, as shown by the
formation of 3am-3ar, which were isolated in 46−75% yield. In
this series, the reaction with enantiopure (R)-N-benzyl-α-
Scheme 4 summarizes the results achieved in conversions
of selected sulfinamides 3 and 5 into their corresponding
sulfonamides
6
by treatment with 1.5 equiv of m-
chloroperbenzoic acid (m-CPBA) in DCM at room temperature.
For most substrates, the transformation proceeded well,
providing the expected products in yields ranging from 46% to
89%. Only for 6g, which stemmed from secondary sulfinamide
5aa, the yields remained low (35%).
methylbenzylamine must be highlighted. It provided
a 1:1
diasteremeric mixture of (S,R)-3ar and (R,R)-3ar in 46% yield,
and to our delight, the diastereomers could be separated by
column chromatography.
O
S
O
O
Until this stage, only O-benzoyl hydroxyl derivatives of
secondary amines had been applied. With the goal to further
extend the substrate scope, the preparation of secondary
sulfinamides 5 from primary amine-based substrates 4[9a, 11] was
investigated. Again, para-tolylsulfinamide (1a) was used as
coupling partner. Gratisfyingly, the aforedeveloped reaction
conditions were also suitable here (Scheme 3), although in
general, the yields of the resulting products 5aa-5aj were only
moderate to good (24–79%). Applying O-benzoyl hydroxyl
amines with a low degree of branching led to the best results
(products 5aa-5ac). Increasing the steric bulk around the amino
group had a negative effect on the reaction outcome as revealed
by the yields of 24% and 38% in the formation of 5ad and 5ae,
respectively. Using chiral O-benzoyl hydroxyl amine derivatives
in reactions with para-tolylsulfinamide (1a) afforded 5af-5aj as
1:1 mixtures of diastereomers. In this series, products 5ah and
5ai derived from the methyl esters of L-phenylalanine and L-
leucine, respectively, are noteworthy because they could be
separated by column chromatography affording single stereo-
isomers. Also the conversion of estrone derivative 4j, which
gave a 62% yield of a 1:1 distereomeric mixture of sulfinamide
5aj, shall be mentioned.
m-CPBA (1.5 equiv)
S
Ar
Ar
NR’R’’
NR’R’’
DCM, RT
3 or 5
6
O
S
O
S
O
S
O
S
O
O
O
O
pTol
pTol
N
N
N
N
S
MeO
O
O
O
6d: 60%
6c: 70%
6a: 89%
6b: 75%
O
O
O
O
N
S
S
O
O
pTol
N
pTol
S
O
pTol
NHBn
N
N
N
O
N
6e: 46%
6g: 35%
6f: 72%
Scheme 4. Preparation of sulfonamides by oxidations of their corresponding
sulfinamides with m-CPBA (on a 0.1 mmol scale).
Sulfonimidamides are mono-aza analogues of sulfonamides,
which have recently attracted attention in both medicinal and
agricultural chemistry.[12] Because of their interesting properties
such as high chemical and metabolic stability, multiple hydrogen
bond acceptor/donor functionalities, and structural diversity,
sulfonimidamides can act as sulfonamide bioisosteres.
Subsequently, medicinal chemists applied them, for example, as
BACE and kinase inhibitors.[13,14] Until now, the utilization of
sulfonimidamides has been restricted by a lack of commercial
availability and limited synthetic accessibility.[15,16] Most often,
they are prepared by nucleophilic substitution of sulfonimidoyl
chlorides, which are obtained by electrophilic chlorination of
sulfinamides followed by substitution with an amine. These
protocols, however, suffer from the required multi-step reaction
sequence and restrictions in substrate scope. Clearly, more
convenient and efficient methods for the preparation of
sulfonimidamides are desirable. In this context, we appreciated
the finding that the aforementioned copper catalysis with O-
benzoyl hydroxylamines as amino source could be adopted for
the conversion of N-aryl sulfinamides into their corresponding
sulfonimidamides (Scheme 5).[17]
O
S
O
S
CuBr2 (20 mol %)
R’
PPh3 (20 mol %)
BzO
R’
N
H
NH2
+
N
DCE, 60 °C
argon, 12 h
R’’
Me
Me
1a (2 equiv)
5
4
O
S
Me
O
O
Me
Me Me
Me
S
R’
S
pTol
N
H
pTol
N
H
pTol
N
H
Me
5aa (R’ = Bn): 64%
5ab (R’ = Bu): 79%
5ac (R’ = Ch): 65%
5ad (R’ = tBu): 24%
(S,R)-5af and (R,R)-5af
(1:1 dr): 76%
5ae: 38%
Me
OBn
O
S
Me
O
S
O
OMe
OMe
pTol
N
H
S
OEt
pTol
N
H
pTol
N
H
O
O
O
(S,S)-5ag and (R,S)-5ag
(1:1 dr): 35%
(S,S)-5ah and (R,S)-5ah (S,S)-5ai and (R,S)-5ai
(1:1 dr): 46%
(1:1 dr): 60%
Me
Under the original reaction conditions with the catalyst
based on CuBr2/PPh3, N-phenyl benzenesulfinamide (7a)
reacted with 2a providing sulfonimidamide 8aa in 59% yield.
After a series of experiments,[11] the optimal reaction conditions
were identified to involve the use of CuBr (20 mol %) in
acetonitrile at 80 °C under argon for 12 h. In this manner, 8aa
was obtained from 7a and 2a in 89% yield. Evaluating the
substrate scope revealed a broad applicability of the method
(Scheme 5).
H
H
Me
N
S
BnO
H
H
O
5aj (1:1 dr): 62%
Scheme 3. Substrate scope of transsulfinamidations with O-benzoyl
hydroxylamines of primary amines (on a 0.2 mmol scale).
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10.1002/anie.201810548
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COMMUNICATION
Reductive elimination of C regenerates the Cu(I) species
R2
CuBr
(20 mol %)
needed for closing the catalytic cycle and provides
a
O
S
R2
BzO
R’
O
S
N
sulfonimidamide, which is stable if N-arylated (to give 8) or labile
if N-unsubstituted (leading to sulfinamides 3 or 5).[18] The latter
N
+
N
MeCN, 80 °C
argon, 12 h
R’’
R1
H
R1
N
R’
2 (R’, R’’ ≠ H)
transformation appears to involve
reductive side reactions.[19]
a loss of ammonia by
R’’
7
(2 equiv)
8
Ar’
8ac (X = CH2): 35%
8af (X = S): 85%
8ag (X = N-Bz): 82%
8ah (X = N-Boc): 82%
8as (X = N-Ts): 72%
Ph
N
O
Cu(II)L
Cu(I)L
R’’’
O
N
O
S
S
OBz
N
2
N
O
R
Ar
Ph
N
R’
S
S
N
N
R’
R
N
R’
R’’
R''
R’’’ = H:
– NH3
O
R’’
X
8at [X = NC(O)NHPh]: 42%
8au (X = CHCO2Me): 60%
3 or 5
R’’’ = Ar: 8
8aa (Ar = Ar’ = Ph): 89%
8ba (Ar = pTol, Ar’ = Ph): 89%
8ca (Ar = pCl-C6H4, Ar’ = Ph): 72%
8da (Ar = pTol, Ar’ = oTol): 70%
8ea (Ar = pTol, Ar’ = mTol): 78%
8fa (Ar = pTol Ar’ = pTol): 66%
8ga (Ar = pTol Ar’ = pF-C6H4): 81%
8ha (Ar = pTol, Ar’ = pCl-C6H4): 84%
8ia (Ar = pTol, Ar’ = pNC-C6H4): 96%
8ja (Ar = pTol Ar’ = pMeO2C-C6H4): 88%
8ka (Ar = pTol, Ar’ = mCl-C6H4): 96%
8la (Ar = pTol, Ar’ = oBr-C6H4): 98%
8ma (Ar = pTol, Ar’ = 3-pyridinyl): 81%
R’’’
N
O
Ph
O
S
Ph
N
N
R
BzO Cu(III)L
N
S
Cu(III)L
O
Ph
N
R’
N
S
R’
R’’
Ph
A
N
R’’ C
N
O
O
S
S
N
O
O
S
O
R’’’
R
N
NHR’’’
R
O
Cu(III)L
R'
1 (or 7)
N
8ai, 81%
Br
8aj, 76%
R’’
B
Me
O
Scheme 6. Proposed reaction pathway.
Ph
O
Ph
N
N
N
N
N
S
N
S
N
O
In conclusion, we discovered a copper-catalyzed trans-
sulfinamidation of primary sulfinamides with O-benzoyl hydroxyl-
amines providing secondary or tertiary sulfinamides. Simple
oxidation reactions of the products lead to the corresponding
sulfonamides. An analogous copper catalysis starting from N-
aryl sulfinamides provides N-aryl sulfonimidamides.
Ph
Ph
Me
8ak, 24%
8av, 76%
Scheme 5. Preparation of N-aryl sulfonimidamides (on a 0.2 mmol scale).
First, the sulfinamide structure was varied. In reactions with
O-benzoyl hydroxylmorpholine (2a), all products (8aa-8ma) were
obtained in high to excellent yields. Neither steric nor electronic
Acknowledgements
factors had an apparent effect.
A remarkable range of
substituents including halo, cyano, carboxyl, and methoxy
groups were tolerated well. Unexpectedly, the highest yield
(98%) was observed in the formation of ortho-bromo aryl-
containing product 8la. Also 8na bearing an N-3-pyridinyl
substituent was obtained in high yield (81%).
H.Y. thanks the China Scholarship Council for pre-doctoral
stipend.
Keywords: Copper catalysis • sulfinamide • transsulfinamidation
To further explore the generality of the sulfonimidamide
formation (Scheme 5), various O-benzoylhydroxyl amines 2
were tested in reactions with sulfinamide 7a. Most educt
combinations afforded the corresponding products in good to
high yields. For example, sulfonimidamides 8af, 8ag, and 8ah
resulting from couplings of 7a with thiomorpholine (2f), N-Bz
piperazine (2g) and N-Boc piperazine (2h) were formed in yields
• sulfonamide • sulfonimidamide
[1]
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of 85%, 82%, and 82%.
Other N-protected piperazine
derivatives worked too, but the yields were slightly lower
(ranging from 24% for 8ak to 81% for 8ai). Reacting 7a with
piperidines 2c and 2u gave sulfonimidamides 8ac and 8au in
yields of 35% and 60%. Finally, also disubstituted morpholine 2v
could be applied as illustrated by the formation of 8av, which
[2]
For selected examples, see: (a) T. A. Dineen, M. A. Zajac, A. G. Myers,
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Shankarling, RSC Adv. 2016, 6, 52724–52728.
was obtained in 76% yield.
8, 9]
In the light of previous work,[2,
the reaction pathway
depicted in Scheme 6 is suggested: When starting from a Cu(II)
salt, the process is initiated by metal reduction to provide a Cu(I)
species. Oxidation by O-benzoylhydroxylamine 2 leads to Cu(III)
intermediate A, which undergoes ligand exchange with
sulfinamide 1 (or 7) to give complex B. Subsequently, B
converts to C by metal migration from nitrogen to sulfur.
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10.1002/anie.201810548
Angewandte Chemie International Edition
COMMUNICATION
[3]
[4]
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[5]
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Both sulfinamides and sulfonamides are regarded as bioisosteres of
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[16] For various structural modifications and applications of sulfonimidamide
derivatives, see: (a) C. Worch, C. Bolm, Synthesis 2007, 1355–1358;
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2010, 75, 3301–3310; (f) F. W. Patureau, C. Worch, M. A. Siegler, A. L.
Spek, C. Bolm, J. N. H. Reek, Adv. Synth. Catal. 2012, 354, 59–64.
[17] Until now, only reactions with N-aryl sulfinamides have been studied. If
other derivatives can be applied needs to be investigated and will be
part of future work.
[18] This assumption was substantiated by the degradation of the NH-
analog of 8ac in the presence of 1a or 2a, which led to 3ac in
significant amounts under the standard catalysis conditions depicted in
Scheme 5. For details, see the Supporting Information.
[7]
[19] The catalysis is not inhibited by the presence of 2 equiv of TEMPO, as
shown by the coupling of 1a and 2a, which gave 3aa in 67% yield under
the standard catalysis conditions depicted in Scheme 2. For details, see
the Supporting Information.
[8]
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This article is protected by copyright. All rights reserved.

10.1002/anie.201810548
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Hao Yu, Zhen Li, and Carsten Bolm*
Page No. – Page No.
Copper-Catalyzed Transsulfin-
amidation of Sulfinamides as a Key
Step in the Preparation of
Sulfonamides and Sulfonimidamides
Copper-catalyzed transsulfinamidation of primary sulfinamides with O-
benzoylhydroxylamines deliver secondary or tertiary sulfinamides.
A simple
oxidation reaction converts the products into sulfonamides. A related copper
catalysis provides N-aryl sulfonimidamides from N-aryl sulfinamides.
This article is protected by copyright. All rights reserved.