Catalytic Chemoselective Sulfimidation with an Electrophilic [CoIII(TAML)]?-Nitrene Radical Complex**

Article abstract of DOI:10.1002/chem.202003566

The cobalt species PPh₄[Co^III(TAML^red)] is a competent and stable catalyst for the sulfimidation of (aryl)(alkyl)-substituted sulfides with iminoiodinanes, reaching turnover numbers up to 900 and turnover frequencies of 640 min^?1 under mild and aerobic conditions. The sulfimidation proceeds in a highly chemoselective manner, even in the presence of alkenes or weak C?H bonds, as supported by inter- and intramolecular competition experiments. Functionalization of the sulfide substituent with various electron-donating and electron-withdrawing arenes and several alkyl, benzyl and vinyl fragments is tolerated, with up to quantitative product yields. Sulfimidation of phenyl allyl sulfide led to [2,3]-sigmatropic rearrangement of the initially formed sulfimide species to afford the corresponding N-allyl-S-phenyl-thiohydroxylamines as attractive products. Mechanistic studies suggest that the actual nitrene transfer to the sulfide proceeds via (previously characterized) electrophilic nitrene radical intermediates that afford the sulfimide products via electronically asynchronous transition states, in which SET from the sulfide to the nitrene radical complex precedes N?S bond formation in a single concerted process.

Full text of DOI:10.1002/chem.202003566

Accepted Article
Accepted Article
Title: Catalytic Chemoselective Sulfimidation with an Electrophilic
[CoIII(TAML)]‒-Nitrene Radical Complex
Authors: Nicolaas P. van Leest, Jarl Ivar van der Vlugt, and Bas de
Bruin
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To be cited as: Chem. Eur. J. 10.1002/chem.202003566
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01/2020

10.1002/chem.202003566
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Catalytic Chemoselective Sulfimidation with an Electrophilic
[CoIII(TAML)]‒-Nitrene Radical Complex
Nicolaas P. van Leest,[a] Jarl Ivar van der Vlugt[a],[b] and Bas de Bruin*,[a]
[a]
N. P. van Leest, Prof. Dr. Ir. J. I. van der Vlugt, Prof. Dr. B. de Bruin
Homogeneous, Supramolecular and Bio-Inspired Catalysis Group
van ‘t Hoff Institute for Molecular Sciences
University of Amsterdam (UvA)
Science Park 904, 1098 XH Amsterdam, The Netherlands
E-mail: b.debruin@uva.nl
[b]
Current address Prof. Dr. Ir. J. I. van der Vlugt
Bioinspired Coordination Chemistry & Homogeneous Catalysis Group
Institute of Chemistry
Carl von Ossietzky University Oldenburg
Carl-von-Ossietzky-Strasse 9-11. 26129 Oldenburg, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: The cobalt species PPh4[CoIII(TAMLred)] is a competent
and stable catalyst for the sulfimidation of (aryl)(alkyl)-substituted
sulfides with iminoiodinanes, reaching turnover numbers up to 900
and turnover frequencies of 640 min-1 under mild and aerobic
conditions. The sulfimidation proceeds in a highly chemoselective
manner, even in the presence of alkenes or weak C‒H bonds, as
supported by inter- and intramolecular competition experiments.
Functionalization of the sulfide substituent with various electron-
donating and electron-withdrawing arenes and several alkyl, benzyl
and vinyl fragments is tolerated, with up to quantitative product yields.
Sulfimidation of phenyl allyl sulfide led to [2,3]-sigmatropic
rearrangement of the initially formed sulfimide species to afford the
corresponding N-allyl-S-phenyl-thiohydroxylamines as attractive
products. Mechanistic studies suggest that the actual nitrene transfer
to the sulfide proceeds via (previously characterized) electrophilic
nitrene radical intermediates that afford the sulfimide products via
electronically asynchronous transition states, in which SET from the
sulfide to the nitrene radical complex precedes N‒S bond formation
in a single concerted process.
sulfimidation and sulfoximidation. N-Haloamides (and derivatives),
(in situ prepared) iminoiodinanes, azides, and heterocyclic nitrene
precursors have all been used as imidation reagents.1a In addition,
uncatalyzed sulfimidation and sulfoximidation of S-alkyl and S-
aryl sulfides with in situ formed PhINNs (Ns = nosyl, 4-
(nitrophenyl)sulfonyl) occurs at prolonged heating in MeCN (16 h,
82 oC) 12 and the I2-catalyzed sulfimidation is also known,
producing N-tosylsulfimides (tosyl = Ts, 4-(methylphenyl)sulfonyl)
at room temperature.13 Alternatively, N,O-group exchange to form
sulfimides from sulfoxides can be achieved with the zwitterionic
Burgess reagent (+NEt3-SO2-N‒-CO-OR).14
Surprisingly, cobalt-catalyzed nitrene transfer to sulfur atoms
remains largely unexplored. While
a single example of
[Co(ClO4)2]-catalyzed sulfoximidation of methyl phenyl sulfoxide
with (in situ formed) PhINNs has been reported,15 there are no
reported examples of cobalt-catalyzed sulfimidation of sulfides, to
the best of our knowledge. Given recent developments in cobalt-
catalyzed N-group transfer reactions, 16 , 17 , 18 we decided to
investigate cobalt catalyzed sulfimidation via nitrene transfer to
sulfides focusing on chemoselective transformations in the
presence of other nitrene-accepting functional groups (alkenes
and weak C‒H bonds). For this purpose we decided to investigate
the reactivity of the previously characterized nitrene radical
adducts of a cobalt-TAML complex 19 (TAML = Tetra-Amido
Macrocyclic Ligand20) towards sulfides. Based on the reactivity
displayed by this Co-platform in alkene aziridination catalysis,18
we envisaged that this cobalt platform could also be a suitable
candidate for chemoselective catalytic sulfimidation reactions.
During our previous studies we identified the TAML ligand as
being redox-active on cobalt (see Scheme 1A for nomenclature
and structures) and we demonstrated that PPh4[CoIII(TAMLred)]
is selectively converted to the catalytically active bis-nitrene
radical complexes PPh4[CoIII(TAMLq)(NR)2] (R = nosyl or tosyl,
Scheme 1B) upon reaction with excess iminoiodinane during the
aziridination reactions.18,19 Moreover, we reported that productive
C‒N bond formation in the aziridination reaction occurs via
unusual electronically asynchronous transition states in which
single-electron transfer (SET) from styrene to the involved
nitrene-radical complex precedes C‒N bond formation in a single
concerted process (Scheme 1C). The formation of the C‒N bond
does not occur via nitrene radical attack (as might be expected),
Introduction
Sulfimides (RN=SR’R”), and their oxidized analogues
sulfoximines (RN=SOR’R”), are important substructures in
several pharmaceuticals as well as chemicals used for crop
protection.1 Moreover, the sulfimide and sulfoximine analogues of
known sulfoxide-based drugs were found to retain their drug-like
2
properties in e.g. ATR-targeted cancer therapy and often
displayed enhanced aqueous solubility, cell permeability and
metabolic stability. Specific (N-arylsulfonyl)sulfimide-based drugs
(ArSO2N=SR’R”, with R’ = alkyl and R” = aryl) have been found to
inhibit osteoclastogenesis and to bind to proteins (e.g. pirin),
causing inhibition of melanoma cell migration.3
Numerous synthetic methodologies1 for the S-imidation of
sulfides and sulfoxides have been developed following the initial
synthesis of S-vinylsulfimides using chloramine-T as the N-group
transfer agent in 1979, 4 and catalysts based on copper, 5
manganese,6 ruthenium,7 iron,8 rhodium,9 silver10 as well as a
11
P450-type enzyme
have been reported for (asymmetric)
1
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but rather via nucleophilic attack of the nitrene lone-pair onto a
(partially) formed styrene radical cation as a result of initial
substrate-to-ligand single-electron transfer. This process is
coupled to TAML-to-cobalt and cobalt-to-nitrene single-electron
transfer and a cobalt centered spin-flip.
sulfimidation reactions could be performed in presence of alkenes
and weak C‒H bonds.18 Specifically, we report the following
findings in this work:
(1) PPh4[CoIII(TAMLred)] is a competent catalyst for nitrene
transfer to sulfides under mild conditions.
(2) Nitrene transfer occurs chemoselectively for sulfimidation in
the presence of alkenes and weak C‒H bonds.
(3) Nitrene transfer proceeds via electrophilic behavior of the
nitrene radical intermediates, involving electronically
asynchronous transition states in which SET from the
sulfide to the nitrene radical complex precedes N‒S bond
formation in a single concerted process.
The main findings of this work are summarized in Scheme 2.
Scheme 1. (A): Oxidation states for the TAML scaffold. (B): previously reported
bis-nitrene radical formation on [CoIII(TAMLred)]‒.19 (C): Electronically
asynchronous transition state for C‒N bond formation in aziridination with
[CoIII(TAMLq)(NNs)2]‒.18
As substrate-to-ligand single-electron transfer precedes bond
formation in these electronically asynchronous transition states,
we reasoned that compounds having low one-electron oxidation
potentials might be suitable substrates for nitrene transfer
catalysis with PPh4[CoIII(TAMLred)] under mild and aerobic
conditions. Moreover, we hypothesized that this reactivity could
allow for selective (late stage) nitrene transfer catalysis when the
chemoselectivity is determined by the oxidation potential of the
functional group (i.e. preferred nitrene transfer to the functionality
that is most easily oxidized). For example, one-electron oxidation
Scheme 2. (A): Previous work on homogeneously catalyzed sulfimidation.5-10
(B): Cobalt-catalyzed sulfimidation approach presented in this paper.
of methyl phenyl sulfide (thioanisole, E = +1.56 V vs SCE)21a
½
occurs at a lower potential than styrene oxidation (E = +1.90 V
½
vs SCE)21b and would therefore lead to preferential sulfimidation
over aziridination. Hence, this mechanism of nitrene transfer to
sulfides could be particularly powerful for a chemoselective
catalytic sulfimidation protocol in the presence of alkenes and
weak C‒H bonds, which are both susceptible to reactions with
nitrene radicals16 but typically have higher oxidation potentials
than sulfides.
Related iron- 22 and manganese-TAML 23 complexes were
found be active in stoichiometric nitrene transfer to thioanisole
derivatives, but catalytic activity has not been reported to date.
Thus, inspired by the catalytic activity of PPh4[CoIII(TAMLred)]
under aerobic conditions in the aziridination of alkenes, we
decided to explore its catalytic activity for sulfimidation reactions.
Given the known reactivity of [CoIII(TAMLred)]‒ for aziridination
chemistry, we also investigated whether chemoselective
Results and Discussion
Optimization of the reaction conditions.
To establish the catalytic competence of PPh4[CoIII(TAMLred)] we
first investigated different classes of sulfides to determine the
preferred substrate class for sulfimidation. Thioanisole (E
=
½
+1.56
V
vs SCE)21a was cleanly converted to N-(4-
nitrobenzenesulfonyl)-S-methyl-S-phenylsulfimide (1Ns) in 77%
o
yield under aerobic conditions in 15 minutes at 25 C in CH2Cl2
with 2.5 mol% PPh4[CoIII(TAMLred)] (entry 1, Table 1).
Diphenylsulfide (E = +1.79 V vs SCE)21b,24 only afforded 19% of
½
the desired product in 15 minutes (longer reaction times lead to
higher yields, see Table 3), whilst dimethylsulfide (E = +0.91 V
vs SCE)21b,24 yielded 40% of the sulfimide, albeit with 55%
½
2
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10.1002/chem.202003566
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conversion of the iminoiodinane to NsNH2 (entry 2 and 3).25
Table 2. Optimization of the reaction time and catalyst loading for the
sulfimidation of thioanisole.
Thiophene (E = +1.91 V vs SCE)21a (entry 4) was not converted
½
to the corresponding sulfimide at all and also sulfoxides, which
have higher oxidation potentials compared to their corresponding
sulfides,21 were not effectively converted to the sulfoximines
(entry 5 and 6). These results indicate that (alkyl)(aryl)-substituted
sulfides are most effectively converted via N-transfer chemistry
due to their relatively low oxidation potentials.
Entry
R
Catalyst loading
(mol%)
Time (min)
Yield
(1R)[a]
1
Ns
2.5
1.0
1.0
1.0
0.1
0.1
0.1
1.0
1.0
‒
30
30
15
5
96%
96%
54%
16%
35%
64%
90%
>99%
90%
0%
Table 1. Initial substrate screening for the imidation of various sulfides and
sulfoxides with PhINNs.
2
Ns
3
Ns
4
Ns
Entry
X
‒
R1
R2
E
(V vs SCE)21
Yield[a]
77%
19%
40%[b]
n.d.
½
5
Ns
120
1
1
2
3
4
5
6
Ph
Ph
Me
Me
Ph
Me
+1.56
+1.79
+0.91
+1.91
‒
6
Ts
‒
7
Ts
5
‒
8
Ts
5
‒
‒(CH=CH‒CH=CH)‒
9
Tces
Ns / Ts
Ns
5
O
O
Ph
Ph
Me
Ph
9%
10
11
30
30
‒
n.d.
[b]
2%
Ratio PhINNs : substrate = 1 : 1. Conditions: 15 minutes, 24 mM PhINNs.
‒ denotes that X is a lone pair. n.d.: not detected. [a] Yields based on 1H NMR
integration using 1,3,5-trimethoxybenzene as an internal standard. [b] 55%
NsNH2 formation observed in 1H NMR.
Conditions: 15 minutes, 24 mM PhINNs. [a] Yields based on 1H NMR integration
using 1,3,5-trimethoxybenzene as an internal standard. [b] 2.5 mol% [PPh4]Cl,
TAMLH4 or CoCl2 was used.
Having established that (alkyl)(aryl)-substituted sulfides are
most effectively converted we set out to further optimize the
reaction conditions. With the nitrene precursor as the limiting
reagent we screened the reaction time and catalyst loading for
formation of 1Ns, 1Ts and 1Tces from thioanisole and the
corresponding iminoiodinane under aerobic conditions at 25 oC in
CH2Cl2.26 Using PhINNs, the highest yield (96%) of 1Ns was
obtained after 30 minutes with 2.5 or 1.0 mol%
PPh4[CoIII(TAMLred)] (entry 1-2, Table 2). Shorter reaction times
resulted in lower yields (entry 3 and 4). Interestingly, a two-hour
reaction using a catalyst loading as low as 0.1 mol% still afforded
1Ns in 35% yield, which corresponds to 350 turnover numbers
(TONs). Using PhINTs as the nitrene precursor at 0.1 mol%
catalyst loading produced 1Ts in 64% (TON = 640 and turnover
frequency (TOF) = 640 min-1) or 90% (TON = 900) after 1 or 5
minutes, respectively. Using 1.0 mol% catalyst and 5 minutes
reaction time yielded 1Ts and 1Tces in quantitative (>99%) or 90%
yield, respectively.
For consistency in the substrate scope screening (performed
mainly with PhINTs and PhINNs, vide infra), we selected 1.0
mol% catalyst loading and 30 minutes reaction time as the
standard conditions. Control reactions without catalyst (entry 10)
did not lead to product formation. The involvement of free ligand
(TAMLH4), [PPh4]+ or CoCl2 on product formation was excluded
(entry 11) as 1Ns was obtained in only 2% yield, thus clearly
demonstrating the catalytic behavior of PPh4[CoIII(TAMLred)].
Chemoselectivity in intermolecular competition reactions.
Kinetic competition experiments for nitrene transfer to S, C=C and
C‒H positions were performed to investigate the intermolecular
chemoselectivity for nitrene transfer reactions. The reactions
were performed with 2.5 mol% catalyst loading, which should lead
to maximal competition between C‒H amination or alkene
aziridination and sulfimidation, as this was previously reported to
be the optimal loading for alkene conversion.18 As substrates we
selected thioanisole, ethylbenzene, styrene and 4-tert-butyl-
styrene (4-tBu-styrene). The latter was included as we previously
showed that aziridination of this substrate proceeds much faster
than for styrene itself,18 thus making it a suitable substrate to
study competition between sulfimidation and aziridination.
Strikingly, in all cases, including 4-tBu-styrene, we observed
>99% selectivity for sulfimidation and preservation of the alkene
functionality (Table 3, entries 1-2). In absence of thioanisole,
aziridination of styrene is strongly favored over C‒H amination of
ethylbenzene (Table 3, entry 3). From these experiments it is
clear that the relative reaction rates for nitrene transfer follow the
order: kS > kC=C > kC‒H. Switching to diphenylsulfide (entries 4 and
5) afforded 82% and 83% selectivity for sulfimidation with PhINNs
in competition with aziridination of styrene or 4-tBu-styrene, with
the only detected by-product being the aziridine in 16% yield. The
chemoselectivity toward sulfimidation significantly increased
(95%) when using PhINTs (instead of PhINNs), consistent with
the higher reactivity of this iminoiodinane in the catalytic system
as reflected by shorter reaction times (vide supra). In addition, we
performed an intermolecular competition reaction between
styrene and thioanisole under the previously reported optimal
3
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styrene aziridination conditions18 with PhINNs (2.5 mol% catalyst
loading, 35 oC, total 5 equivalents substrate). This led to formation
of 1Ns in 91% yield, without detectable formation of the aziridine
(see Supporting Information).
even significantly lower reaction temperatures (‒61 oC or ‒78 oC)
still afforded 2Ts after 2 hours in 74% or 31% yield. The more
electron-rich 4-methoxythioanisole was converted to 3Ts in
quantitative yield and the electron-withdrawing para-fluoro- and
ortho-chloro-substituted thioanisoles yielded 4Ts and 5Ts in 92%
and >99% yield, respectively. We did not observe any
transformation of the weakly activated C‒H positions (highlighted
in grey) in these reactions by 1H NMR spectroscopy. Substitution
of the methyl group in thioanisole for ethyl or iso-propyl selectively
afforded 7Ts (90%), 7Ns (99%) and 8Ts (>99%), as depicted in
Scheme 3. The more strongly activated ‒CH2 position of benzyl
phenyl sulfide or 2-(phenylethyl)-phenyl-sulfide did not undergo
any reaction, with both substrates being selectively converted to
9Ts and 10Ts in 88% and 79% yield, respectively.
Table 3. Intermolecular competition experiments to investigate the
chemoselectivity for sulfimidation in presence of C=C and weak C‒H bonds.
Predominant
Entry
A
B
R
product (ANR
)
and selectivity [a]
To investigate intramolecular competition with alkenes, we
employed phenyl vinyl sulfide, which afforded selective formation
of 11Ts in 49% yield (Scheme 3), without any indication for
aziridine formation based on 1H NMR spectroscopy. Using phenyl
allyl sulfide as the substrate with either PhINTs or PhINNs led to
clean formation of N-allyl-S-phenyl-thiohydroxylamines 13Ts
(78%) and 13Ns (65%), respectively. These products arise from
[2,3]-sigmatropic rearrangement of the initially formed S-allyl-
sulfimides, as reported in literature,5b, 28 and thus indicate the
initial S-imidation of phenyl allyl sulfide. Again, we did not observe
1
Ns
>99%[b]
2
3
4
5
Ns
Ns
>99%[b]
1
any reaction with the alkene or weak C‒H position by H NMR
spectroscopy. Lastly, methyl-(4-(phenoxymethyl)-phenyl) sulfane
as substrate selectively provided (98% yield) access to 14Ts,
which has been studied in the context of cancer research as a
drug to bind to the nuclear protein pirin to inhibit melanoma cell
migration.3
>99%[b]
Mechanistic studies.
Ns,
[Ts]
To probe the involvement of radical intermediates in the
sulfimidation reactions, we performed the sulfimidation of
thioanisole with PhINTs and 1.0 mol% catalyst loading in
presence of 5 equiv. of the well-known radical trap 2,2,6,6-
tetramethylpiperinidyloxyl (TEMPO). This resulted in a yield of
only 50% of 1Ts, whereas the reaction in absence of TEMPO
quantitatively afforded this sulfimide product. The radical trapping
experiment thus indicates the involvement of radical-type
intermediates, in agreement with formation of (previously
characterized18,19) nitrene radical species formed upon reaction
of [CoIII(TAMLred)]‒ with iminoiodinanes.
82%[c], [95%][d]
Ns,
[Ts]
83%[c], [95%][d]
Ratio A : B : PhINR = 1.5 : 1.5 : 1.0. [PhINR] = 24 mM. [a] Selectivities based
on 1H NMR integration using 1,3,5-trimethoxybenzene as an internal standard.
[b] Reactions were stopped before 17% conversion of A + B (50% conversion
of PhINNs). [c] After 1 hour (conversion PhINNs = 90%). [d] After 25 minutes
(conversion PhINTs = 33%).
To get more insight into the radical and electronic effects
governing the reactions, a Hammett analysis29 was performed by
intermolecular competition experiments under standard
Chemoselectivity in intramolecular competition reactions.
Having established the intermolecular chemoselectivity for nitrene
transfer to sulfides, we next explored the intramolecular
chemoselectivity for sulfimidation in the presence of alkenes and
weak C‒H bonds. Alkene fragments prone to aziridination are
highlighted purple in Scheme 3 and reactive C‒H positions, i.e.
with a tabulated27 bond dissociation energy (BDE) ≤85.0 kcal
mol-1 or 85 < BDE < 95 kcal mol-1 are marked in green and grey,
respectively. We employed 1.0 mol% PPh4[CoIII(TAMLred)] as the
catalyst at 25 C under aerobic conditions in CH2Cl2 throughout
these studies.
Sulfimidation of para- or meta-methylthioanisole afforded
products 2Ts, 2Ns, 3Ts and 3Ns in quantitative yield (Scheme 3).
Interestingly, 2Ts was also obtained in >99% yield at 0 C, and
o
conditions with PPh4[CoIII(TAMLred)] (1.0 mol%, aerobic, 25 C,
24 mM PhINTs in CD2Cl2). Compared to the amount of PhINTs,
1.5 eq thioanisole and 1.5 eq of a para-functionalized thioanisole
(X = Me, OMe or F) were present. The kx/kH ratio was then
determined by the relative formation of para-functionalized-
sulfimide versus 1Ts (see also SI). We employed both electronic30
(σ+) and radical31 (σ•) Hammett constants and plotted log(kx/kH)
versus ρ+σ++ρ•σ•. Multiple coefficient linear regression afforded ρ•
= 0.25 and ρ+ = ‒0.57 (R2 = 0.99, see SI), which indicates
predominant contributions from electronic effects (|ρ+/ρ•| = 2.28)32
and positive charge buildup on the sulfide substrate in the
product-forming transition state, therefore demonstrating
electrophilic behavior of the nitrene radical intermediates (vide
infra).
o
o
4
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Scheme 3. Substrate scope for the sulfimidation of (alkyl)(aryl)-substituted sulfides with PPh4[CoIII(TAMLred)] and PhINTs, PhINNs or PhINTces. Yellow: desired
position for nitrene transfer (sulfimidation). Purple: alkene prone for aziridination. Green: weak C‒H position (BDE ≤85 kcal mol-1). Grey: C‒H position with
85<BDE<95 kcal mol-1. Yields based on 1H NMR integration using 1,3,5-trimethoxybenzene as an internal standard. [a] 5 minutes reaction time. [b] Same yield at
0 oC (30 min). [c] 2 h. at ‒61 oC. [d] 2 h. at ‒78 oC.
The large |ρ+/ρ•| ration obtained from the Hammett analysis,
in combination with the negative ρ+ (–0.57), is suggestive for
electron transfer from the sulfide to the nitrene complex during or
prior to N‒S bond formation, similar to the previously reported
[CoIII(TAMLred)]‒ catalyzed sulfimidation computationally with
DFT at the BP86/def2-TZVP/disp3 level of theory at the triplet
(S = 1) spin surface (see also SI).18,19 To compare the
performance of the catalyst in N-tosyl and N-nosyl nitrene transfer,
electronically asynchronous transition states (ρ+ = ‒0.80, ρ• = 0.14, and to compare the mechanism with the previously reported
|ρ+/ρ•| = 5.71) for C‒N bond formation in PPh4[CoIII(TAMLred)]
catalyzed aziridination reactions.18 Although the error in the ρ•
Hammett value is rather large (0.16) in this case, the improved fit
of the Hammett plot when including radical parameters does
reflect the importance of radical stabilization effects on the sulfide
substrate during the product-forming transition state. A Hammett
analysis employing only electronic effects afforded an identical ρ+
value of ‒0.57 (but with a lower R2 of 0.96, see SI), again
signifying a (dominant) electrophilic behavior of the nitrene radical
intermediates.
We next set out to further investigate the mechanism of the
chemoselective sulfimidation using computational studies. Under
the applied conditions PPh4[CoIII(TAMLred)] is quantitatively
converted to PPh4[CoIII(TAMLq)(NR)2] upon reaction with PhINR
(R = tosyl, nosyl) and the latter is a catalytic intermediate in nitrene
transfer (aziridination).18 We therefore focused on the
intermediacy of this anionic nitrene species during catalytic
sulfimidation. Based on previously reported NEVPT2-CASSCF
(multi-configurational N-electron valence state perturbation theory
corrected complete active space self-consistent field) and DFT
(density functional theory) calculations we studied the
aziridination, which operates via electronically asynchronous
transition states, we calculated the full mechanisms for both the
tosyl (Ts superscript) and nosyl (Ns superscript) substituted
nitrenes (Scheme 4).
Mono-nitrene radical formation from A (reference point) and
PhINR (R = Ns or Ts) via barrierless ligand-to-substrate single-
electron transfer affords BNs and BTs in exergonic reactions
(ΔGo = ‒29.4 and ‒26.2 kcal mol-1, respectively). Reaction with
another equivalent PhINR via a second ligand-to-substrate single-
electron transfer event proceeds through a low-lying transition
state (TS1Ns: ΔΔG‡ = +12.0 kcal mol-1, TS1Ts: ΔΔG‡ = +11.6 kcal
mol-1) to afford bis-nitrene radicals CNs (ΔGo = ‒30.3 kcal mol-1)
and CTs (ΔGo = ‒25.1 kcal mol-1). N‒S bond formation on the
formed bis-nitrene radical complexes is essentially barrierless at
the SCF (self-consistent field) energy surface, and hence the free
energy barrier should be primarily determined by (translational)
entropy contributions (estimated at ~7-10 kcal mol-1). This yields
the respective products as van der Waals adducts in a highly
exergonic manner (DNs: ΔGo = ‒67.2 kcal mol-1 and DTs: ΔGo = ‒
63.7 kcal mol-1), concomitant with one-electron reduction of the
electrophilic TAML backbone. The SCF barrierless product
5
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formation is the result of the high oxidation state of the TAMLq in
C, thus precluding a barrier for initial substrate-to-ligand single-
electron transfer. Endergonic release product 1Ns (ΔGo = ‒58.7
kcal mol-1) and 1Ts (ΔGo = ‒55.9 kcal mol-1) from D regenerates
the mono-nitrene radical B, which can re-enter the bis-nitrene
cycle.
mechanism as described for styrene aziridination by
[CoIII(TAMLred)]‒.18 However, N‒S bond formation to afford the
sulfimidation product via the bis-nitrene radical complex (C) is
barrierless at the SCF energy surface, which was not observed
for the corresponding aziridination of styrene. The differences in
activation and formation energies between the N-tosyl and
N-nosyl nitrene transfer pathways are only small, and do not
explain the faster reactions of PhINTs than PhINNs with
thioanisole (Table 2, vide supra). However, this difference in
reaction rates is most likely the result of the higher solubility of
PhINTs (8.2 mM) in comparison to PhINNs (0.5 mM, see SI) in
CH2Cl2, thus limiting the reaction rate to the rate of solvation of
the iminoiodinane. As the kinetics of these reactions are likely
determined by the low solubility of the nitrene precursors, we
believe that the mono-nitrene pathway (from B to E via TS2) is
the dominant pathway under the applied catalytic reaction
conditions (i.e. in the presence of excess thioanisole). The
significant Hammett ρ+ (‒0.57) and ρ• (0.25) values seem
inconsistent with almost barrierless N‒S bond formation (bis-
nitrene pathway), and hence also the experimental Hammett data
are suggestive of a dominant mono-nitrene pathway. The lower
calculated activation energies for sulfimidation (+13.9 kcal mol-1)
in comparison to aziridination (+14.6 kcal mol-1)18 along the mono-
nitrene pathways are consistent with the observed
chemoselectivity in the inter- and intramolecular competition
experiments (vide supra). The observed selectivity and calculated
mechanisms are therefore also consistent with electrophilic
behavior of the nitrene radical intermediates.
Mono-nitrene radical B can also react directly with thioanisole
via an electronically asynchronous transition state TS2Ns (ΔΔG‡ =
+13.9 kcal mol-1) and TS2Ts (ΔΔG‡ = +13.8 kcal mol-1). In this
transition state, N‒S bond formation is preceded by substrate-to-
ligand single-electron transfer and the nitrene-N lone pair attacks
the (partially) formed thioanisole radical cation. Simultaneously,
single-electron transfer from the sulfide-S to the nitrene-N occurs
to afford the zwitterionic sulfur ylide. During this process, the spin
state on cobalt changes from low spin (S = 0 in B) to intermediate
spin (S = 1 in TS2 and E). As a consequence, the total
wavefunction adapts to a broken-symmetry solution, causing the
formation of β-spin in a mainly sulfur-localized N‒S σ* orbital,
which is then transferred to the α-spin-bearing non-bonding orbital
on the nitrene (see SI). The formation of the van der Waals
adducts ENs and ETs is exergonic (ΔGo = ‒34.0 and ‒31.9 kcal
mol-1, respectively) and product dissociation is again endergonic
(ΔGo = ‒29.2 kcal mol-1 for 1Ns and ‒29.7 kcal mol-1 for 1Ts).
The positive charge buildup on the substrate due to
electrophilic reaction of the nitrene intermediates, as also evident
from the Hammett analysis, in combination with the electronically
asynchronous transition state found for reaction of the mono-
nitrene radical species with thioanisole, support a similar
Scheme 4. Proposed mechanism for the [CoIII(TAMLred)]‒ catalyzed sulfimidation of thioanisole to afford 1Ns and 1Ts via either a mono-nitrene (right) or bis-nitrene
(left) pathway. Free energies (ΔGo298K in kcal mol-1) calculated with DFT at the BP86/def2-TZVP/disp3 (m4-grid) level of theory at the triplet (S = 1) spin surface.
6
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Experimental Section
General procedure for the catalytic sulfimidation reactions. A flame-
dried vial (4 mL) was charged with iminoiodinane (48.0 µmol; 1.0 eq.),
CH2Cl2 (1.8 mL; total concentration iminoiodinane of 24.0 mM), sulfide
(72.0 µmol; 1.5 eq.; 100 µL of a 720 mM stock solution in CH2Cl2),
PPh4[CoIII(TAMLred)] (0.40 mg; 0.48 µmol; 1.0 mol%; 100 µL of a 4.8 mM
stock solution in CH2Cl2) and closed with a cap. The reaction mixture was
stirred under aerobic conditions at 25 oC for 30 minutes. 1,3,5-
Trimethoxybenzene (0.67 mg; 4.0 µmol; 100 µL of a 40.0 mM stock
solution in CH2Cl2) was added as an internal standard, the reaction mixture
was filtered (syringe filter, PTFE, 0.45 µm) to remove unreacted
iminoiodinane, concentrated under reduced pressure at 25 oC, dissolved
in deuterated solvent, filtered (syringe filter, PFTE, 0.45 µm) and analyzed
by 1H NMR spectroscopy.
Conclusion
We have shown that PPh4[CoIII(TAMLred)] is an effective catalyst
for the sulfimidation of (alkyl)(aryl)-substituted sulfides under mild
conditions (25 oC, aerobic, 1.0 mol%). TONs up to 900 and TOFs
up to 640 min-1 are reported, demonstrating the stability and
activity of the catalyst under practical conditions. Moreover, this is
the first example of a cobalt-catalyzed sulfimidation reaction via
nitrene transfer to sulfides. In the presence of alkenes and weak
C‒H bonds, nitrene transfer proceeds chemoselectively towards
the sulfide, as supported by inter- and intramolecular competition
reactions, which we attribute to the lower oxidation potential of the
sulfides and the electrophilic behavior of the nitrene radical
intermediates. Electron-donating (Me, OMe) and -withdrawing (F,
Cl) substituents on the aryl moiety in thioanisole derivatives are
tolerated, and methyl substitution in thioanisole for ethyl, iso-
propyl, benzyl, ethylphenyl, and vinyl all afford the respective
sulfimidation products in generally good yields. Sulfimidation of
phenyl allyl sulfide leads to [2,3]-sigmatropic rearrangement to
yield the N-allyl-S-phenyl-thiohydroxylamine products. Late-stage
sulfimidation of ethyl-(4-(phenoxymethyl)-phenyl)-sulfane affords
a small drug molecule in excellent yield. Hammett analysis
indicates that positive charge buildup and significant radical
stabilization on the sulfide substrate occur in the transition state
leading to sulfimide product formation. Combined with the
computational data, we suggest that the N‒S bond formation is
initiated by substrate-to-ligand single-electron transfer (mono-
nitrene pathway) in an electronically asynchronous transition
state. The observed chemoselectivity is expected to contribute to
new (late-stage) sulfimidation reactions wherein the oxidation
potential of the functional groups determines the preferred
nitrene-accepting moiety.
Supporting Information. Experimental details, synthetic procedures,
NMR spectra, HRMS data, geometries (xyz coordinates) and energies of
stationary points and transition states (DFT).
Acknowledgements
Financial support from The Netherlands Organization for
Scientific Research (NWO TOP-Grant 716.015.001 to BdB) and
the research priority area Sustainable Chemistry of the University
of Amsterdam (RPA SusChem, UvA) is gratefully acknowledged.
Ed Zuidinga is thanked for HRMS measurements.
Keywords: sulfimidation • cobalt • nitrene radical • redox-active
ligand • chemoselectivity
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Entry for the Table of Contents
Cobalt-catalyzed sulfimidation of (aryl)(alkyl)-substituted sulfides with iminoiodinanes proceeds under mild conditions and with high
chemoselectivity in presence of alkenes and weak C‒H bonds. PPh4[CoIII(TAMLred)] mediates the nitrene transfer reactions with a high
turnover number and frequency, while the electrophilicity of the nitrene radical intermediate determines the chemoselectivity.
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