Regioselective differentiation of vicinal methylene C-H bonds enabled by silver-catalysed nitrene transfer

Article abstract of DOI:10.1039/c9cc04006d

Silver-catalyzed nitrene insertion enables the formation of benzosultams in good yield and with regioselectivity complementary to other transition metal nitrene-transfer catalysts. Preferential formation of six-membered benzosultam rings predominates for alkyl-substituted benzenesulphonamide precursors. Ligand-controlled tunability is also achieved for benzenesulphonamides with γ-branched alkyl substituents. Mechanistic probes suggest that the reaction pathway differs depending on whether a α (benzylic) or β (homobenzylic) C-H bond undergoes amidation, as well as the catalyst identity.

Full text of DOI:10.1039/c9cc04006d

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C9CC04006D
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ARTICLE
Regioselective differentiation of vicinal methylene C-H bonds
enabled by silver-catalysed nitrene transfer
Ryan J. Scamp,a Bradley Scheffer,b and Jennifer M. Schomakerb,*
Received 00th January 20xx,
Accepted 00th January 20xx
Silver-catalyzed nitrene insertion enables the formation of benzosultams in good yield and with regioselectivity
complementary to other transition metal nitrene-transfer catalysts. Preferential formation of six-membered benzosultam
rings predominates for alkyl-substituted benzenesulphonamide precursors. Ligand-controlled tunability is also achieved for
benzenesulphonamides with γ-branched alkyl substituents. Mechanistic probes suggest that the reaction pathway differs
depending on whether a α (benzylic) or β (homobenzylic) C-H bond undergoes amidation, as well as the catalyst identity.
DOI: 10.1039/x0xx00000x
www.rsc.org/
transformations was encouraging, and inspired efforts to utilize our
ligand-controlled strategy to improve regioselectivity among vicinal
C–H bonds, as well as supplant inherent structural or electronic
biases that disfavour functionalization at C-H sites that are typically
preferred with other nitrene transfer catalysts.
Introduction
Nitrene transfer serves as an effective tool for the rapid and
efficient formation of C–N bonds. Contemporary methods involve
the use of transition metal complexes to stabilize the formation of
transient nitrene intermediates for selective insertion into C–H or
C=C bonds. Despite numerous advances in the field, many nitrene
insertion reactions remain largely substrate-controlled, due to
reactive nitrene species and/or transition metal catalysts possessing
specific, rigid ligand architectures that limit the ease of possible
steric and electronic modifications.1-3 These catalysts span many
transition metals that include Rh,4-9 Fe,10-18 Co,19,20 Cu,21-24 and Ag.25-
A.
O
S
Díaz-Requejo, Pérez, Dauban
O
S
O
S

p-Tol
p-Tol
NH
NH
[Tp*,BrAg]2
PhI(OAc)2
TsHN
p-Tol
O
Bu
TsHN
N


H
NHTs
S


Et
Et
p-Tol
NH2
+

Low regio- and stereoselectivity
TsN
CH2Cl2
-selective (up to 1 : 4.5 : 1.5     )
up to 1.3 : 1 dr
B.
Zhang
O
O
S
O
O
O
S
O
R
S
R
R
NH
N3
NH
[Co(Por)]
30
Progress in the field is thus driven by the development of new

C6H5Cl, 80 o
C
R
R
33-97% yield
R = Me, Et
C. This work
catalytic systems that complement established trends in terms of
chemo-, regio-, and stereoselectivity. Our group has discovered the
highly flexible coordination sphere of silver(I) presents new oppor-
tunities for catalyst-controlled nitrene transfer.31-34 In our hands,
Ag(I) catalysis displays significant synthetic versatility, enabling
tunable, chemoselective aziridination versus allylic C–H insertion in
alkenes and allenes,31,34 effective direct amination of propargylic C–
H bonds in the presence of competing insertion sites,32 and tunable,
site-selective C-H amidation of competing C-H bonds.33

2.7 : 1 selectivity
R
O
O
Ag
[(Py5Me2) ]2(OTf)2
O
O
S
R1
R1
O
O
R2
small
or
H2N
S
S
R1
Ag
[(Py5Me2) ]2(OTf)2
HN
HN
R2

t
Ag
[( Bu3tpy) ]2(OTf)2
PhIO
R2
R2

R2
R2
bulky
any
tunable control
via sterics
selectivity for stronger
homobenzylic C-H bond
Scheme 1. Progress in regioselective functionalizations of vicinal C-H bonds.
The prevalence of aliphatic amines in pharmaceutically relevant
compounds makes their formation of great interest to the synthetic
community.36 Several examples of C–H amination using benzene-
sulphonyl azides as nitrene precursors have been reported. Redox-
active metals are known to form transient nitrene species from
benzenesulphonyl azides, which subsequently insert into C–H bonds
with varying regioselectivity. For example, Zhang reported the use
of cobalt(II) porphyrin complexes in regioselective benzylic C-H
bond amidations (Scheme 1B).20 Additionally, Katsuki demonstrated
enantioinduction in similar reactions employing chiral Ir(I) salen
complexes, although the degree of regio- and enantioselectivity was
highly variable and substrate-dependent.37 Unfortunately, the
factors that dictate regioselectivity in these systems are poorly
understood. Product ratios could be varied by incorporating
ancillary substituents on the ligand distal to the metal binding site,
suggesting that remote steric interactions between ligand and
substrate may have a profound impact on the reaction outcome
though conformational control. This concept was further explored
by Arnold and co-workers via engineering of cP450 enzymes to
The selective functionalization of C–H bonds using group transfer
reactions remains of intense interest, owing to the ubiquity of these
bonds in complex organic frameworks. Regioselectivity amongst
vicinal methylene C–H bonds is a particularly daunting challenge, as
interrelated steric and electronic environments often preclude
effective site-selective functionalization. For example, while silver
homoscorpionate complexes, such as [Tp*,BrAg]2 (Tp*,Br
:
hydrotris(4-bromo-3,5-dimethyl)pyrazolyl borate), are competent in
the amination of simple hydrocarbons, these reactions exhibit
minimal regioselectivity governed by substrate control (Scheme
1A).35 Nonetheless, the ability of silver to facilitate these
aDepartment of Chemistry, Yale University, 275 Prospect St., New Haven, CT,
06511, USA.
bDepartment of Chemistry, University of Wisconsin-Madison, 1101 University
Avenue, Madison, WI, 53706, USA.
Electronic Supplementary Information (ESI) available. DOI:10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1. Catalyst optimization for homobenzylic amination.
achieve tunable amination at either a benzylic or homobenzylic C-H
bond with high levels of regioselectivity.14 More recently, Hartwig
demonstrated the utility of an Ir(Me)-PIX cofactor13 in addressing
issues with competing azide reduction that plague Fe-based
metalloenzymes.38 Despite these advantages, the need for
specialized expertise and equipment can be a barrier to widespread
use of these strategies; a transition metal catalyst that could be
tuned for amidation of benzylic or homobenzylic C-H bonds simply
by changing the ligand would be highly desirable.
View Article Online
DOI: 10.1039/C9CC04006D
O
O
S
O
nPr
O
nPr
S
NH
N
AgOTf, ligand
PhIO
O
O
nPr
S
1a
1aa
NH2
O
O
4 Å MS, CH2Cl2
absence of light
nPr
1b
S


NH
1
entrya
ligand (equiv)
yield (%)b
[1a+1aa]:1b
1a:1aa
In this paper, we showcase how the unusual features of silver-
catalysed benzosultam formation are harnessed for regioselective
differentiation of vicinal methylene C-H bonds (Scheme 1C).
Convenient features of our system include: 1) the use of
sulphonamide precursors that avoids potentially explosive azides, 2)
the ability to promote regioselectivity through electronics, 3)
preference for amidation of weaker benzylic C–H bonds over their
typically more reactive homobenzylic neighbours, and 4) the ability
to further tune regioselectivity in bulky substrates via orthogonal
steric and electronic control.
1c
2
tpa (0.12)
tpa (0.12)
tpa (0.12)
50 [46]
65
53 [41]
86
1 : 3.6
1 : 3.3
1 : 3.6
1 : 4.5
1 : 4.8
>20:1
>20:1
>20:1
1.6:1
1.6:1
3d
4
Py5Me2 (0.12)
5e
Py5Me2 (0.12)
tBu2bipy (0.3)
58
6
7
16 [42]
1 : 1.0
<1:20
(MeO)2bipy (0.3)
Me3tpy (0.12)
tBu3tpy (0.12)
59
91
1 : 1.5
1 : 3.3
1:2.1
1.9:1
8
85
1 : 4.0
2.0:1
9
f
10
11
12
84
40 [45]
22 [51]
92
1 : 1.0
1 : 1.6
3.0 : 1
2.7 : 1
>20:1
>20:1
>20:1
>20:1
Rh2(esp)2
f
Rh2(TPA)4
g
[FePc]Cl /AgSbF6
Co(OEP)
13h
aConditions:
0.1 equiv AgOTf, x equiv ligand, 3.5 equiv PhIO, 4 Å MS, 0.05 M CH2Cl2,
protected from light with Al foil. bNMR yields. cExposed to ambient light. d1.2 equiv
PhI(OAc)2. ePhCF3 solvent. f2%catalyst loading. g10% loading. hSee ref. 20.
Results and discussion
Investigations began by employing sulphonamide 1 as a model
system to explore the reactivity of various catalysts (Table 1, see
Table S1-1 for catalyst structures). Tris(2-pyridylmethyl)amine (tpa)
was expected to promote benzylic insertion at the α C-H bond,
similar to its previously reported performance with sulfamate esters
(entry 1).32 Remarkably, amination occurred predominantly at the
homobenzylic position instead. Total conversion and product yields
improved in the absence of light, indicating that catalytic
intermediates are vulnerable to photodecomposition on the
timescale for C–H amination (entry 2). Further exploration of
catalytically competent ligands revealed an optimal balance of yield
and regioselectivity in the presence of [Ag(Py5Me2)OTf]2 (entry 4).
Overoxidation of 1a to 1aa is thought to depend on the efficiency of
the silver catalyst at breaking down the polymeric PhIO.39 Bipyridine
ligands (entries 6-7) were not as effective in the reaction, although
terpyridines, which form dimeric species in solution, performed
better (entries 8-9). Comparisons with other established catalyst
systems (entries 10-13) highlighted the unique utility of silver in
benzenesulphon-amide nitrene insertion; for example, Rh2(esp)2
(entry 10) demonstrated similar yields to the optimized silver
catalysts, but with no regioselectivity. Conversely, modest
regioselectivity was achieved with Rh2(TPA)4, but in poor yield
(entry 11). The overall product yield for [Fe(Pc)]Cl was similarly low,
but showed moderate selectivity for the benzylic position,
consistent with the presence of radical intermediates previously
proposed by White for C–H amination.18 These comparisons
underscore the unconventional behaviour of silver catalysts in
nitrene insertion.
H insertion, presumably through superior orbital overlap for
benzylic activation, as compared to the α position. Truncation of
the alkyl chain in 6 demonstrated the limitation of [Ag(Py5Me2)OTf]2
for homobenzylic amidation, instead favouring formation of the 5-
membered ring. However, the observation of product resulting
from amidation at the β C-H in the presence of the more activated
benzylic α methylene group was promising for the future design of
silver catalysts for selective amidation of primary C-H bonds.
Regioselectivity in the presence of [Ag(Py5Me2)OTf]2 was
completely lost when an ester functionality was installed in 7,
further highlighting the influence of inductive effects on selectivity.
Table 2. Substituent effects on regioselectivity.
Py Me
with
2 as the ligand
5
O
O
O
O
O
O
O
O
S
S
O
Br
S
NH2
N
S
NH2
NH2
NH2




O




1
2
3
4
77% (1 : 4.8)
89% (1 : 6.3)
80% (<1 : 20)
46% (<1 : 20)
O
O
O
S
O
O
S
O
ligand
Py5Me2
H
S
NH2
NH2
NH2



40% (1 : 1.0)

Ph

CO Et
2

tBu3tpy
5
6
7
58% (6.3 : 1)b
62% (<1 : 20)
aConditions:
26% (1 : 1.7)
0.1 equiv AgOTf, 0.12 equiv ligand, 3.5 equiv PhIO, 4 Å MS, 0.05 M CH2Cl2,
protected from light with Al foil. bNMR yield; 4:1 amine/imine formation at  position.
To further elucidate the relative roles of steric and electronic
effects in benzosultam formation, substrates 8-11 containing alkyl
branching were investigated (Table 3). Although previous work with
Having established [Ag(Py5Me2)OTf]2 as the optimal catalyst for
homobenzylic C–H amination, we next sought to probe the effects
of alkyl and aryl substitution on the reaction outcomes (Table 2).
While the 2,5-dialkylbenzenesulphonamide 2 behaved similarly to
1, the introduction of heteroatom substituents meta to the
sulphonamide groups in 3 and 4 led to exclusive formation of six-
membered benzosultams. These results suggest that the
electrophilic silver-nitrene intermediate responds to inductive
effects through the benzene ring. The effect of the substituent
identity on the alkyl side chain was explored with substrates 5-7.
Installing a phenyl ring at the β position (5) led to an increase in β C-
33
[Ag(Py5Me2)OTf]2 indicated that sterics would play a predominant
role in discriminating between the α and β C–H bonds, results with
8 and 9 proved surprising. Amidation of the tertiary C–H bonds
were heavily favoured, leading to single products, irrespective of
the location of the methinyl C-H. Discrimination between the
methinyl C–H bonds in 10 was especially challenging, giving rise to
minimal α selectivity with silver catalysts supported by either
t
Py5Me2 or Bu3tpy. The propensity of the electron-deficient silver
2 | J. Name., 2012, 00, 1-3
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nitrene to favour electron-rich 3o positions appears to supersede improved regioselectivities for these examples in thVeiepwrAersticelne cOenlionef
steric pressure to deliver the quaternary amide product in high Rh2(esp)2 was taken as evidence of the inDflOueI:n1c0e.10o3f9/dCis9tCaCl 0s4te0r0i6csD,
regiomeric excess. Inspired by the excellent regioselectivities especially given the lack of selectivity for this same catalyst with a
observed with 8-9, 11 was interrogated for the potential to react at sterically-unbiased substrate (see Table 1, entry 12). In contrast,
a distal C-H bond; however, no macrocyclization was observed and [Ag(tButpy)OTf]2 exhibits complementary site-selectivity that
the resulting α/β selectivity was low for Py5Me2. Interestingly, the mimics the same results seen for the sterically unhindered 1 (see
use of [Ag(tButpy)OTf]2 restored the regioselectivity to levels similar Table 1, entry 10).
to those observed for linear alkyl chains (vide supra). These results
Table 5. Comparisons of catalytic behaviour of Ag complexes with Rh2(esp)2.
led to the hypothesis that catalyst control of the reaction might be
achievable for systems where the γ position possesses a greater
steric profile than that displayed in 11.
O
S
O
O
S
O
O
S
O
O O
tBu
tBu
tBu
tBu
S
NH2
NH2
NH2
NH2








R
Table 3. Effects of branching on regioselectivity of nitrene transfer.
8
9
10
Aga
79% (1.1 : 1)
92% (1 : 6.3)
97% (3.5 : 1)
13
Aga
Agb
Rhc
89% (>20 : 1)
----
89% (<1 : 20)
----
77% (<1 : 20)
R = Cy Agb
>99% (1.1 : 1)
75% (1.6 : 1)
8% (<1 : 20 Ha/Hb)
O
O
O
O
O
O
O
O
S
Rhc
S
S
S
NH2
NH2 iPr
NH2
NH2
>99% (>20 : 1)







Aga
14

56% (4.6 : 1)
85% (1 : 3.8)
96% (11 : 1)
iPr
aAg
: 5 mol% [Ag(Py5Me2)(OTf)]2, PhIO (3.5 eq), 4 A MS, CH2Cl2.
: 5 mol% [Ag( Butpy)(OTf)]2, PhIO (3.5 eq), 4 A MS, CH2Cl2.
8
9
10
Agb
t
11
R = Bu
t
bAg
cRh
Py5Me2
81% (>20 : 1)
aConditions:
Rhc
Py5Me2
89% (<1 : 20)
Py5Me2
tBu3tpy
>99% (1.1 : 1)
75% (1.6 : 1)
Py5Me2
tBu3tpy
73% (1 : 2.7)
53% (1 : 5.6)
: 2 mol% Rh2(esp)2, PhI(OAc)2 (1.2 eq), MgO (2.4 eq), CH2Cl2.
0.1 equiv AgOTf, 0.12 equiv ligand, 3.5 equiv PhIO, 4 Å MS, 0.05 M CH2Cl2,
protected from light with aluminum foil.
In order to acquire a better understanding of the mechanistic
principles guiding reactivity, deuterated 16 was prepared as a probe
to elucidate how the pathways of the silver-catalyzed nitrene
transfer differ with catalyst identity (Scheme 2). The amidation of
16 with [Ag(tButpy)OTf]2 revealed KIE values of 2.8 and 3.2 at the
benzylic and homobenzylic positions, respectively. In contrast,
employing [Ag(Py5Me2)OTf]2 as the catalyst gave KIE values of 6.7
(benzylic) and 4.2 (homobenzylic). The relatively low KIE values for
the former catalyst suggest, but do not prove, that the nitrene
insertion behaves as if it is a concerted process, irrespective of
whether the C-H bond is benzylic or homobenzylic. Based on our
previous investigations into the mechanisms of intermolecular
nitrene insertion,34 which show that concerted silver-catalyzed
nitrene transfer is forbidden due to its electronic configuration, it is
likely the low KIE indicates a barrierless HAT/radical recombination
step, rather than a truly concerted C–H amination pathway.
However, rapid radical rebound does not allow corroboration of
this mechanism through the use of radical inhibitors. The nature of
the C–H bond (benzylic vs. homobenzylic) had a noticeable effect on
the KIE when [Ag(Py5Me2)OTf]2 was used in the amidation reaction.
The KIE of 6.7 at the benzylic α position suggesting that a stepwise,
radical-based pathway may be operative. Similar to C-H amination
of the homobenzylic bond, the use of radical inhibitors does not aid
in distinguishing between concerted and radical pathways, as the
rate of radical rebound in intramolecular reactions is too rapid.
To test this hypothesis, a series of substrates containing varying
degrees of substitution at the β carbon were prepared (Table 4).
Gratifyingly, [Ag(Py5Me2)OTf]2 responded as expected to these
modifications, enforcing nitrene insertion activity predominantly at
the benzylic methylene, albeit in varying ratios. This effect
correlates with the extent of branching at the γ carbon, indicating
that altered selectivity can likely be attributed to steric interactions
between the substrate and the catalyst (compare substrates 12-13
with 14-15). Equally intriguing was the observation that this effect
was unique to [Ag(Py5Me2)OTf]2. When the catalyst was switched to
[Ag(tButpy)OTf]2, the α:β selectivity was largely unaffected by the
substitution at β and continued to favor amidation at the β C-H
bond. This retention of regioselectivity across 12-15 was observed
despite the fact that [Ag(tButpy)OTf]2 displayed activity similar to
[Ag(Py5Me2)OTf]2 during initial screening studies (see Table 1,
entries 4 and 10).
Table 4. Tunable catalyst-controlled regioselectivity through distal sterics.
O
O
O
O
O O
O
S
O
S
S
S
NH2
NH2
NH2
NH2




R




12
Py5Me2
tBu3tpy
14
13
15
, R = adamantyl
89% (6.3 : 1)b
85% (1 : 3.8)
56% (4.6 : 1)c
85% (1 : 5.9)
79% (1.6 : 1)
76% (1 : 5.9)
79% (1.1 : 1)
92% (1 : 6.3)
O
S
O
O
S
aConditions
O
N
: 0.1 equiv AgOTf, 0.12 equiv ligand, 3.5 equiv PhIO, 4 Å MS, 0.05 M CH2Cl2,
D
covered with foil. b2.4:1 amine/imine at  position. c6.0:1 amine/imine at  position.
N
D
O
O
S
The performance of the silver catalysts [Ag(Py5Me2)OTf]2 and
[Ag(tButpy)OTf]2 were compared with Rh2(esp)2 to better define
how their behaviour diverges from an established system (Table 5).
Substrates 8-10 and 13-14 were chosen for their ability to act as
effective indicators of steric interactions between substrate and
catalyst. Rh2(esp)2 and [Ag(Py5Me2)](OTf)2 both preferred methinyl
over methylene C–H bonds in 8-9. However, in contrast to Ag
catalysts, Rh2(esp)2 was not effective when a second tertiary
position was introduced in 10, suggesting that the scope of
Rh2(esp)2 is limited by if the sterics are too demanding. This
conclusion was further supported by the fact that the preference
for amidation at the α C-H site improved using Rh2(esp)2 with the
sterically biased 13-14 when compared to [Ag(Py5Me2)(OTf)]2. The
D
conditionsa
NH2
D


O
O
O
O
S
D
S
16
D
N
D
H
NH
50%  deuteration
50%  deuteration
D
16a
D
16b
D
tBu3tpyb
k /kD = 2.8
k /kD = 3.2
8%,
8%,
48%,
58%,
H
H
b
Py5Me2
k /kD = 6.7
k /kD = 4.2
H
H
aConditions:
0.1 equiv AgOTf, 0.12 equiv ligand, 3.5 equiv PhIO, 4 Å MS, 0.05 M
CH2Cl2, protected from light with Al foil. bCorresponding values from average of 2 runs.
Scheme 2. Kinetic isotope effects for benzylic and homobenzylic sites.
This journal is © The Royal Society of Chemistry 20xx
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7
Liang, C.; Robert-Peillard, F.; Fruit, C.; Muller, P.; Dodd, R. H.;
The KIE of 4.2 at the homobenzylic β C-H bond was also higher
than that observed for [Ag(tButpy)OTf]2 at the same site, also
suggesting a possible radical intermediate. However, the typical
KIEs for such processes are often much higher if the H-atom
abstraction process is assumed to occur through a transition state
where the Ag, N, and H atom are linear. It may be that the
conformational strain required for formation of the 5-membered
ring enforces a nonlinear transition state for the HAT/radical
rebound process, consistent with the more moderate KIE of 4.2 that
was observed experimentally.
View Article Online
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Conclusions
Silver(I)-catalyzed nitrene transfer processes continue to
show unusual behaviour compared to other transition metals
competent for this type of group transfer reaction. Herein, we
report the superior ability of silver complexes to consistently
enable the amidation of homobenzylic methylene C-H bonds
with good selectivity relative to their typically more active
benzylic methylene neighbours. Explorations of substituent
effects on the aryl ring revealed that the site-selectivity of
sulphonamide nitrene insertion strongly depend on electronic
factors. Despite this, steric effects between the catalysts and
groups on the substrate distal from the reaction center may be
exploited to enable tunable control over the regioselectivity.
These results showcase silver’s unusual versatility; it is not
constrained to steric control alone, as comparative studies
with Rh2(esp)2 suggest is the case for dinuclear Rh(II) catalysts,
nor is it heavily biased toward sites with low BDE as seen with
Zhang's cobalt catalysts. Kinetic isotope effects suggest that
homobenzylic C-H amination occurs through a barrierless
HAT/radical recombination process, while the mechanism of
amidation at the benzylic α site is ligand-dependent, thus
demonstrating versatility in terms of the mechanism as well.
The adaptable nature of silver described in this manuscript has
inspired other work in our group that enables tunable, catalyst
control of group transfer reactions, which will be described in
forthcoming publications.
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Acknowledgements
This work was funded through an NSF-CAREER Award
1254397 to JMS, as well as by the Wisconsin Alumni Research
Foundation. The NMR facilities at UW-Madison are funded by
the NSF (CHE-9208463, CHE-9629688) and NIH (RR08389-01).
The National Magnetic Resonance Facility at Madison is
supported by the NIH (P41GM103399, S10RR08438,
S10RR029220) and the NSF (BIR-0214394). Mass spectrometry
was acquired on a Q Exactive Plus Orbi Mass Spectrometer
funded by the NIH (1S10OD020022-1).
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