Nondirected, cu-catalyzed sp3 C-H aminations with hydroxylamine-based amination reagents: Catalytic and mechanistic studies

Article abstract of DOI:10.1021/acs.organomet.7b00003

This work demonstrates the use of hydroxylamine-based amination reagents RSO₂NH-OAc for the nondirected, Cu-catalyzed amination of benzylic C-H bonds. The amination reagents can be prepared on a gram scale, are benchtop stable, and provide benzylic C-H amination products with up to 86% yield. Mechanistic studies of the established reactivity with toluene as substrate reveal a ligand-promoted, Cu-catalyzed mechanism proceeding through Ph-CH₂(NTsOAc) as a major intermediate. Stoichiometric reactivity of Ph-CH₂(NTsOAc) to produce Ph-CH₂-NHTs suggests a two-cycle, radical pathway for C-H amination, in which the decomposition of the employed diimine ligands plays an important role.

Full text of DOI:10.1021/acs.organomet.7b00003

Article
pubs.acs.org/Organometallics
Nondirected, Cu-Catalyzed sp3 C−H Aminations with Hydroxylamine-
Based Amination Reagents: Catalytic and Mechanistic Studies
Anqi Wang, Nicholas J. Venditto, Julia W. Darcy, and Marion H. Emmert*
Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, 100 Institute Road, Worcester, Massachusetts 01609,
United States
S
* Supporting Information
ABSTRACT: This work demonstrates the use of hydroxyl-
amine-based amination reagents RSO2NH-OAc for the
nondirected, Cu-catalyzed amination of benzylic C−H
bonds. The amination reagents can be prepared on a gram
scale, are benchtop stable, and provide benzylic C−H
amination products with up to 86% yield. Mechanistic studies of the established reactivity with toluene as substrate reveal a
ligand-promoted, Cu-catalyzed mechanism proceeding through Ph-CH2(NTsOAc) as a major intermediate. Stoichiometric
reactivity of Ph-CH2(NTsOAc) to produce Ph-CH2-NHTs suggests a two-cycle, radical pathway for C−H amination, in which
the decomposition of the employed diimine ligands plays an important role.
amination reagents, such as azides14,15 or N-halogenated
INTRODUCTION
■
sulfonamides;6,7,13,17,18 alternatively, a two-reagent mixture of
Benzylic amines are important substructures in biologically
active compounds; however, the synthesis of such structures is
oxidant and amine can affect similar reactivity.6,10,19−21
However, commonly used reagents or reagent mixtures all
typically achieved through functional group interconversion
suffer from specific drawbacks: The protecting group on the
processes.1−3 Direct aminations of benzylic C−H bonds would
introduced amine functionality is typically not easily variable, as
streamline the synthesis of benzylic amines,4−12 in particular, if
only few electrophilic amination reagents or precursors are
first-row transition metals can be employed as catalyst
precursors. Efforts to this end have recently produced a series
commercially available. This limits the direct use of most
known protocols in synthetic applications or requires cleavage
of Co13−15 and Cu catalysts6,16−21 that achieve nondirected,
of the introduced protecting group after C−H amination.
intermolecular benzylic C−H aminations. The majority of these
Furthermore, the stability of many reagents is problematic and
established protocols (Scheme 1A) employ electrophilic
restricts their general use: Azides are explosive, while N-
halogenated sulfonamides and hypervalent iodine reagents are
Scheme 1. Previously Established, Intermolecular,
Nondirected Benzylic C−H Amination Systems and the
Catalytic System Described in This Manuscript
readily hydrolyzed in the presence of water.
Due to these drawbacks, research in our group22 and by
others (for example, see Scheme 1B)4 has focused on
establishing stable and versatile, hydroxylamine-based, electro-
philic amination reagents that are active reagents for non-
directed C−H amination reactions. Herein, we report that
these reagents can be employed in combination with Cu
3
catalysts to achieve benzylic Csp −H aminations (Scheme 1C).
The described protocol is, unlike prior Cu-based benzylic C−H
amination systems, strongly affected by steric hindrance around
the target C−H bonds.
Based on detailed mechanistic studies, we propose a catalytic
reaction pathway proceeding through radical intermediates and
two subsequent, connected catalytic cycles. Furthermore, our
studies suggest that the requirement for an excess of benzylic
substrate in these reactions is due to the formation of radical
addition products in a second catalytic cycle. Overall, the herein
reported system shows mechanistic features that have not been
observed for other, similar Cu-based catalyst systems, provides
Received: January 3, 2017
© XXXX American Chemical Society
A
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interesting regioselectivities, and avoids the use of hydrolytically
unstable or hazardous amination reagents.
to 5) provided slightly lower yields. Interestingly, the oxidation
state of the Cu catalyst precursor did not play a major role
(entries 4/5): Use of CuCl or CuCl2 leads to almost identical
yields of C−H amination product (27% and 30%, respectively).
Overall, Cu(OTf)2 showed the best reactivity (36% yield)
among simple Cu salts.
Reactions in the absence of added Cu salts (entry 7) did not
provide any benzylic C−H amination product. Furthermore,
reactions performed under air instead of under N2 atmosphere
(entry 8) showed a small decrease in product yield, indicating
that oxygen may interfere with the catalytic cycle.
In order to further improve the reactivity of the catalyst
system, we explored the effects of a series of bidentate ligands.
Addition of most common ligands (nacnac ligands; bisoxazo-
lines; IPr; 1,2-diamines; diimines derived from (MeCO)2 and
arylamines) did not enhance the yield observed with simple Cu
salts; however, several of the diimine ligands shown in Figure
117,18 resulted in an enhancing effect when added to the
RESULTS AND DISCUSSION
■
Catalytic Optimizations. Initial screening studies with the
hydroxylamine-derived reagents focused on establishing C−H
amination reactivity for the functionalization of toluene. We
reasoned that a catalyst able to transform primary, benzylic C−
H bonds such as in toluene can also be expected to show
analogous reactivity in the cleavage and amination of secondary
and tertiary benzylic C−H bonds due to their lower bond
dissociation energies (88.0 kcal/mol for PhCH3, 84.0 kcal/mol
for PhCH2CH3, 82.5 kcal/mol for PhCH(CH3)2).23
Initial screenings established that C−H amination reactivity
can be observed with TsNH-OAc as reagent and toluene as
arene substrate and solvent, employing simple Cu salts as
catalyst precursors (Table 1, entries 1−6). In order to enable
a
Table 1. Reaction Optimization and Background
b
entry
conditions
Cu(BF4)2·6H2O
yield (%)
1
33
33
21
27
30
36
<1
27
14
37
39
39
34
33
25
48
40
33
49
32
28
48
38
2
[Cu(MeCN)4]PF6
Cu(OAc)2
3
4
CuCl
5
CuCl2
6
Cu(OTf)2
7
no Cu
8
Cu(BF4)2·6H2O, air
Cu(BF4)2·6H2O, 2
Cu(BF4)2·6H2O, 3
Cu(BF4)2·6H2O, 4
Cu(BF4)2·6H2O, 5
Cu(BF4)2·6H2O, 6
Cu(BF4)2·6H2O, 7
Cu(BF4)2·6H2O, 8
Cu(BF4)2·6H2O, 9
Cu(OTf)2·6H2O, 9
[Cu(MeCN)4]PF6, 9
CuCl2, AgBF4 (10 mol %), 9
CuCl2, AgOTf (10 mol %), 9
CuCl2, AgPF6 (10 mol %), 9
Cu(BF4)2·6H2O, 9, 120 °C
Cu(BF4)2·6H2O, 9, 100 °C
Figure 1. Structures of diimine ligands promoting C−H amination
reactivity in combination with Cu(BF4)2·6H2O.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
reaction mixture. We then synthesized a series of ligands with
para-substitution in the aromatic moieties (2−5, Figure 1) to
systematically study substituent effects on catalysis.
In agreement with literature observations,18 electron-
donating substitutents (ligands 2 and 3; Table 1, entries 9
and 10) showed relatively low reactivities, even though the
presence of the methoxy-substituted ligand 3 resulted in a yield
of 37% (entry 10), similar to the highest yields obtained in the
absence of L-type ligands (36%; entry 6). Ligands 4 and 5
bearing electron-withdrawing substituents resulted in slightly
higher yields (39% each; entries 11 and 12). This led us to
explore a series of diimine ligands with two or more electron-
withdrawing substituents (ligands 6−9, Figure 1); of these, the
C6F5 moiety in ligand 9 resulted in 48% yield (Table 1, entry
16). Combining ligand 9 with Cu(OTf)2 or [Cu(MeCN)4]PF6,
which were both effective catalyst precursors in the ligand-less
optimization, did not lead to enhanced reactivity (40% and 33%
yield, respectively; entries 17 and 18). This trend (lower
reactivity with OTf and PF6 counteranions) held true for
reactions forming CuII catalyst precursors in situ through
reaction of CuCl2 with the corresponding Ag salts (entries 19−
21): While the reactions catalyzed by CuCl2/AgBF4 afforded
moderate yields (49%), reactions employing CuCl2/AgOTf or
CuCl2/AgPF6 provided much decreased product yields (32%
and 28%, respectively). This suggests that the counteranions
play a role in the catalytic activity; furthermore, Ag largely does
not seem to influence the outcome of the C−H amination
a
Conditions (unless noted otherwise): Toluene (2.00 mL, 1.73 g, 18.8
mmol, 146 equiv), Cu catalyst (5.0 mol %), ligand (5.0 mol %),
amination reagent 1 (28.7 mg, 0.125 mmol, 1.00 equiv), 110 °C, 48 h,
N2. Yields were determined by quantitative H NMR analysis of the
crude reaction mixtures, using 1,3-dinitrobenzene as internal standard;
yields are reported as average yields of at least 2 experimental trials;
corresponding standard deviations are generally <2% (see SI).
b
1
distinction between small reactivity differences, all catalytic
experiments were performed at least twice or until the obtained
standard deviations of replicate trials were <2%.
Among the simple catalyst precursors, salts with weakly
binding anions (Cu(BF4)2, [Cu(MeCN)4]PF6, Cu(OTf)2;
entries 1, 2, and 6) provided higher yields (33 to 36%), while
salts with more strongly coordinating counteranions (entries 3
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a
catalysis, which is in contrast to reactivity patterns observed in
intramolecular and allylic C−H aminations.24 Further opti-
mization by adjustment of the reaction temperature resulted in
the same reactivity at 120 °C as observed at 110 °C (49%; entry
22), while lower reaction temperatures (100 °C; entry 23)
afforded lower yields (38%) of BnNHTs.
Scheme 3. Scope of Amination Reagents
Overall, the reaction optimization reveals that perfluorinated,
highly electron-withdrawing aryl groups (ligand 9) are the most
activating substituents. We speculate that this is due to their
stability under the reaction conditions, either against hydrolysis
or addition reactivity of radical intermediates. Further studies to
this end will be presented in the Mechanistic Investigations
section of this manuscript.
Synthesis of Different Amination Reagents. Following
catalytic optimization, we prepared a variety of amination
reagents with different protecting and leaving groups to be
tested in benzylic C−H amination. Most of these reagents were
synthesized in a two-step procedure (Scheme 2A) in analogy to
Scheme 2. Synthesis of Amination Reagents
a
Conditions: Toluene (2.00 mL, 1.73 g, 18.8 mmol, 146 equiv),
amination reagent (0.125 mmol, 1.00 equiv), Cu(BF4)2·6H2O (2.3 mg,
6.3 μmol, 5.0 mol %), ligand 9 (3.0 mg, 6.3 μmol, 5.0 mol %), 110 °C,
1
48 h, N2. Yields were determined by quantitative H NMR analysis of
the crude reaction mixtures, using 1,3-dinitrobenzene as internal
standard.
corresponding C−H amination products (28−35%). These
data suggest that factors other than electron-donating or
electron-withdrawing substituent effects may influence reac-
tivity. One such factor may be the stability of the aromatic
groups against radical addition. However, as the data show, the
aromatic nature of the protecting group is not generally
necessary for maintaining reactivity: mesylate-protected amina-
tion reagent 17 produced the respective amination product in
40% yield.
In contrast, no C−H amination reactivity of toluene was
observed with amination reagents such as AcHN-OAc, TsAcN-
OAc, TsBnN-OAc, or BzNH-O2COR, suggesting that the
activating effect of the sulfonate protecting group (possibly
through stabilization of the radical character in catalytic
intermediates),27 the leaving group acetate, and the NH
functionality of the electrophilic amination reagents are all
crucial for catalytic reactivity.
Arene Substrate Scope. Next, we explored the scope of
the reaction regarding employable arene substrates (Table 2);
the amination reagent that resulted in the highest yields with
toluene (1) was employed in all these reactions. When
compared to the C−H amination of toluene (48% yield;
entry 1), reactions employing substrates with secondary
benzylic C−H bonds afforded similar (EtPh, 45%; entry 2)
or higher C−H amination yields (PhCH2Ph 86%; entry 3).
One exception to this trend was observed with isobutylben-
zene (3%; entry 4); we speculate that the lack of reactivity may
be caused by steric hindrance28 at the benzylic position.
Cumene as a substrate (entry 5) produces only traces of
benzylic C−H amination product, which also suggests that the
established catalyst system is sensitive to steric bulk around the
site of C−H amination. Interestingly, no such selectivity is
observed with other Cu catalyst systems that are active for
benzylic C−H aminations; instead, [Cu(MeCN)4]PF6/
a preparation described in the literature.25 This direct synthesis
takes advantage of the higher nucleophilicity of the NH2 moiety
in hydroxylamine under weakly basic conditions, which
determines the chemoselectivity of the first acylation step.
However, several reagents with electron-withdrawing sub-
stituents on their sulfonyl protecting groups could not be
obtained cleanly using the two-step procedure; these reagents
were synthesized employing a temporary protecting group
strategy (Scheme 2B).26
Generally, all reagent preparations were straightforward, and
the majority of reagents were prepared on gram scales
(examples of scales between 0.2 to 7.0 g product are described
in the SI). All reagents are bench and air stable and were stored
without additional precautions. Many of the prepared reagents
were not known in the literature prior to this work (for
complete characterizations, see SI).
Scope of Amination Reagents. The resulting reagents
were subjected to the optimized C−H amination conditions
(Table 1, entry 16). Interestingly, varying the leaving group
from acetate in reagent 1 to pivalate (Scheme 3, reagent 10) or
trifluoroacetate (reagent 11) decreased the catalytic efficiency
(34% and 4% yields), suggesting that the identity of the leaving
group is crucial for catalysis.
Adjusting the substituents of the sulfonate group from tolyl
to phenyl (reagent 12) resulted in only a small decrease in yield
to 44%, while both electron-donating (OMe, reagent 16) and
electron-withdrawing substituents on the aryl moieties (NO2,
CF3, Cl; reagents 13−15) afforded further lowered yields of the
C
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a
dissociation energy, as long as this bond is not significantly
sterically hindered. Therefore, a combination of both steric and
electronic factors influences C−H amination selectivity in the
established systems, resulting in a reactivity order of 2° > 1° ≫
3°. A competition experiment (entry 13) between ethylbenzene
and cumene further supports this conclusion.
Table 2. Arene Substrate Scope
These observations are generally in agreement with literature
reports on other Cu catalysts, which show a preference for the
secondary benzylic C−H bond,16 but typically also attack
primary, nonbenzylic C−H bonds, resulting in a mixture of
three different products (18a, 18b, and p-H3CC6H4-
CH2CH2NHTs). This suggests that the combination of
Cu(BF4)2/9 and amination reagent 1 is generally less reactive
than comparative Cu C−H amination systems, but at the same
time more selective for secondary and primary benzylic bonds.
Substituted toluenes (entries 7−9) generally afforded low to
moderate yields of benzylic C−H amination product (24 to
43%); no clear trend can be delineated between electron-
withdrawing and electron-donating substituents. This is in
agreement with the amination reagent scope (see Scheme 3
above), in which both electron-withdrawing and electron-
donating substituents on amination reagents 13 to 16 afford
lower yields than the tolyl-substituted amination reagent 1.
Overall, this observation suggests that factors other than simple
electronic substituent factors may play a role in the established
system. As both electron-withdrawing and electron-donating
substituents have shown stabilizing effects on radical centers,29
the described reactivity may well be influenced by such effects.
However, initial rates measured with different para-substituted
toluenes do not show any clear correlations with Hammett
parameters (σ/σ+) or radical stabilization parameters (σ•; see
SI).
In contrast to arenes with functional group substitution,
arenes with cyclic alkyl substructures afforded higher yields
than observed with toluene (64% and 76%, respectively; entries
10 and 11). Similarly high yields have been observed with these
substrates when employing other Cu-based catalyst sys-
tems,17,21 and this phenomenon has previously been associated
with decreasing values of benzylic C−H bond dissociation
energies for the respective substrates.21
Interestingly, THF is also a suitable substrate for C−H
amination, providing the aminated hemiaminal product in 67%
yield (entry 12). As the bond dissociation energy for the Cα−H
bond in THF (70 kcal/mol) is significantly lower than the
bond dissociation energy of the benzylic C−H bond in
toluene,23,30 this finding is in agreement with the above
observed higher yields for substrates with lower bond
dissociation energies (entries 10/11).
Mechanistic Investigations. As the developed reaction
system shows some similarities to literature-known systems, but
also distinctly different reactivity (e.g., lack of C−H amination
of sterically hindered C−H bonds), we pursued mechanistic
studies to gain insight into pathways involved in product and
side product formation.
Our initial studies were aimed at confirming that ligand 9
binds to the Cu precatalyst under catalytic conditions. To this
end, we prepared a catalytic reaction mixture in analogy to the
optimized conditions (see Experimental Section for details).
This reaction mixture was heated to 110 °C for 15 min, diluted
with MeOH, and then analyzed by electrospray ionization mass
spectroscopy (ESI-MS). The obtained mass spectrum (Scheme
4) showed the presence of [CuI(9)(H2O)2]+ in positive ion
mode. This complex is likely formed from the precursor
a
Conditions: Substrate (2.00 mL, 94−197 equiv), Cu(BF4)2·6H2O
(2.3 mg, 6.3 μmol, 5.0 mol %), ligand 9 (3.0 mg, 6.3 μmol, 5.0 mol %),
amination reagent 1 (28.7 mg, 0.125 mmol, 1.00 equiv), 110 °C, 48 h,
b
N2. NMR yields were determined by quantitative 1H NMR analysis of
the crude reaction mixtures, using 1,3-dinitrobenzene as internal
standard; yields are reported as average yields of at least 2
experimental trials; corresponding standard deviations are generally
<2% (see SI).
TsNNaCl17 and TpBr3Cu(NCMe)/PhINTs16 both readily
form the product of benzylic C−H amination with cumene as
substrate.
Reacting a substrate with both secondary and primary
benzylic C−H bonds (entry 6) produces the secondary C−H
amination product 18a as the major product (55%), with the
minor product 18b being formed in 12% yield as a result of
primary C−H bond cleavage. This observation suggests that the
catalyst prefers cleavage of the C−H bond with the lower bond
D
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a
Scheme 4. ESI-MS Spectrum (Positive Ion Mode) and
Scheme 5. Product Formation vs Time
a
Predicted Spectrum for [CuI(9)(H2O)2]+
a
The difference in the m/z axis reflects a known 0.3 amu calibration
discrepancy.
a
Conditions: Toluene (2.00 mL, 1.73 g, 18.8 mmol, 146 equiv), 1
(0.125 mmol, 1.00 equiv), Cu(BF4)2·6H2O (2.3 mg, 6.3 μmol, 5.0 mol
%), ligand 9 (3.0 mg, 6.3 μmol, 5.0 mol %), 110 °C, N2.
Cu(BF4)2·6H2O and ligand 9 by coordination and one-electron
reduction. In combination with the above-discussed similar
performance of CuI and CuII salts as catalyst precursors, this
suggests that Cu compounds of either oxidation state may
provide entry into the catalytic cycle; moreover, both oxidation
states may be involved during catalysis.
Interestingly, decomposition of 9 occurs upon extended
reaction times: An analogous ESI-MS analysis of a reaction
mixture after 24 h showed signals for complex 20 (Figure 2; for
In contrast to the kinetics of product formation, the highest
rate of TsNH2 formation (red line in Scheme 5) is detected
during the first 4 h of the reaction; its yield decreases minimally
in the latter part of the reaction from 52% at 4 h to 45% after
48 h. The kinetics for formation of the other side product,
bitolyl (black dotted line), are more similar to the kinetics of
product formation: slow formation in the initial 4 h and
accelerated formation after 4 h. These observations combined
imply that the reaction mechanism involves an intermediate
which is formed directly from amination reagent 1; this reaction
produces TsNH2 as a side product. In a second step after the
first 4 h, the accumulated intermediate is then transformed into
the product BnNHTs; this second step also forms bitolyl as the
side product.
Figure 2. Complex ion 20 detected by ESI-MS in a reaction mixture
after 24 h.
Importantly, 1H NMR analyses of the crude reaction
mixtures suggested that a broad peak at 4.23 ppm may be
associated with the proposed intermediate, as the peak grows in
over the first 4 h and then disappears. Isolation of the
intermediate from the reaction mixture (11% yield), spectro-
scopic characterization, and independent synthesis (see SI for
details) identify the intermediate as BnTsN-OAc, in which the
N−O bond is still intact.
In a subsequent investigation, we studied the temperature
dependence of the formation of product, intermediate, and side
products under otherwise unchanged optimized reaction
conditions. Scheme 6 illustrates that the yields of TsNH2 and
BnTsN-OAc are similar at 70 and 90 °C, suggesting that these
two products are formed through a common catalytic cycle.
Moreover, the combined yields of BnTsN-OAc and BnNHTs
under these conditions are close to the observed yield of
TsNH2, suggesting that formation of BnNHTs from BnTsN-
OAc does not produce TsNH2.
Furthermore, the temperature dependence of the yields for
intermediate and BnNHTs suggests that reaction pathways
producing BnTsN-OAc can be accessed at lower temperatures
(28% at 70 °C; 43% at 90 °C) than the formation of product
(3% BnNHTs at 70 °C; 8% at 90 °C). This observation implies
that the activation barrier for the formation of BnTsN-OAc is
significantly lower than the activation barrier for the conversion
of BnTsN-OAc to BnNHTs.
spectra, see SI), in which Cu is ligated by two diamine ligands.
This suggests that the speciation of the Cu complexes in the
reaction mixture changes over the course of the reaction; this
changing coordination environment may at the same time cause
changes in catalytic reactivity (see discussion vide infra).
A subsequent ligand decomposition study (see SI for details)
confirms that among the tested ligands, ligand 9 is the most
stable diimine and undergoes hydrolysis very slowly. In
contrast, ligands with more electron-donating aryl groups
(e.g., ligands 2 and 3 with C6H4-NMe2/OMe substituents)
hydrolyze more quickly. This suggests that the relative
significant stability of ligand 9 plays a role in the catalytic
amination activity.
Next, we investigated the kinetics of product formation over
time (Scheme 5) under the optimized reaction conditions,
employing toluene as substrate and 1 as amination reagent.
Scheme 5 shows that formation of the C−H amination product
BnNHTs (blue line) mainly occurs after 4 h and is mostly
complete after 16 h. However, the amination reagent
TsNHOAc (1; purple line in Scheme 5) is consumed within
the first 4 h of the reaction. This suggests that BnNHTs is not
formed directly from the amination reagent and that another
reaction intermediate may accumulate during the first 4 h,
which then affords BnNHTs in a second reaction step.
E
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absence of ligand. The respective rates of substrate disappear-
ance, intermediate, and product formation under conditions
with and without ligand are illustrated in Scheme 8.
Scheme 6. Products after 48 h at Different Reaction
Temperatures
Scheme 8. Comparison of Rates of Product Formation and
Substrate Disappearance with/without Ligand 9
Reactions of isolated BnTsN-OAc under conditions
analogous to the optimized catalytic reaction conditions
(Scheme 7) support this hypothesis: Only 6% of BnNHTs is
Scheme 7. Reactivity of Catalytic Intermediate
Demonstrating Formation of BnNHTs
Interestingly, consumption of the amination reagent 1 is
significantly slower in the absence of ligand 9, suggesting that
the electron-donating features of Cu ligation by 9 accelerate the
reaction of the catalyst with the amination reagent. At the same
time, the rates of formation for TsNH2 and the intermediate
BnTsN-OAc are both significantly slower in the absence of 9,
which suggests that both products are formed in the same
reaction cycle. In contrast, formation of the product BnNHTs is
not significantly affected by ligand presence or absence in the
first 6 h of the reaction. Similarly, the rates of bitolyl formation
with and without ligand 9 only deviate from each other at
longer reaction times. Both of the latter observations imply that
a change in catalytic species may be occurring at extended
reaction times and/or that a different species than a Cu species
ligated to 9 may be responsible for conversion of BnTsNOAc
to BnNHTs.
obtained after 24 h with the optimized catalyst system,
suggesting a relatively slow transformation of BnTsNOAc
into BnNHTs associated with a high activation barrier.
Interestingly, the conversion of BnTsN-OAc to product
shows a dependence on the catalyst used: when employing
simple Cu(BF4)2·6H2O, the obtained yield of BnNHTs (84%)
is much higher. Furthermore, conversion of BnTsN-OAc to
BnNHTs requires Cu as catalyst, as shown by a lack of
reactivity in the absence of Cu; the presence of air also inhibits
the formation of BnNHTs from BnTsNOAc.
In combination, the studies illustrated in Scheme 7
demonstrate that BnTsN-OAc is a likely catalytic intermediate
for the formation of BnNHTs. The data also imply that the
transformation of BnTsN-OAc into the product may be
catalyzed by a nonligated Cu species under C−H amination
conditions. Together with the finding that ligand 9 decomposes
to form diamine complex 20, this suggests that ligand
decomposition (e.g., by radical addition or diimine hydrolysis)
may need to occur in the reaction mixture before the product
can be formed efficiently, which is one possible explanation for
the observed “timelag” in the reaction kinetics (see Scheme 5
above).
Mechanistically, all of the studies above are consistent with a
mechanism that proceeds through two catalytic cycles: The first
cycle forms BnTsN-OAc and TsNH2 with a relatively low
energetic barrier; then, a second catalytic cycle with a higher
activation barrier transforms BnTsN-OAc into BnNHTs and
produces bitolyls as side products. In agreement with our
experimental findings and prior mechanistic work in related,
Cu-catalyzed C−H amination systems,20 we thus propose a
reaction mechanism for the herein described catalytic protocol,
as shown in Scheme 9.
We propose that the amination reagent reacts with two CuI
catalysts, resulting in the formation of a CuII amide 20 and a
CuII acetate species. Species like 20 have previously been
proposed to be active in C−H cleavage,20 which results in
formation of a benzylic radical. In a parallel reaction, the CuII
In order to gain further insight into the role of the ligand in
catalysis, a similar time course study was undertaken in the
F
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kinetic data (see Scheme 5 above) and with the observation
that bitolyls are formed as side products in all productive
stoichiometric reactions of the intermediate BnTsN-OAc
(Scheme 7 above). However, it is possible that the benzylic
radical formed in cycle 1 also undergoes bitolyl formation
instead of reaction with CuII species 21. This reaction may be
occurring particularly if the reaction of the CuII acetate species
with the second equivalent of amination reagent is slow, which
is a scenario that would likely occur at low concentrations of
amination reagent (i.e., after 2 h under the catalytic conditions
shown in Scheme 5). Alternatively, a benzylic radical formed in
cycle 2 may also react with 21; as such, crossover between the
two catalytic cycles may be possible.
Scheme 9. Plausible Mechanistic Hypothesis for Cu-
Catalyzed, Benzylic C−H Amination
Such “crossover” reactivity may be responsible for the higher
yields observed when employing substrates with lower C−H
bond dissociation energies. In these cases, the respective
benzylic radicals R• are relatively long-lived. This may enable a
reaction between [CuII]-OAc and the byproduct TsNH2 to
form [CuII]-NHTs; this species in turn could then undergo a
radical rebound reaction with the benzylic radical R• and form
R-NHTs. This hypothesis is further in agreement with the slow
consumption of TsNH2 observed in the time study upon
extended reaction times (Scheme 5).
The mechanistic hypothesis described in Scheme 9 has
several consequences: (1) The need to use an excess of toluene
as substrate is explained by the need for cycle 2 to access the
product BnNHTs. As such, reactions with 1 equiv substrate
may be possible when a catalytic system that only undergoes
cycle 1 can be developed. (2) Similarly, the high reaction
temperature required to access BnNHTs may stem from the
higher activation barrier of cycle 2, likely caused by the less
electrophilic nature of the CuII amide species 22. (3) The
strong preference for sterically unhindered C−H bonds may be
rationalized by the significant steric hindrance at CuII amide
species 21 that recombines with the benzylic radical for C−N
bond formation. (4) The mechanism in Scheme 9 proposes
radical species as key intermediates due to the observed
formation of bitolyl.
In order to gain insight into the feasibility of the proposed
radical intermediates, we synthesized a benzylic substrate 24
with a neighboring cyclopropyl moiety. This substrate has
previously been used to obtain information on the radical
character of related reactions.31 When subjecting 24 to the
standard catalytic reaction conditions (Scheme 10), 5% of the
ring-opened product 25 was observed; no direct C−H
amination product 26 with the cyclopropyl moiety still intact
was obtained.
acetate species can react with a second equivalent of amination
reagent to produce AcOH and a new CuII species 21, in which
the N−O bond remains unbroken. 21 then can react with the
benzylic radical to form a new C−N bond in coordinated
intermediate BnTsN-OAc; release of BnTsN-OAc and TsNH2
subsequently reforms the two [CuI] species.
The intermediate BnTsN-OAc then enters the second
catalytic cycle and undergoes N−O bond cleavage, oxidizing
two [CuI] species to the corresponding CuII compounds.
Complex 22 is a CuII amide species capable of H atom
abstraction in analogy to the reactivity proposed for cycle 1.
However, intermediate 22 can be expected to be less
electrophilic than 20, which might provide a rationale for the
higher activation barrier of cycle 2. The higher reactivity of
nonligated Cu catalysts for cycle 2 can be explained with an
analogous rationale: Nonligated CuII salts would be expected to
be more electrophilic than CuII species coordinated to a
diimine ligand and thus might be more active for H atom
abstraction in cycle 2. Upon reaction between 22 and 1 equiv of
toluene, a CuI complex 23 is formed that releases the product
BnNHTs and reforms 1 equiv of catalyst. However, formation
of 23 through H atom abstraction also causes the formation of
a benzylic radical, which can react with another equivalent of
substrate in a radical addition pathway; the resulting bitolyl
radical may then react with the CuII acetate species to form
AcOH and regenerate 1 equiv of [CuI] catalyst.
Scheme 10. Reactivity of Radical Clock Substrate 24
The proposed mechanism suggests that bitolyl is formed
concurrently with the product BnNHTs, in agreement with the
G
DOI: 10.1021/acs.organomet.7b00003
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Organometallics
Article
hydroxymethanesulfonamide, which was used for the next synthetic
step without further purification. This compound has been previously
reported; the observed 1H and 13C NMR spectra were consistent with
the data reported in the literature.25
This suggests that benzylic radicals, such as proposed in the
mechanistic hypothesis (Scheme 9), are feasible intermediates
of the described benzylic C−H amination protocol. We
speculate that the low yield of amination product 25 obtained
is due to the significant steric hindrance of the benzylic C−H
bond in 24; similarly hindered substrates generally show low
yields of amination product under the herein established
conditions (see entries 4 and 5, Table 2).
N-Acetoxymethanesulfonamide. N-Acetoxymethanesulfonamide
was synthesized in analogy to a literature known procedure:22 4.85 g
(43.7 mmol, 1.00 equiv) of N-hydroxymethanesulfonamide was
dissolved in 120 mL of tetrahydrofuran at −78 °C, and 3.82 mL
(5.30 g, 52.4 mmol, 1.20 equiv) of triethylamine was added dropwise.
After stirring the mixture for 15 min at −78 °C, 3.74 mL (4.11 g, 52.4
mmol, 1.20 equiv) of acetyl chloride was added dropwise. The reaction
mixture was stirred for 4 h at −78 °C. The reaction mixture was then
allowed to warm to room temperature, and the precipitate formed in
the reaction was filtered off. The solvent of the filtrate was evaporated
to afford a white solid. The resulting solid was dissolved in 50 mL of
dichloromethane and washed with 2 × 20 mL of 1 M aqueous HCl.
The organic phase was dried over MgSO4 and filtered, and the solvent
of the filtrate was removed under reduced pressure. The thus obtained
crude product was dissolved in a boiling solvent mixture of 10 mL of
ethyl acetate and 30 mL of hexane. The resulting solution was stored
at 2 °C overnight. The crystals formed were isolated by filtration and
dried under high vacuum to afford 3.1 g (47% yield) of the title
compound as a white solid.
SUMMARY AND CONCLUSIONS
In summary, we have established new types of reagents for the
Cu-catalyzed amination of benzylic Csp −H bonds. The
■
3
employed electrophilic amination reagents can be synthesized
and stored on gram scales, eliminating the need to form
reagents in situ (e.g., as for PhINR) and potential explosion
hazards (e.g., as for azides). Importantly, the established
reagents allow variations of the introduced protecting group.
Various arene substrates with weak, benzylic C−H bonds as
well as THF have been successfully employed as substrates
under the optimized conditions. Unlike in previously reported
systems, tertiary or sterically crowded secondary C−H bonds
undergo C−H amination only in low yields, suggesting that a
sterically crowded intermediate may be responsible for C−N
bond formation or C−H abstraction in the catalytic cycle.
Our detailed mechanistic studies suggest a new mechanism
for C−N bond formation that proceeds through two
subsequent catalytic cycles, a previously undocumented type
of reactivity in Cu-catalyzed benzylic C−H aminations. As the
first catalytic reaction that yields BnTsN-OAc can be performed
at relatively low temperatures, future catalyst developments will
focus on improving the chemoselectivity for this reaction,
which has the potential to reduce the required arene substrate
loading.
1H NMR (500 MHz, CDCl3, 25 °C): δ [ppm] = 8.60 (br, 1H;
NH), 3.10 (d, 2H; CH3SO2-), 2.28 (s, 3H; −COCH3).13C NMR (125
MHz, CDCl , 25 °C): δ [ppm] = 169.5, 39.0, 18.5. IR (ATR): v
̃
3
[cm−1] = 3128 (s), 1758 (s), 1390 (s), 1329 (s), 1194 (s), 1160 (s),
1060 (s), 1008 (s), 979 (s), 961 (s), 935 (s), 862 (s), 795 (s), 715 (s),
646 (s). HRMS calcd 175.9988 (M + Na), found 175.9975.
Representative Procedure for Cu-Catalyzed, Benzylic C−H
Amination of Toluene. In a nitrogen-filled glovebox, Cu(BF4)2·
6H2O (2.3 mg, 6.3 μmol, 5.0 mol %), ligand 9 (3.0 mg, 6.3 μmol, 5.0
mol %), amination reagent 1 (28.7 mg, 0.125 mmol, 1.00 equiv), and
dry toluene (2.00 mL, 146 equiv) were added in this sequence to a 4
mL scintillation vial, equipped with a Teflon-coated stir bar. The vial
was sealed with a Teflon-lined vial cap and heated to 110 °C on a
preheated vial plate under vigorous stirring (1500 rpm). After stirring
the mixture for the required reaction time, the vial was taken off the
heating block, and the mixture was allowed to cool to room
temperature. Volatiles were removed under reduced pressure (rotary
evaporator). A solution containing 1,3-dinitrobenzene (5.0 mg, 29
μmol) as NMR standard in 0.5 mL CDCl3 was added into the reaction
vial. The resulting mixture was filtered through Celite. The filtrate was
Overall, this manuscript describes a new reaction protocol for
3
Cu-catalyzed C−H amination of relatively weak Csp −H bonds
that proceeds through a radical pathway. A previously
undocumented, two stage mechanistic hypothesis provides a
rationalization for unusual, stepwise reaction kinetics. However,
the high reaction temperature, limited commercial availability
of the reagents, and the requirement to use an excess of
benzylic substrates are currently limiting the practicality of the
protocol.
1
used directly for quantitative H NMR measurements (15 s relaxation
time, NS = 32) to determine the product yield by measuring the ratio
of integrals for the two benzylic protons of PhCH2NHTs (peak at 4.11
ppm) and the aromatic signal of 1,3-dinitrobenzene at 8.55 ppm (for
details see SI).
EXPERIMENTAL SECTION
Isolation of C−H Amination Product N-Benzyl-4-methyl-
benzenesulfonamide from Reaction Mixture. In a glovebox,
Cu(BF4)2·6H2O (11.5 mg, 31.5 μmol, 5.0 mol %), ligand 9 (15.0
mg, 31.5 μmol, 5.0 mol %), amination reagent 1 (143.5 mg, 0.625
mmol, 1.00 equiv), and toluene (10.0 mL, 146 equiv) were added in
this sequence to a 20 mL scintillation vial equipped with a Teflon-
coated stir bar. The vial was sealed with a Teflon-lined vial cap and
heated to 110 °C on a preheated vial plate under vigorous stirring
(1500 rpm). After 48 h, the vial was taken off the heating block, and
the mixture was allowed to cool to room temperature. The solvent was
removed under reduced pressure. CHCl3 (5 mL) was added to the
mixture, and the resulting suspension was filtered through Celite. The
filtrate was concentrated under vacuum (rotary evaporator) to yield
the crude product which was purified by column chromatography
using ethyl acetate/hexanes (1:4) as eluent. 73 mg (45% yield) of pure
title compound was obtained. 1H and 13C NMR analysis are in
agreement with literature reported spectra.32
■
Representative Procedures for Synthesis of Electrophilic
Amination Reagents. N-Hydroxymethanesulfonamide. N-Hydrox-
ymethanesulfonamide was synthesized in analogy to a literature known
procedure:25 16.7 g (240 mmol, 2.00 equiv) of hydroxylamine
hydrochloride was dissolved in 24 mL of DI water at 0 °C. A solution
of 33.2 g (240 mmol, 2.00 equiv) of K2CO3 dissolved in 36 mL water
was added dropwise into the hydroxylamine hydrochloride solution
while maintaining the internal reaction temperature (thermometer in
the reaction mixture) between 5 and 15 °C with an external ice/water
bath. After stirring the solution for 15 min, 120 mL of tetrahydrofuran
and 30 mL of methanol were added; subsequently, 15.4 mL (21.3 g,
120 mmol, 1.00 equiv) of methanesulfonyl chloride was added
portionwise while maintaining the internal reaction temperature
between 5 and 15 °C. Upon complete addition, the reaction
temperature was allowed to rise to room temperature. After stirring
for 4 h at room temperature, the organic solvents were removed under
reduced pressure (rotary evaporator). The resulting aqueous
suspension was extracted with 2 × 200 mL diethyl ether. The
combined organic layers were dried over MgSO4. The solvent of the
mixture was then removed under reduced pressure and dried under
high vacuum to afford 15.1 g (73% yield) of crude N-
Isolation of Reaction Intermediate BnTsN-OAc from Catalytic
Reaction Mixture. In a glovebox, Cu(BF4)2·6H2O (46 mg, 126 μmol,
5.0 mol %), ligand 9 (60 mg, 126 μmol, 5.0 mol %), TsNH-OAc (1)
(574 mg, 2.5 mmol, 1.00 equiv), and dry toluene (40.0 mL, 34.7 g, 376
mmol, 146 equiv) were added in this sequence to a 100 mL nitrogen
H
DOI: 10.1021/acs.organomet.7b00003
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Article
flask, equipped with a Teflon-coated stirbar. The flask was sealed
tightly and removed from the glovebox, and the reaction was heated
for 4 h to 110 °C in a preheated heating block under vigorous stirring.
The flask was removed from the heating block, and the mixture was
allowed to cool to room temperature. The solvent was removed under
reduced pressure. CHCl3 (5 mL) was added to the mixture. The
resulting suspension was filtered through Celite. 25 mL of hexanes was
added to the filtrate. The precipitated white solid (TsNH2) was filtered
off. The solvent of the resulting filtrate was removed under reduced
pressure to afford an off-white solid as crude product, which was
purified by column chromatography using hexanes and ethyl acetate
(5:1; Rf of the product is 0.20 in this mixture) as eluent. 87 mg (11%
yield) of the title compound were isolated as a white solid.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge funding of this work by the NIH (National
Institute of General Medical Sciences award 1R15GM107939-
01A1). We thank Ronald L. Grimm (WPI) for his assistance in
measuring and interpreting ESI-MS spectra and Sergio
Granados Focil (Clark University, Worcester, MA) for his
assistance with 19F NMR spectra.
1H NMR (500 MHz, CDCl3, 25 °C): δ [ppm] = 7.84 ppm (d, 2H;
Ar−H), 7.43 ppm (d, 2H; Ar−H), 7.30 ppm (m, 5H; Ar−H), 4.20
ppm (br, 2H; PhH2NH−), 2.50 ppm (d, 2H; CH3SO2-). 13C NMR
(125 MHz, CDCl3, 25 °C): δ [ppm] = 168.6, 145.9, 133.0, 130.1,
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1
afford 900 mg (75% yield) of the product as white crystals. The H
NMR, 13C NMR, and IR spectra obtained were identical to the spectra
determined for BnTsN-OAc that had been isolated from the catalytic
reaction mixture.
ESI-MS Analysis of Reaction Solution To Indicate Binding of
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temperature. The solvent was removed under reduced pressure.
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MeOH and was used directly for ESI-MS analysis.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00003.
Experimental procedures, spectroscopic data
(1H/13C/19F NMR, IR, HRMS), and detailed optimiza-
tion data (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mhemmert@wpi.edu.
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