Mechanistic insights into C-H amination via dicopper nitrenes

Article abstract of DOI:10.1021/ja400879m

We examine important reactivity pathways relevant to stoichiometric and catalytic C-H amination via isolable β-diketiminato dicopper alkylnitrene intermediates {[Cl₂NN]Cu}₂(μ-NR). Kinetic studies involving the stoichiometric aminatio

Full text of DOI:10.1021/ja400879m

Article
pubs.acs.org/JACS
Mechanistic Insights into C−H Amination via Dicopper Nitrenes
Mae Joanne B. Aguila, Yosra M. Badiei, and Timothy H. Warren*
Department of Chemistry, Georgetown University, Box 571227-1227, Washington, D.C. 20057, United States
S
* Supporting Information
ABSTRACT: We examine important reactivity pathways
relevant to stoichiometric and catalytic C−H amination via
isolable β-diketiminato dicopper alkylnitrene intermediates
{[Cl2NN]Cu}2(μ-NR). Kinetic studies involving the stoichio-
metric amination of ethylbenzene by {[Cl2NN]Cu}2(μ-NtBu)
(3) demonstrate that the terminal nitrene [Cl2NN]CuNtBu
is the active intermediate in C−H amination. Initial rates
exhibit saturation behavior at high ethylbenzene loadings and
an inverse dependence on the copper species [Cl2NN]Cu,
both consistent with dissociation of a [Cl2NN]Cu fragment from 3 prior to C−H amination. C−H amination experiments
employing 1,4-dimethylcyclohexane and benzylic radical clock substrate support a stepwise H-atom abstraction/radical rebound
pathway. Dicopper nitrenes [Cu]2(μ-NCHRR′) derived from 1° and 2° alkylazides are unstable toward tautomerization to
copper(I) imine complexes [Cu](HNCRR′), rendering 1° and 2° alkylnitrene complexes unsuitable for C−H amination.
Scheme 1. C−H Amination via Metal−Nitrenes
INTRODUCTION
■
Catalytic C−H amination represents an appealing approach for
preparation of nitrogen containing compounds without
requiring typical functional group manipulations.1 A majority
of these protocols are proposed to proceed through metal−
nitrene species [M]NR′2 which may directly react with a C−
H bond in substrates R−H to give amines R−NHR′.
Commonly, isolable or in situ prepared nitrene precursors
such as iminoiodinanes PhINR based on electron-deficient
sulfonylamines H2NSO2R or carbamates H2NC(O)OR have
been used with dirhodium3,4 or ruthenium catalysts.5−7
Nonetheless, the quest for more earth abundant, economical
C−H functionalization catalysts motivates the investigation of
first-row transition metal systems based on Mn,8 Fe,9,10 Co,11,12
and Cu.13−16
Only in a few cases, however, may discrete metal-nitrene
species be isolated and subjected to detailed analysis. Che
isolated and kinetically studied the novel (porph)Ru(
NSO2R′)2 featuring trans-[M]NSO2R′ moieties.5 Based on
the primary KIEs of 4−11 observed in reactions with benzylic
C−H bonds in substrates R−H, these reactions were suggested
to proceed via H-atom abstraction (HAA)/radical recombina-
tion (RR) pathways to give the C−H amination products
RNH(SO2R′). Cenini crystallographically characterized the
related electron-poor derivative (porph)Ru(NArF)2 (ArF =
3,5-(CF3)2C6H3).17 Isolation of the bis(amide) (porph)Ru(N-
(1-cyclohexenyl)ArF)2 derived from the addition of 2 equiv of
the cyclohexenyl radical to (porph)Ru(NArF)2 in the C−H
amination of cyclohexene suggested a similar HAA/RR
mechanism. These stepwise C−H amination pathways should
be contrasted with an asynchronous concerted mechanism
identified using stereochemical probes via putative [Rh2]NTs
species (Scheme 1).3
Previously we described the isolation of dicopper nitrenes
[Cu]2(μ-NR) (R = aryl, Ad) obtained from the reaction of
copper(I) β-diketiminates with organoazides N3R.15,18 For
instance, the dicopper nitrene {[Cl2NN]Cu}2(μ-NAd) (1)
([Cl2NN] = 2,4-bis(2,6-dichloro)phenylimido)pentyl) may be
isolated from the reaction of {[Cl2NN]Cu}2(μ-benzene) (2)
with the organoazide N3Ad (Ad = 1-adamantyl). This species
formally inserts the NAd group into sp3-hybridized C−H bonds
under stoichiometric and catalytic conditions (Scheme 2).15
Furthermore, this is the first example of an isolated copper
nitrene species that participates in intermolecular nitrene
transfer to C−H substrates.
Despite considerable interest, no terminal copper nitrene
complex has been isolated to allow for clear mechanistic
studies.16 The dicopper nitrenes {[Cl2NN]Cu}2(μ-NAd),
{[Me3NN]Cu}2(μ-NAd), and {[Me3NN]Cu}2(μ-NAr) (Ar =
3,5-Me2C6H3) represent the only species characterized by X-ray
(Figure 1). Solution studies suggested the possibility of
dissociation of a β-diketiminato copper(I) fragment from
[Cu]2(μ-NAr) (Figure 1) during the formation of an
Received: January 25, 2013
© XXXX American Chemical Society
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R-H as well as capture of the resulting radical R• to give the
functionalized amines R−NHR′.22
Scheme 2. Copper Nitrene-Based C−H Amination
Herein we report mechanistic investigations into stoichio-
metric and catalytic C−H amination via dicopper nitrenes that
points to the importance of dissociation of a β-diketiminato
fragment [CuI] from [Cu]2(μ-NR′) species to generate
terminal nitrenes [Cu]NR′ that directly react with C−H
substrates R−H. Use of stereochemical probes provides insight
into the nature of the C−H → C−N transformation.
Examination of reactions with 1° and 2° alkyl azides
N3CHRR′ (R, R′ = H or alkyl) reveal that dicopper nitrenes
[Cu]2(μ-NCHRR′) may be isolated, but rapidly convert to
[CuI](NHCRR′) species in arene solvents where dissocia-
tion of a β-diketiminatio copper(I) fragment [CuI] is favored.
RESULTS AND DISCUSSION
■
Synthesis and Characterization of {[Cl2NN]Cu}2(μ-
NtBu) (3). Stirring the copper(I) precursor {[Cl2NN]Cu}2(μ-
benzene)15 (2) with the 3° organoazide N3 Bu in pentane gives
t
{[Cl2NN]Cu}2(μ-NtBu) (3) as green crystals in 46% yield
(Scheme 3). The X-ray structure of 3 shows a bridging nitrene
Scheme 3. Synthesis and X-ray Structure of Dicopper
Nitrene 3
Figure 1. Previously investigated copper nitrenes.
unsymmetrical species [Cu](μ-NAr)[Cu′] in the presence of
an additional β-diketiminate-like species [Cu′].18
Since the first observation of C−H amination and alkene
aziridination with sulfonyl azides in the presence of copper,19
copper sulfonylnitrene species have attracted significant interest
(Figure 1).16 Calculations on Nicholas’s cationic bis(imine)
copper system showed that κ2-N,O-NTs copper species
represent the most likely intermediates for the C−H
amination.20 The close separation of calculated triplet (ground)
and multiconfigurational singlet (excited) states leads to a
bifurcation of reaction pathways: the former is predicted to
react through stepwise HAA/RR, while the latter should react
in a concerted fashion. Quite recently, Lewis acid adducts of a
cationic copper-tosylnitrene supported by tridentate amine
isolated at low temperature have been reported.21 Substantiated
by XAS and resonance Raman studies, DFT studies point to a
κ2-N,O-NTs binding mode in which the nitrene N-donor
engages a Lewis acid such as Sc(OTf)3. Reactivity studies reveal
that this species aminates sp3 C−H bonds in substrates such as
toluene and even cyclohexane in modest yields (21−35%).
Direct, asynchronous, insertion of a metal-nitrene into a C−
H bond and H-atom/radical rebound (HAA/RR) represent
two opposing pathways considered for C−H functionalization
with metal nitrenes (Scheme 1). While putative [Rh]2
NSO2R intermediates have been probed with radical clock
substrates to give evidence for a concerted pathway,3 related
copper-based systems employing diimine ligands provide
evidence for contributions from both pathways.20 Moreover,
the identification of an HAA/RR pathway for β-diketiminato
[Cu]NR′ species would specifically implicate three-coor-
dinate copper(II) amides [CuII]-NHR′ as active intermediates.
Recent synthetic and kinetic studies have revealed such [CuII]-
NHR′ species to be active in stoichiometric C−H functional-
ization themselves, capable of both HAA of benzylic substrates
unit similar in form to the N-adamantyl variant 1.15 The nearly
C2-symmetric tert-butylnitrene complex 3 exhibits Cu−Nnitrene
distances of 1.808(3) and 1.815(3) Å nearly identical to those
in 1 (1.810(2) Å). The Cu···Cu separation of 2.9147(6) Å in 3
is somewhat shorter than that found in 1 (2.969(1) Å) likely
t
due to the slightly smaller steric impact of the Bu group
1
compared to Ad. H and 13C{1H} NMR spectra of 3 reveal
only one type each of N-aryl p-H and m-H environments, even
down to −70 °C in toluene-d8, indicating facile rotation about
the Cu−Nnitrene bonds at the expense of any Cu···Cu interaction
(Supporting Information Figures S9−S10 and Scheme S7).
Kinetic Investigation of [Cu]2(μ-NtBu) Reactivity with
Ethylbenzene. We performed a series of kinetics experiments
that support the dissociation of a [Cl2NN]Cu fragment ([Cu])
from 3 to generate the terminal nitrene [Cl2NN]CuNtBu
([Cu]NtBu) responsible for C−H amination reactivity
(Scheme 4a). The progress of the stoichiometric reaction of
3 ([3]0 ∼ 0.5 mM) and varying equivalents of ethylbenzene
was monitored through loss of the intense optical band of the
dicopper nitrene 3 ([Cu]2(μ-NtBu)) at λmax = 714 nm (ε =
3960 M−1 cm−1) using the method of initial rates (Supporting
Information Figure S2). The initial rate of decay of [Cu]2(μ-
B
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Scheme 4. Kinetic Analysis of Stoichiometric C−H Amination of Ethylbenzene (R−H) by 3 at 40 °C in Benzene
NtBu) (3) in benzene at 40 °C increases with added
ethylbenzene (1000−10000 equiv), but exhibits saturation at
higher ethylbenzene concentrations (Scheme 4b). This
behavior is inconsistent with direct reaction between the
dicopper nitrene [Cu]2(μ-NtBu) (3) and ethylbenzene. This
also indicates a pre-equilibrium step involving dissociation of
[Cu] from [Cu]2(μ-NtBu) (3) to form the terminal nitrene
[Cu]NtBu prior to the irreversible C−H functionalization
step (Scheme 4a).
mixture of 3° C−H amination products R-NHtBu (Scheme 5a).
We also found that the amount of secondary inserted products
Scheme 5. Catalytic C−H Amination of Mechanistic Probes
To more closely monitor the dissociation of [Cu] from
[Cu]2(μ-NtBu) (3) that enables C−H amination by [Cu]
NtBu, we followed the stoichiometric reaction of [Cu]2(μ-
NtBu) (3) with ethylbenzene in the presence of varying
concentrations of added [Cu]. An inverse dependence of the
rate on both the concentration of [Cu] and R−H is expected
from the rate law derived from steady-state approximation of a
mechanistic scenario that involves dissociation of [Cu] from
[Cu]2(μ-NtBu) (k1/k−1) to give low concentrations of [Cu]
NtBu that participates in C−H amination (k2) (Scheme 4a and
Supporting Information Scheme S1). Careful control of the
concentration of ethylbenzene is essential to observe a clear
dependence of the initial rate on added [Cu]. Employing an
ethylbenzene concentration of 16.5 mM (50 equiv/3), kinetic
analysis at 40 °C reveals an inverse dependence of initial rate of
loss of 3 on the concentration of added [Cu] (0−20 equiv/3).
A plot of 1/kobs versus the concentration of added [Cl2NN]Cu
is linear whose y-intercept is the inverse of the rate constant k1
= 1.1(3) × 10−4 s−1 for dissociation of [Cu] from [Cu]2(μ-
NtBu) (3) under these conditions (Scheme 4c).
depends on the relative accessibility of the distinct 2° C−H
bonds in the cis and trans isomers. The cis isomer gave only one
product, while the trans-isomer gave two products (Supporting
Information Scheme S4). Functionalization of the 3° C−H
bond in the cis-substrate is more favorable than in the trans-
substrate, giving a 3°:2° C−H amination product distribution
of 75:25 and 25:75, respectively. This may be the result of
greater steric interactions between the axial 4-methyl group in
the trans-substrate and the [Cl2NN]CuNtBu intermediate as
it approaches the somewhat weaker tertiary C−H bond
(Supporting Information Scheme S5).
Stereochemical Probes: Mechanism of C−H Function-
alization. We then turned our attention to the mechanism by
which [Cl2NN]CuNtBu formally inserts the NtBu moiety
into C−H bonds. Concerted (likely asynchronous) and
stepwise (HAA/RR) pathways represent two limiting mecha-
nistic scenarios by which C−H substrates R-H could react with
the key [Cl2NN]CuNtBu intermediate to give R−NHtBu.
We employed two different types of mechanistic probes R−H
that each support a stepwise HAA/RR pathway by providing
evidence for the intermediacy of the corresponding radical R•
in the C−H amination of R−H by 3.
Use of a benzylic radical clock further supports a stepwise
mechanism for C−H amination (Scheme 5b). HAA from the
benzylic position of 1-benzyl-trans-2-phenylcyclopropane (4)
results in a radical that quickly rearranges (k = 3.6(5) × 108
s−1)23 to its ring-opened form. C−H amination of radical clock
t
4 (1 equiv) with excess N3 Bu at 100 °C employing a full
Reaction of cis- and trans-1,4-dimethylcyclohexane (20
equivalent of [Cu] gives only one product, the ring-opened
t
1
equiv) with N3 Bu catalyzed by 5 mol % {[Cl2NN]-
product in 80% yield. H NMR analysis of the HCl-salt of this
Cu}2(benzene) (2) at 100 °C leads to the C−H amination
of 3° and 2° C−H bonds in these substrates in combined yields
of 58% and 50% for the cis- and trans-isomers, respectively
(Supporting Information Scheme S3). Importantly, amination
of the 3° C−H bond in either the cis- or trans-isomer leads to
the same two products in essentially equal ratios (46:54 and
44:56, respectively). These findings clearly indicate the
intermediacy of a 3° radical R• that leads to a diastereomeric
product clearly shows the trans-configuration of the resulting
CC bond in the ring opened product (JHH for vinylic H = 16
Hz).
Formation of Copper Imine Complexes from New
Dicopper Alkylnitrenes. In our examination of the range of
alkylazides that may participate in C−H amination using our
catalytic protocols, we used representative 1° and 2° organo-
azides N3R to probe the possibility of new isolable dicopper 1°
C
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Figure 2. X-ray structures of dicopper alkylnitrenes [Cu]2(μ-NCHRR′) 5 and 6 and imine adducts [Cu](HNCRR′) 7 and 8.
and 2° alkylnitrene species. Addition of N3CH2CH2Ph or N3Cy
to 2 in chlorobenzene or pentane results in immediate
coloration of the chlorobenzene or pentane solution (Scheme
6). Dark purple crystals of {[Cl2NN]Cu}2(μ-NCH2CH2Ph)
(5) and dark blue green crystals of {[Cl2NN]Cu}2(μ-N(c-
C6H11)) (6) may be isolated suitable for X-ray diffraction by
low temperature crystallization from pentane immediately
following their synthesis (Figure 2). The Cu−Nnitrene distances
in 5 (1.782(3) and 1.793(3) Å) and 6 (1.793(3) and 1.804(3)
Å) are similar to those in 1 and 3. These Cu−N distances are
shorter than the Cu−Namide distance of 1.839(9) Å in the
copper(II) amide compound [Cl2NN]Cu-NHAd.22 The
Cu···Cu contacts of 2.8673(6) and 2.8782(7) Å in 5 and 6,
however, are further contracted than those found in 1 and 3
due to the lower steric demand of the smaller N-alkyl
product nor did attempted catalytic C−H amination of
ethylbenzene with N3CH2CH2Ph or N3Cy in the presence of
t
2. While the ethylbenzene C−H amination product with N3 Bu
does not bind to the [Cu] catalyst in benzene-d6, the imine
products HNCRR′ in 7 and 8 do bind to the [Cu] catalyst in
benzene-d6, indicating that these imines could inhibit efficient
catalytic transformations of the corresponding azides
N3CHRR′.
The X-ray structures of 7 and 8 (Figure 2) reveal trigonal
coordination at Cu with Cu−Nimine distances of 1.885(5) and
1.914(2) Å. These compounds have short CNimine distances
of 1.223(8) and 1.275(3) Å, respectively, compared to the C−
Nnitrene distances of 5 and 6 (1.434(4) and 1.435(5) Å,
respectively). The aldimine N−H moieties give rise to high
energy bands at 3283 and 3276 cm−1 in the IR spectra of 7 and
8.
substituents. This is also results in a less obtuse Cu−Nnitrene
−
Cu angle of 106.65(16)° for 5 and 106.30(17)° for 6 as
compared to 107.09(13)° for 3.
DISCUSSION AND CONCLUSIONS
■
We found that these 1° and 2° alkylnitrene complexes 5 and
6 are more significantly thermally sensitive than 1 and 3. Rather
than participating in C−H amination of substrates such as
ethylbenzene, dissolution of either 5 or 6 in benzene at RT
results in the rapid conversion to the copper(I) imine adducts
[Cl2NN]Cu(HNCHCH2Ph) (7) or [Cl2NN]Cu(HNc-
C6H10) (8) along with release of [Cl2NN]Cu (Scheme 6). α-H
Terminal copper nitrenes have long been considered as reactive
intermediates in the nitrene group transfer reactions of alkene
aziridination and C−H amination. Due to their high anticipated
reactivity illustrated by reaction with unactivated 2° and 3° C−
H bonds, challenges still remain in the isolation of these
species. Nonetheless, a “protected” form of the terminal nitrene
allows for the isolation of dicopper nitrenes [Cu]2(μ-NR) that
may dissociate a [Cu] fragment to reveal low concentrations of
the reactive terminal species [Cu]NR. Importantly, this
strategy also allows for the isolation of dicopper nitrenes for
which the terminal species may be inherently unstable as we
found for 1° and 2° species 5 and 6. This approach has also
been applied to the isolation of cationic N-tosylnitrene
complexes which has an additional κ2-N,O bonding mode
accessible. For instance, Vedernikov and Caulton first described
a purple complex of formulation {[LCu]2(NTs)}2+ upon
reaction of PhINTs and their copper(I) catalyst.14,24 In a
related chelating amine framework, formal substitution of a
[LCu]+ fragment for ScOTf3 resulted in [N3]Cu(μ-NTs)-
ScOTf3, a formulation supported by spectroscopy and theory
(Figure 1).21
Scheme 6. Facile Nitrene to Imine Transformation
migration qualitatively takes place much more quickly in
benzene than in solvents that do not coordinate well to the
[Cl2NN]Cu fragment such as ether or pentane. Thus, loss of
[Cl2NN]Cu from 5 and 6 to form the corresponding terminal
1° and 2° alkylnitrene complexes [Cl2NN]CuNCHRR′
likely precedes α-H migration to give the imine adducts 7
and 8. Consistent with the rapid conversion of [Cl2NN]Cu
NCHRR′ intermediates to the corresponding imines [Cl2NN]-
Cu(NHCRR′), attempted C−H amination of ethylbenzene
with either 5 or 6 did not provide any C−H functionalized
Our studies of C−H amination that proceed through the
terminal copper alkylnitrene [Cl2NN]CuNR clearly reveal
that C−H amination takes place via a stepwise HAA/RR
mechanism. A joint experimental/theory report by Nicholas,
Houk, and colleagues that examined putative cationic
{(diimine)Cu(NTs)}+ intermediates provided evidence for
competing direct insertion and HAA/RR pathways. For
D
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instance, reaction of a catalyst mixture prepared from the
diimine ligand in Figure 2 and [Cu(NCMe)4]PF6 (10 mol %)
with PhINTs in the presence of radical clock substrate 4 gave
an 18% and 6% yield of the ring opened and ring closed C−H
amination products.20
suggests the relationship kHAA ≈ 6 × 10−6/Keq. While we do not
have an experimental value for Keq corresponding to
dissociation of [Cl2NN]Cu from {[Cl2NN]Cu}2(μ-NtBu) (3)
in benzene (Scheme 4a, eq 1), Keq is lower than 10−2 based on
NMR analysis. No new nitrene species could be seen in the RT
NMR spectrum of 3 in benzene-d6. Based on calculations that
accompanied the initial report of 1,15,27 dissociation of a [CuI]
fragment from 1 as [Cl2NN]Cu(benzene) corresponds to ΔG
= +5.8 kcal/mol at 298 K. Taking into account the
Previous studies with the closely related [Cl2NN]Cu/N3Ad
catalytic system revealed a linear correlation between the
ln(rate) of C−H amination of substrates R-H and the C−H
bond strength.15 Normalizing for the number of equivalent
reacting C−H bonds, a C−H bond in cyclohexane (C−H BDE
= 97 kcal/mol) reacts 480 times slower than a C−H bond in
Indane (C−H BDE = 85 kcal/mol) at 110 °C. A rate limiting
HAA process was also suggested for Ray’s recently reported
Lewis acid stabilized tosylnitrene due to the linear correlation
of ln(rate) versus C−H bond strength.21 Furthermore, kinetic
isotope measurements reveal similar KIEs for copper nitrene
intermediates that engage in HAA reactions. The [Cl2NN]Cu/
N3Ad system gave KIEs of 5.3(2) and 6.6(1) for the C−H
amination of ethylbenzene and cyclohexane at 110 °C,
respectively.15 Importantly, stoichiometric C−H amination of
ethylbenzene with {[Cl2NN]Cu}2(μ-NAd) gave an identical
KIE of 5.1(2) under related conditions. Nicholas observed a
KIE of 4.6 in the C−H amination of cumene by the
{(diimine)Cu}+/PhINTs system at RT20 while Ray reported
a KIE of 5.1 in the HAA of dihydroanthracene at −90 °C. KIEs
in the range of 4−12 have been reported for species such as
(porph)Ru(NTs)2 suggested5,6 and [Me3NN]NiNAd
demonstrated25 to participate in HAA reactions, though higher
KIEs that deviate significantly from the value for classical H-
atom transfer (6.5)26 have been observed via Fe(III)-imide
intermediates by Betley (13−24).9
Clear evidence for a HAA/RR pathway for reaction of
[Cl2NN]CuNR′ with R−H indicates that [Cl2NN]Cu-NHR′
species serve as intermediates in C−H amination. Previously,
we have shown that 2 equiv of [Cl2NN]Cu-NHAd engage in
stoichiometric C−H amination of ethylbenzene by a HAA/RR
sequence.22 Thus, it is of interest to compare the intrinsic HAA
reactivity of the terminal copper nitrene [Cl2NN]CuNR′ and
copper(II) amide [Cl2NN]Cu-NHR′ (R′ = Ad, tBu) species. A
rate constant of 2.2(2) × 10−5 M−1 s−1 at 25 °C could be
measured for HAA of ethylbenzene by [Cl2NN]Cu-NHAd
(Scheme 7).22
concentration of neat benzene, an equilibrium constant Keq
≈
1 × 10−3 may be crudely estimated at 40 °C. Using this
estimate of Keq for dissociation of [CuI] from [Cu]2(μ-NtBu),
we find that HAA of ethylbenzene by [Cl2NN]CuNtBu
should possess a bimolecular rate constant in the vicinity of ca.
6 × 10−3 M−1 s−1 at 40 °C.
These data speak to the very high HAA reactivity of the
t
terminal nitrene species [Cl2NN]CuNR′ (R′ = Ad, Bu)
species which is at least 2 orders of magnitude greater than that
of [Cl2NN]Cu-NHAd22 and the closely related nickel-imide
[Me3NN]NiNAd (kHAA = 2.4(2) × 10−5 M−1 s−1 for
ethylbenzene at 35 °C).25 The origin of the high reactivity of
terminal alkylnitrene species [Cl2NN]CuNR is the high N−
H bond strength in the copper(II) amide [Cl2NN]Cu-NHR′
calculated to be 98.4 kcal/mol for [Cl2NN]Cu-NHAd.25 In
comparison, the N−H BDEs in [Cl2NN]Cu(NH2Ad) and
[Me3NN]Ni-NHAd are calculated to be 68 and 85.2 kcal/mol,
respectively.22,25
Unfortunately, the high reactivity of terminal copper nitrene
species also facilitates rapid α-H migration reactions via
[Cl2NN]CuNHRR′ intermediates to give imine adducts
[Cl2NN]Cu(HNNRR′). Such rearrangements in copper−
alkylnitrene complexes are reminiscent of α-H migration
processes observed in free singlet alkylnitrenes.28,29 For
instance, photolysis of the alkyl azide CH3N3 results in
formation of HNCH2 via singlet [CH3N].28 A related α-H
migration takes place from an Ir(III) benzylazide complex
[Ir](N3CH2Ph) with loss of N2 to give the corresponding
[Ir](NHCHPh) species, but no Ir-nitrene intermediate was
observed.30 Although this α-H migration limits the use of 1°
and 2° alkylazides for catalytic C−H amination with the
[Cl2NN]Cu catalyst, we recently reported an alternative
protocol with this catalyst that employs unactivated alkylamines
t
such as H2NCy and H2NCH2CH2Ph with BuOOtBu as
While we are unfortunately unable to directly compare the
oxidant.22
t
C−H bond reactivity of [Cl2NN]CuNR′ (R′ = Ad or Bu)
The β-diketiminato copper nitrenes {[Cl2NN]Cu}2(μ-NR′)
species, it is clear that it is much higher. Analysis of the
experimental data and the rate law derived from steady state
analysis (Scheme 4a and Supporting Information Table S3)
t
(R′ = Ad, Bu) represent sparse members of isolated and/or
well characterized late first row transition metal imides/nitrenes
that show high reactivity toward C−H amination of strong sp3
C−H bonds. Zhang provided EPR evidence supporting the
presence of porphyrin Co(III)-nitrene radical intermediates
capable of HAA/RR with 2° benzylic C−H substrates.11 A high
spin dipyrromethene FeIII-imido [Fe]NAr′ (Ar′ =
4-tBuC6H4) isolated by Betley and co-workers directly aminates
toluene.9 We recently reported that the β-diketiminato
nickel(III) imide [Me3NN]NiNAd undergoes HAA with
benzylic R−H substrates indane, ethylbenzene, and toluene to
form the nickel-amide [Me3NN]Ni-NHAd and hydrocarbyl
radical R•. Attack of the nickel-imide by R• led to formation of
the nickel(II) amides [Me3NN]Ni−N(R)Ad, though the C−H
amination product HN(R)Ad is observed in the reaction of
[Me3NN]NiNAd with indane.25 Hillhouse et al. has isolated
a low-coordinate nickel imido complex with an especially bulky
NHC ligand, (IPr*)NiN(dmp) (dmp =2,6-dimesitylphen-
Scheme 7. Roles for [Cl2NN]CuNR′ and [Cl2NN]Cu-
NHR′ in C−H Amination
E
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Journal of the American Chemical Society
Article
(3960 cm−1 M−1) with other prominent optical bands centered at 459
and 598 nm (Supporting Information Figure S1). Anal. Calcd. For
C38H35Cl8N5Cu2: C, 46.93; H, 3.63; N, 7.20. Found: C, 47.33; H,
3.86; N, 6.69.
yl).31 This nickel imido complex reacts with ethene, forming
the vinylamine (dmp)NH(CHCH2).
Since the rate of C−H amination via HAA/RR is strongly
coupled to the loss of a [CuI] fragment from dicopper nitrenes
[Cu]2(μ-NR′), synthetic studies that focus on the use of
especially bulky β-diketiminato ligands and/or nitrene sub-
stituents that discourage the formation of dinuclear species
should be expected to yield a significant rate enhancement.
Coupled with the calculated strength of the N−H bond in
[Cl2NN]Cu-NHAd (98.4 kcal/mol) formed via HAA of a
substrate R−H via terminal [Cl2NN]CuNAd,25 such
approaches may place the catalytic functionalization of methane
(C−H BDE = 105 kcal/mol)32 via β-diketiminato [Cu]NR′
species within reach.33
{[Cl2NN]Cu}2(μ-NCH2CH2Ph) (5). N3CH2CH2Ph (0.050 g, 0.340
mmol) in 2 mL of chlorobenzene was added to a stirring solution
{[Cl2NN]Cu}2(benzene) (0.060 g, 0.060 mmol) in 5 mL of
chlorobenzene. The initially yellow color of the solution turned dark
blue/purple in 2 min with effervescence of N2(g). The solution was
stirred for only 10 min at room temperature, and the solvent was
immediately removed in vacuo. The resulting purple residue was
dissolved in cold pentane (3 mL) and then filtered through a short
Celite stick (ca. 1 cm3) and allowed to stand overnight at −35 °C.
Dark blue/purple crystals formed from the solution to afford 0.040 g
(66%) of the product suitable for X-ray diffraction. Room temperature
benzene-d6 solutions of this compound convert quickly (<10 min) to
[Cl2NN]Cu(NHCHCH2Ph) (7) and [Cl2NN]Cu(benzene)15 as
1
EXPERIMENTAL SECTION
monitored by H NMR.
■
{[Cl2NN]Cu}2(μ-NCy) (6). N3Cy (0.170 g, 1.36 mmol) in 5 mL of
pentane was added to a stirring slurry of {[Cl2NN]Cu}2(benzene)
(0.259 g, 0.264 mmol) in 10 mL of pentane. The initially yellow color
General Procedures. All experiments were carried out in a dry
nitrogen atmosphere using an MBraun glovebox and/or standard
Schlenk techniques, unless otherwise stated. 4A molecular sieves were
activated in vacuo at 180 °C for 24 h. Dry benzene and
dichloromethane were purchased from Aldrich and were stored over
activated 4A molecular sieves under nitrogen. Diethyl ether and
tetrahydrofuran (THF) were first sparged with nitrogen and then
dried by passage through activated alumina columns. Pentane was first
washed with conc. HNO3/H2SO4 to remove olefins, stored over
CaCl2, and then passed through activated alumina columns. All
deuterated solvents were sparged with nitrogen, dried over activated
of the slurry turned greenish blue in 2 min with effervescence of N2(g)
.
The mixture was stirred for 10 min at room temperature and
immediately filtered through a short Celite stick (ca. 1 cm3), and the
solvent was removed in vacuo. The resulting dark blue-green residue
was extracted with cold pentane (∼1.5 mL, −35 °C), passed through a
short Celite stick (ca. 1 cm3), and allowed to stand overnight at −35
°C. Dark blue crystals formed that were suitable for X-ray diffraction.
Room temperature benzene-d6 solutions of this compound convert
quickly (<5 min) to [Cl2NN]Cu(NHc-C6H10) (7) and [Cl2NN]-
4A molecular sieves, and stored under nitrogen. H and 13C NMR
1
Cu(benzene)15 as monitored by H NMR spectroscopy, undergoing
1
spectra were recorded on a Varian 400 MHz spectrometer (400 and
100.4 MHz, respectively). All NMR spectra were recorded at room
temperature unless otherwise noted and were indirectly referenced to
TMS using residual solvent signals as internal standards. GC-MS
spectra were recorded on a Varian Saturn 2100T, elemental analyses
were performed on a Perkin-Elmer PE2400 microanalyzer in our
laboratories, and UV−vis spectra were recorded on a Cary 50
spectrophotometer.
α-H migration qualitatively faster than 5.
[Cl2NN]Cu(NHCHCH2Ph) (7). N3CH2CH2Ph (0.030 g, 0.204
mmol) in 3 mL of ether was added to a stirring solution
{[Cl2NN]Cu}2(benzene) (0.100 g, 0.103 mmol) in 7 mL of ether.
The initial yellow color of the solution turned dark blue/purple in 2
min with effervescence of N2(g) and left to stir for 1 h at RT upon
which the solution turned back to the initial yellow color. The solution
was filtered through Celite and concentrated in vacuo to ca. 2 mL and
allowed to stand overnight at −35 °C. Pale yellow crystals crashed out
of solution that were collected and dried to afford 0.090 g (78%) of
All reagents were obtained commercially unless otherwise noted
and typically stored over activated 4A molecular sieves. Ethylbenzene
was obtained from Acros and purified by passing each through
activated alumina. {[Cl2NN]Cu}2(μ-benzene) (2) was prepared by
literature methods15 or may be obtained from Strem Chemicals (#29-
7050). cis- and trans-1,4-Dimethylcyclohexane were obtained from
TCI America and purified by passing each through activated alumina.
1
crystals that were suitable for X-ray diffraction. H NMR (400 MHz,
benzene-d6): δ 7.71 (d, 1, NH imine), 7.08 (d, 4, Ar-m- H), 7.03 (d, 2,
Ph), 6.96 (t, 1, Ph), 6.67 (dd, 1, Ph), 6.37 (t, 2, Ar-p-H), 6.20 (dt, 1,
HNCHCH2), 5.03 (s, 1, backbone-CH), 3.18 (d, 2, HNCHCH2),
1.86 (s, 6, backbone CH3). 13C{1H} NMR (100 MHz, benzene-d6): δ
171.76 (CH imine), 164.1, 148.94, 134.84, 130.59, 129.60, 29.36,
129.21, 128.58, 127.47, 123.16, 95.41, 45.50, 23.52. IR, thin film: 3283
cm−1 (N−H). Anal. Calcd. For C25H22Cl4N3Cu: C, 52.70; H, 3.89; N,
7.37. Found: C, 52.57; H, 3.66; N, 7.07.
Following literature procedures, N3 Bu34 and N3Cy35 were prepared by
t
t
reaction of NaN3 with either BuOH or CyBr under appropriate
conditions. N3CH2CH2Ph was prepared via modification of published
procedures involving tosylation of PhCH2CH2OH36 followed by
reaction of PhCH2CH2OTs with NaN3.37 Caution! While some
organoazides can explosively decompose upon heating, exposure to
high fluxes of light, or exposure to some metal complexes and some
metal surfaces, we did not experience any such uncontrolled reactivity
in this work. All catalytic reactions with azides at elevated temperatures
were performed in pressure vessels behind a Plexiglas shield.
[Cl2NN]Cu(NHC6H10) (8). N3Cy (0.166 g, 1.33 mmol) in 5 mL of
ether was added to a stirring slurry of {[Cl2NN]Cu}2(benzene) (0.245
g, 0.205 mmol) in 10 mL of ether. The color of the mixture turned
greenish blue in 2 min with effervescence of N2(g). The mixture was left
to stir for 24 h at RT upon which its color turned back to the initial
yellow color. The mixture was filtered through Celite and concentrated
in vacuo to ca. 2 mL and allowed to stand overnight at −35 °C. Yellow
crystals that crashed out of solution were collected and dried to afford
Preparation of Compounds. {[Cl2NN]Cu}2(μ-NtBu) (3). To slurry
of {[Cl2NN]Cu}2(benzene) (0.173 g, 0.177 mmol) in 30 mL of
t
pentane was added a solution of N3 Bu (0.143 g, 1.44 mmol) in 20 mL
1
0.135 g (49%) that was suitable for X-ray diffraction. H NMR (400
of pentane. This yellowish suspension was stirred for 24 h at RT; after
∼10 min, it turned into a yellow-green slurry. The mixture was passed
through a short Celite stick (ca. 1 cm3), and the solvent was
immediately removed in vacuo. The dark green residue was taken into
∼10 mL pentane, filtered through a short Celite stick (ca. 1 cm3),
concentrated in vacuo to ∼3 mL, and allowed to stand overnight at
−35 °C. Dark green blocks of the product formed (0.079 g, 46%) that
MHz, benzene-d6): δ 7.38 (s, 1, NH imine), 7.10 (d, 4, Ar-m-H), 6.37
(t, 2, Ar-p-H), 5.03 (s, 1, backbone-CH), 2.02 (t, 2, α-CH2 from C),
1.88 (s, 6, backbone-CH3), 1.14 (d, 2, β-CH2 from C), 0.99 (t, 2, α-
CH2 from C), 0.87 (q, 2, γ-CH2 from C), 0.81 (d, 2, β-CH2 from
C). 13C{1H} NMR (100 MHz, benzene-d6): δ 183.42 (CH
imine), 163.80, 149.03, 130.61, 128.50, 122.85, 95.21, 39.41, 38.84,
27.14, 26.91, 25.06, 23.57. IR, thin film: 3276 cm−1 (N−H). Anal.
Calcd. For C23H24Cl4N3Cu: C, 50.43; H, 4.42; N, 7.67. Found: C,
50.65; H, 4.43; N, 7.40.
1
were suitable for X-ray diffraction. H NMR (400 MHz, benzene-d6,
RT): δ 6.99 (d, 8, Ar-m-H), 6.42 (t, 4, Ar-p-H), 5.15 (s, 2, backbone
−CH), 1.64 (s, 12, backbone −CH3), 0.75 (s, 9, tBu −CH3). 13C{1H}
NMR (100 MHz, benzene-d6): δ 164.85, 147.31, 128.51, 128.27,
125.70, 100.11, 73.96, 29.95, 23.43. UV−vis: λmax (benzene) = 714 nm
Kinetic Measurement by UV−Vis Spectroscopy. Solutions for
kinetic analysis by UV−vis spectroscopy were prepared using freshly
F
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Journal of the American Chemical Society
Article
prepared and crystallized 3. A known amount of 3 was dissolved in RT
benzene to a known volume using a volumetric flask. This sample was
used for UV−vis analysis and stored frozen at −35 °C until needed. A
known portion of this stock solution (unfrozen) was added with
appropriate amounts of ethylbenzene and {[Cl2NN]Cu}2(benzene),
followed by dilution to 10.0 mL with benzene at RT. The decreasing
concentration of 3 at 40.0 °C was quantified by UV−vis spectroscopy
employing an 18 s scan interval, by considering the decrease in
absorbance at λmax = 714 nm. The method of initial rates was used for
kinetic analyses to minimize the effect of [Cl2NN]Cu generation in
C−H amination by {[Cl2NN]Cu}2(μ-NtBu) which leads to a
deceleration of effective rates. Details of these kinetic analyses may
be found in the Supporting Information.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional synthetic, characterization, and kinetics details, along
with X-ray details including fully labeled thermal ellipsoid plots
for compounds 3 and 5−8 (also provided in .cif format). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
thw@georgetown.edu.
Notes
Catalytic Amination of cis- and trans-1,4-Dimethylcyclohex-
t
t
The authors declare no competing financial interest.
ane with N3 Bu. Two portions of N3 Bu (0.198 g, 2.00 mmol) were
dosed, one mixed with cis-1,4-dimethylcyclohexane (6.00 mL, 41.8
mmol) and the other with the trans-isomer (6.00 mL, 40.6 mmol). A
solution of {[Cl2NN]Cu}2(benzene) (1.00 mL, 0.025 M, 0.025 mmol,
ACKNOWLEDGMENTS
■
We are grateful to NSF (CHE-1012523) for financial support
of this work. We appreciate many insightful conversations with
Prof. Tom Cundari of the University of North Texas. We also
t
t
2.5 mol % relative to N3 Bu = 5 mol % [Cu] relative to N3 Bu) in
benzene was added into each of the aliquot of the azide-substrate
solution (3.00 mL). These reaction mixtures were heated for 48 h at
100 °C in a sealed, thick walled reaction vessel. The color of the
solution changed from light yellow to dark green. The mixtures were
quenched by exposing to air for several hours, filtered through Celite
stick, and analyzed via GC/MS in CH2Cl2. GC/MS indicated that
there are no other products except for the aminated products. The
solvent was removed in vacuo from each reaction mixture, the residue
was taken as the crude yield for the reaction, 55% (0.105 g) for the cis-
isomer, and 50% (0.0915 g) for the trans-isomer. Amination at both
tertiary and secondary C−H bonds was observed, with selectivity of
3°:2° 75:25 and 25:75 for cis- and trans-isomer, respectively. Tertiary
products were obtained in the same distribution (44:56 for trans-
isomer and 46:64 for cis-isomer), irrespective of substrate used.
Detailed analysis of the product distribution from the catalytic
amination of these substrates is found in the Supporting Information.
Catalytic Amination of a Benzylic Radical Clock. The susbtrate
1-benzyl-trans-2-phenylcyclopropane (4) was prepared following a
modified cyclopropanation procedure of trans-1,3-diphenylpropene23
with trifluoroacetic acid, diethylzinc, and diiodomethane.38 Detailed
synthetic procedures are provided in the Supporting Information.
A solution of 1-benzyl-trans-2-phenylcyclopropane (0.150 g, 0.720
thank Dr. Roland Frohlich of the University of Munster,
̈
̈
Germany, for assistance with the refinement of the X-ray
structure of 3.
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