Copper-nitrene complexes in catalytic C-H amination

Article abstract of DOI:10.1002/anie.200804304

(Chemical Equation Presented) Hydrocarbons activate! Isolable β-diketiminato dicopper-nitrene complexes such as 1 derived from the reaction of [{(Cl₂NN)Cu}₂(μ-benzene)] and 1-adamantylazide are potent towards nitrene insertion into unactivated sp ³-hybridized C-H bonds. 1 allows stoichiometric and catalytic intermolecular C-H amination of hydrocarbons to give secondary amines (see scheme). Catalyst loadings as low as 0.05 mol% may be used.

Full text of DOI:10.1002/anie.200804304

Angewandte
Chemie
DOI: 10.1002/anie.200804304
Synthetic Methods
ꢀ
Copper–Nitrene Complexes in Catalytic C H Amination**
Yosra M. Badiei, Adriana Dinescu, Xuliang Dai, Robert M. Palomino, Frank W. Heinemann,
Thomas R. Cundari,* and Timothy H. Warren*
ꢀ
The direct catalytic transformation of typically inert carbon–
hydrogen bonds into carbon–oxygen, carbon–nitrogen, and
carbon–carbon bonds represents a significant challenge in
organic synthesis and the chemical industry.[1] Ideally, such
reactions would not require the presence of a functional
group that is discarded later in the course of the chemical
transformation, but would proceed with atom and energy
efficiency and be of minimal environmental impact.
Chemical species capable of directly promoting this
transformation often contain multiple bonds between late
transition metals to oxygen, nitrogen, or carbon centers.[2]
Nature provides inspiration with enzymes such as cycto-
chrome P-450, which is efficient at inserting an oxygen atom
the development of more general systems for C H bond
functionalization.
In this context, we recently isolated a dicopper complex
[{(Me3NN)Cu}2(m-NAr)] (Ar= 3,5-dimethylphenyl) in which
a nitrene is bound between two b-diketiminate copper
fragments.[12] Solution studies supported the intermediacy of
terminal copper–nitrene [Cu] = [(Me3NN)Cu] through the
dissociation of a b-diketiminate copper fragment from
[{(Me3NN)Cu}2(m-NAr)]. The terminal nitrene could not be
directly observed owing to an unfavorable dissociation
constant [Eq. (1); [Cu] = [(Me3NN)Cu].
benzene
½½Cuꢁ ðm-NArÞꢁ
½Cuꢁ¼NAr þ ½½CuꢁðbenzeneÞꢁ
ð1Þ
ƒƒƒ!
2
ꢀ
into hydrocarbon C H bonds through an iron–oxo inter-
[3]
In an attempt to encourage the dissociation of one copper
b-diketiminato fragment, [(Me3NN)Cu], by using the steric
bulk of the nitrene substituent, we carried out the reaction of
1-adamantylazide (N3Ad) with [{(Me3NN)Cu}2(m-toluene)] in
diethyl ether (Scheme 1a). Immediate crystallization of the
reaction mixture allowed the isolation of green
[{(Me3NN)Cu}2(m-NAd)] (1). Single crystal X-ray crystallo-
=
=
mediate ([Fe] O). The use of iminoiodanes (PhI NR) has
led to the generation of related metal–nitrene intermediates
=
([M] NR), which in certain cases, exhibit stoichiometric
reactivity with carbon–hydrogen bonds to give amines.[4]
Several catalytic protocols based on Rh,[5] Ru,[6] Ag,[7]
Au,[8] Cu,[9] and other metals for the amination of benzylic or
ꢀ
allylic C H bonds with iminoiodanes bearing electron-
graphic data for
1
(Cu-Nnitrene = 1.785(6), 1.821(5) ꢀ;
deficient N substituents represent useful methodologies for
[2,10,11]
Cu···Cu = 2.901(2) ꢀ) are quite similar to that found in
[{(Me3NN)Cu}2(m-NAr)].[12] Solutions of 1 are more thermally
sensitive than those of its arylnitrene counterpart as the color
of the solution changed from green to red during recrystal-
lization attempts. This red substance can be isolated in 80%
ꢀ
ꢀ
the transformation of C H into C N bonds.
In these
catalytic cases, metal–nitrene species are inferred, but their
high reactivity makes their characterization as the active
intermediates difficult. This lack of characterization is unfor-
tunate, as a fundamental understanding of metal–nitrene
ꢀ
species that mediate catalytic C N bond formation would aid
[*] Dr. A. Dinescu, Prof. T. R. Cundari
Department of Chemistry, Center for Advanced Scientific Comput-
ing and Modeling (CASCaM), University of North Texas
Denton, TX 78203 (USA)
E-mail: t@unt.edu
Y. M. Badiei, Dr. X. Dai, R. M. Palomino, Prof. T. H. Warren
Department of Chemistry, Georgetown University
Box 571227, Washington, DC 20057-1227 (USA)
Fax: (+1)202-687-6209
E-mail: thw@georgetown.edu
Dr. F. W. Heinemann
Department of Chemistry and Pharmacy, Friedrich-Alexander-
University Erlangen-Nꢀrnberg, Erlangen (Germany)
[**] The authors acknowledge funding from the National Science
Foundation (CHE-0135057 and CHE-0716304 to T.H.W and CHE-
0701247 to T.R.C.), the Alexander von Humboldt Foundation (re-
invitation award to T.H.W.), and the Deutsche Forschungsgemein-
schaft (SFB 583). Y.M.B. thanks Georgetown University for a
Dissertation Fellowship and R.M.P. thanks the NSF REU program
under CHE-0552586.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804304.
Scheme 1. a) Synthesis and X-ray crystallographic structures of 1 and
ꢀ
2. b) Intramolecular C H amination with a bulky b-diketiminate ligand.
Angew. Chem. Int. Ed. 2008, 47, 9961 –9964
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9961

Communications
yield from the reaction between [{(Me3NN)Cu}2(m-toluene)]
and 2 equivalents of N3Ad in diethyl ether at room temper-
ature for 24 hours (Scheme 1a).[13]
The X-ray crystal structure of the red, dimeric product 2
clearly shows coordination of the secondary amine function-
ality, ArCH2NHAd, to each copper center (Cu-N =
2.040(4) ꢀ). The amine results from the intramolecular
ꢀ
insertion of an adamantylnitrene functionality into a C H
bond of one b-diketiminate ortho-methyl group. 1H NMR
spectra of 2 in [D6]benzene show two inequivalent benzylic
CH2NHAd resonances, and IR spectroscopy indicates the
presence of a new N H bond (nNH = 3218 cmꢀ1). This mode of
ꢀ
nitrene insertion into b-diketiminate N-aryl o-methyl sub-
stituents appears to be general. Reaction of [(Me2NNtBu)Cu-
(benzene)], which contains backbone tert-butyl groups
instead of methyl groups and two 2,6-Me2C6H3 groups as
N-aryl substituents, leads to a similar intramolecular nitrene
insertion to give a monomeric product (Scheme 1b).
Scheme 2. Synthesis of dicopper nitrene 4 and its stoichiometric
ꢀ
amination of C H bonds.
We reasoned that the use of chemically inert substituents
at the ortho-aryl position of the b-diketiminate N groups
could thwart intramolecular nitrene insertion and enable the
functionalization of more synthetically useful, exogenous
ꢀ
C H bonds. [{(Cl2NN)Cu}2(m-benzene)] (3), having Cl sub-
stituents in the ortho positions of the b-diketiminate N-aryl
groups, can be prepared in 94% yield from the reaction of the
free diimine [H(Cl2NN)][14] and CuOtBu in benzene. Reaction
of [{(Cl2NN)Cu}2(m-benzene)] with N3Ad in chlorobenzene
results in the isolation of [{(Cl2NN)Cu}2(m-NAd)] (4) as a
green crystalline material in 63% yield. X-ray crystallo-
graphic analysis shows 4 to be similar in structure to
[{(Me3NN)Cu}2(m-NAr)] and 1, possessing an NAd ligand
symmetrically bridged between two Cu centers which are
related through C2-symmetry (Cu-Nnitrene 1.810(2) ꢀ; Cu···Cu:
2.969(1) ꢀ; Scheme 2).
ꢀ
Scheme 3. Proposed catalytic cycle for C H amination with N3Ad
catalyzed by [{(Cl2NN)Cu}2(m-benzene)] (3).
products of 90% or higher were achieved with toluene,
ethylbenzene, and indane. Cyclohexane, with its very strong
C H bond (95.5 kcalmol ), required 48 hours to reach high
conversion; this reaction time could be significantly shortened
by employing microwave heating (T= 1208C, 1.5 h). By using
benzene as the solvent, the catalytic amination of 1 equivalent
of the substrate with 2.5 mol% 3 gives yields from 31–82%. In
addition, clean nitrene insertion into the sp2-hybridized
ꢀ1
ꢀ
Benzene solutions of dicopper nitrene 4 exhibit diamag-
13
netic 1H and C NMR spectra with a backbone C H
ꢀ
1H NMR resonance at d 5.14 ppm. Solutions of 4 in benzene
exhibit an intense green color owing to a low-energy charge-
transfer band at lmax = 717 nm (e = 5870mꢀ1 cmꢀ1) with a
shoulder at l = 589 nm. At room temperature, benzene
solutions of 4 (ca. 0.1 mm) exhibit a half-life of approximately
3 hours. Heating 4 in [D6]benzene at 808C for 4 hours gives
H2NAd in 95% yield as identified by GC/MS methods.
ꢀ
aldehyde C H bond occurs to give 91% yield of the amide
(1 equivalent of benzaldehyde, 5 mol% 3, at 808, 16 hours in
benzene). In some cases, the catalyst loadings may be reduced
to 0.05 mol%, such as in the amination of ethylbenzene
(5 equiv) with N3Ad in benzene at 1108C (90% yield; 900
ꢀ
Dissolution of dicopper nitrene 4 into several hydro-
turnovers/Cu). A proposed mechanism for the catalytic C H
3
ꢀ
carbons containing sp C H bonds, however, results in clean
amination, based on our observations resulting from the use
of stoichiometric amounts of reagents, is shown in Scheme 3.
The decreased yield for the toluene amination is princi-
[15]
ꢀ
transfer of the NAd moiety into these C H bonds. For
instance, heating samples of 4 in neat toluene or cyclohexane
at 808C for 3–4 hours results in quantitative nitrene transfer
to provide the secondary amines PhCH2NHAd and
CyNHAd, respectively. For indane, a hydrocarbon with
=
pally because of the formation of imine PhCH NAd that
results from the oxidation of the primary product
(PhCH2NHAd). For instance, PhCH2NHAd reacts with
1 equivalent of N3Ad in the presence of 2.5 mol% 3 to give
ꢀ
weaker benzylic C H bonds, this reaction takes place at
=
room temperature with a qualitatively comparable rate. This
PhCH NAd in 68% yield along with H2NAd at 1108C in
ꢀ
result suggests that nitrene C H insertion, rather than
dissociation of a [(Cl2NN)Cu] fragment from 4, may be rate
benzene [Eq. (2)]. This enables the direct conversion of
toluene into the corresponding benzylic imine under related
catalytic conditions by the use of a N3Ad/toluene ratio of 2:1,
limiting (Scheme 2 and Scheme 3).
ꢀ
=
This intermolecular C H functionalization reaction may
which gives PhCH NAd in 60% yield with benzene as the
be carried out under catalytic conditions employing N3Ad
with 2.5 mol% [{(Cl2NN)Cu}2(benzene)] (3) in neat hydro-
carbons at 1108C (Table 1).[15] The yields of the isolated
solvent [Eq. (3)]. We did not observe the subsequent oxida-
tion of the amine derived from ethylbenzene or indane under
similar catalytic conditions.
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Chemie
ꢀ
Table 1: Catalytic amination of C H bonds with 1-adamantylazide
(N3Ad) employing 2.5 mol% [{(Cl2NN)Cu}2(m-benzene)] (3).
Entry Substrate Product
Yield [%][a] t [h]
Yield [%][d]
31
1
92
90
4
5
2
3
82 (85)[e]
80
24
1
50
80
4
5
6
93
90
48 (1.5)[c] 32 (40)[e]
Figure 1. Catalytic rates of amination at 1108C relative to ethylbenzene
ꢀ
[ln(ksubstrate/kethylbenzene)] versus C H bond strength. All rates were
91[b]
16
91
ꢀ
normalized for the number of equivalent participating C H bonds.
[a] All reactions were run in neat hydrocarbon substrate at 1108C and
amines were isolated as hydrochloride salts. Reported yields are for
isolated products. [b] 1 equivalent substrate in benzene, T=808C;
isolated as amide. [c] Reaction carried out with microwave-assisted
radiation, T=1208C. [d] Reaction with 1 equivalent substrate and
1 equivalent azide in [D6]benzene; yields determined by 1H NMR
methods. [e] Yields determined by using NMR methods employing
5 equivalents substrate in [D6]benzene.
the DFT level support our experimental inability to directly
observe this species owing to an unfavorable equilibrium
constant for the dissociation of a [(Cl2NN)Cu] fragment from
dicopper nitrene 4 to give the terminal nitrene 5 (DG =
+ 17.1 kcalmolꢀ1; DH = + 25.9 kcalmolꢀ1 at 1 atm and 298 K)
[see Eq. (1)].
Several DFT studies of copper–nitrenes complexes have
recently been published, indicating a triplet ground state.[16,17]
In light of the research by Borden et al. on metal-free NPh[18]
and theoretical studies by Cundari et al. on simpler copper–
nitrene models,[19] we felt it prudent to a) employ complete
active space self-consistent field (CASSCF)[20] multiconfigu-
ration techniques instead of DFT methods, and b) model the
full experimental models with CASSCF/MM hybrid methods.
Several noteworthy results emanated from our computational
=
analysis of [(Cl2NN)Cu NAd] (see Figure 2 and the Support-
ing Information). First, the ground state is a singlet, not a
triplet as has been either assumed[17] or inferred[16] from
previous DFT studies of copper–nitrene species having
bidentate N-donor ligands.[21] Instead, it is predicted to be a
singlet biradical on the basis of extensive CASSCF calcula-
tions[19] of both simple and elaborate models of the exper-
The connection between decreasing yields with decreas-
ing substrate loadings for the other substrates employed is
ꢀ
because of the competition between C H amination and
=
formation of the diazene AdN NAd. A control experiment
performed in benzene shows that 3 cleanly converts AdN3
imental intermediates reported herein. The singlet ground
ꢀ1
=
=
into AdN NAd after 3 days at 1108C.
state of [(Cl2NN)Cu NAd] is calculated to be 18 kcalmol
Competition experiments employing pairs of substrates
(5 equiv each) at 1108C in benzene established that the
below the triplet excited state. Second, the inability of DFT
methods to correctly model the singlet ground state arises
from the significant diradical nature of the copper–nitrene
bond. The calculated natural orbital occupation numbers
ꢀ
strength of the C H bond is a key factor that controls the
relative rates of catalytic amination with N3Ad (Figure 1).
Furthermore, employing a 1:1 ratio of the substrate to its
perdeutero analogue gives a kinetic isotope effect (KIE), kH/
kD, of 5.3(2) for ethylbenzene and 6.6(1) for cyclohexane at
1108C. Notably, heating the isolated [{(Cl2NN)Cu}2(m-NAd)]
(4) in ethylbenzene isotopomers at 1108C gives the same KIE
(5.1(2)) within experimental error. These values are on the
low end of the range (4.8–11) observed in the stoichiometric
CH insertion of ruthenium imides, which is thought to
proceed by a hydrogen atom abstraction/rebound mecha-
nism.[4]
ꢀ
(NOONs) for the orbitals that define the Cu dp Nnitrene pp
bond deviate significantly from 2.0eꢀ and 0.0eꢀ. The NOONs
for the singlet ground state of 5 are 1.5eꢀ and 0.5eꢀ. This
indicates a substantial contribution to the ground state
CASSCF wavefunction from states involving pCuN!p*CuN
transitions. The pertinent natural orbitals are shown in
Figure 2. Third, whereas the triplet excited state of
=
[(Cl2NN)Cu NAd] has a more linearly coordinated nitrene
ligand (Cu-N = 1.78 ꢀ; Cu-N-C = 1648) the singlet ground
state has bent nitrene coordination (Cu-N = 1.82 ꢀ; Cu-N-
C = 1298). Presumably, such a bent arrangement of the
nitrene ligand will permit access of a wider array of hydro-
carbon substrates at the copper–nitrene active intermediate.
Density functional theory (DFT) calculations were
employed to address the putative terminal intermediate
=
[(Cl2NN)Cu NAd] (5) (Scheme 3). Initial calculations at
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Communications
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Figure 2. a) The calculated geometry and b) the CuN p and CuN p*
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balls represent atoms modeled with quantum (CASSCF) techniques
and tubes depict atoms modeled with the MM3 force field. H atoms
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ꢀ
=
=
for Cu N (p*).
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NAd)], reported herein possess an unexpected potency
ꢀ
towards nitrene insertion into C H bonds. For the first
time, nitrene precursors bearing aliphatic N substituents
participate in catalytic amination of strong, unactivated sp3
ꢀ
C H bonds such as those in cyclohexane. In contrast to other
catalytic systems, which employ electron-poor, heteroatom-
rich N substituents such as sulfonyl or carbamate groups to
ꢀ
achieve C H bond insertion, the use of a tertiary organic
ꢀ
[13] For a related intramolecular amination of a C H bond from a
azide allows direct formation of N-functionalized secondary
organic amines. Whereas organic azides offer the possibility
=
discrete TpCo NAd intermediate, see: D. T. Shay, G. P. A. Yap,
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[15] T. H. Warren (Georgetown University), PCT Int. Appl. WO
2008073782, 2008.
[16] J. Conradie, A. Ghosh, J. Chem. Theory Comput. 2007, 3, 689.
[17] Q. Meng, F. Wang, X. Qu, J. Zhou, M. Li, THEOCHEM 2007,
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[18] W. T. Borden, N. P. Gritsan, C. M. Hadad, W. L. Karney, C. R.
Kemnitz, M. S. Platz, Acc. Chem. Res. 2000, 33, 765.
[19] T. R. Cundari, A. Dinescu, A. B. Kazi, Inorg. Chem. 2008, in
press.
to directly introduce NR groups with organic N functional-
[22]
ities into C H bonds either intramolecularly[23] or inter-
ꢀ
molecularly,[24] they can suffer lower efficiencies as compared
to their sulfonylnitrene intermediates.[10] Notably, the inex-
pensive copper catalyst[9,25] which is quite robust, allowing low
catalyst loadings to give 900 turnovers/Cu in the amination of
5 equivalents of ethylbenzene with N3Ad.
In terms of catalyst design, the meta stability of long
sought copper–nitrene intermediates provides useful rates for
ꢀ
catalytic C H functionalization while also permitting char-
acterization through experimental and computational meth-
ods. As such, this b-diketiminato copper-based system
provides a credible starting point for the rational engineering
of improved metal catalysts for hydrocarbon functionaliza-
tion.
[20] B. O. Roos, P. R. Taylor, E. M. Siegbahn, Chem. Phys. 1980, 48,
157.
[21] Copper tosylnitrenes with tetradentate ligands have also been
predicted to be triplet species at the DFT level: P. Comba, C.
Lang, C. Lopez de Laorden, A. Muruganantham, G. Rajaraman,
H. Wadepohl, M. Zajaczkowski, Chem. Eur. J. 2008, 14, 5313.
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Received: September 1, 2008
Published online: November 17, 2008
[23] a) B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey, T. G.
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ꢀ
Keywords: amination · C H activation · copper ·
density functional calculations · nitrenes
.
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Angew. Chem. Int. Ed. 2008, 47, 9961 –9964