Copper-catalyzed oxidative dehydrogenative carboxylation of unactivated alkanes to allylic esters via alkenes

Article abstract of DOI:10.1021/ja510093x

We report copper-catalyzed oxidative dehydrogenative carboxylation (ODC) of unactivated alkanes with various substituted benzoic acids to produce the corresponding allylic esters. Spectroscopic studies (EPR, UV-vis) revealed that the resting state of the catalyst is [(BPI)Cu(O₂CPh)] (1-O₂CPh), formed from [(BPI)Cu(PPh₃)₂], oxidant, and benzoic acid. Catalytic and stoichiometric reactions of 1-O₂CPh with alkyl radicals and radical probes imply that C-H bond cleavage occurs by a tert-butoxy radical. In addition, the deuterium kinetic isotope effect from reactions of cyclohexane and d₁₂-cyclohexane in separate vessels showed that the turnover-limiting step for the ODC of cyclohexane is C-H bond cleavage. To understand the origin of the difference in products formed from copper-catalyzed amidation and copper-catalyzed ODC, reactions of an alkyl radical with a series of copper-carboxylate, copper-amidate, and copper-imidate complexes were performed. The results of competition experiments revealed that the relative rate of reaction of alkyl radicals with the copper complexes follows the trend Cu(II)-amidate > Cu(II)-imidate > Cu(II)-benzoate. Consistent with this trend, Cu(II)-amidates and Cu(II)-benzoates containing more electron-rich aryl groups on the benzamidate and benzoate react faster with the alkyl radical than do those with more electron-poor aryl groups on these ligands to produce the corresponding products. These data on the ODC of cyclohexane led to preliminary investigation of copper-catalyzed oxidative dehydrogenative amination of cyclohexane to generate a mixture of N-alkyl and N-allylic products.

Full text of DOI:10.1021/ja510093x

Article
pubs.acs.org/JACS
Copper-Catalyzed Oxidative Dehydrogenative Carboxylation of
Unactivated Alkanes to Allylic Esters via Alkenes
Ba L. Tran,‡ Matthias Driess,§ and John F. Hartwig*,‡
‡Department of Chemistry, University of California, Berkeley, California 94720, United States
§Metallorganische Chemie und Anorganische Materialien, Institut fur Chemie, Technische Universitat Berlin, Strasse des 17. Juni 135,
̈
̈
Sekr. C2, 10623 Berlin, Germany
S
* Supporting Information
ABSTRACT: We report copper-catalyzed oxidative dehydro-
genative carboxylation (ODC) of unactivated alkanes with
various substituted benzoic acids to produce the corresponding
allylic esters. Spectroscopic studies (EPR, UV−vis) revealed
that the resting state of the catalyst is [(BPI)Cu(O2CPh)] (1-
O2CPh), formed from [(BPI)Cu(PPh3)2], oxidant, and benzoic
acid. Catalytic and stoichiometric reactions of 1-O2CPh with
alkyl radicals and radical probes imply that C−H bond cleavage
occurs by a tert-butoxy radical. In addition, the deuterium
kinetic isotope effect from reactions of cyclohexane and d12-cyclohexane in separate vessels showed that the turnover-limiting
step for the ODC of cyclohexane is C−H bond cleavage. To understand the origin of the difference in products formed from
copper-catalyzed amidation and copper-catalyzed ODC, reactions of an alkyl radical with a series of copper−carboxylate,
copper−amidate, and copper−imidate complexes were performed. The results of competition experiments revealed that the
relative rate of reaction of alkyl radicals with the copper complexes follows the trend Cu(II)−amidate > Cu(II)−imidate >
Cu(II)−benzoate. Consistent with this trend, Cu(II)−amidates and Cu(II)−benzoates containing more electron-rich aryl groups
on the benzamidate and benzoate react faster with the alkyl radical than do those with more electron-poor aryl groups on these
ligands to produce the corresponding products. These data on the ODC of cyclohexane led to preliminary investigation of
copper-catalyzed oxidative dehydrogenative amination of cyclohexane to generate a mixture of N-alkyl and N-allylic products.
oxidation of the alkene to an allylic alcohol derivative directly
from an alkane is poorly developed.
INTRODUCTION
■
The oxidation of alkanes to alcohols or ketones and the
dehydrogenation of alkanes to alkenes are both widely studied
targets for C−H bond functionalization.1−5 For example, the
oxidation of cyclohexane to a mixture of cyclohexanol and
cyclohexanone is a large-scale commercial process for the
production of adipic acid.6 The oxidation of propene at the
allylic C−H bond to form acrolein7 also is a well-known large-
scale C−H bond oxidation process, and the oxidation of allylic
C−H bonds to allylic esters is being studied actively for
applications in target-oriented synthesis.8−17
The dehydrogenation of light alkanes is being studied as a
route to ethylene, propene, butene, butadiene, isobutene, and
isoprene, with hydrogen as the single side product18 or with an
oxidant to consume the hydrogen and make the reaction, called
oxidative dehydrogenation (ODH), favorable thermodynami-
cally.
Although alkane dehydrogenation and allylic oxidation are
both known reactions, the combination of these two reactions
in a single process is rare. One can envision that such a process
could occur by initial dehydrogenation of an alkane to an
alkene, followed by oxidation of allylic C−H bonds in the
alkene product. Indeed, one form of such a reaction is the well-
established synthesis of maleic anhydride from butane.19
However, the combination of dehydrogenation and selective
Recently, two examples of copper-catalyzed oxidative
dehydrogenative cross-coupling reactions of an aldehyde and
toluene with cyclohexane to generate allylic esters have been
reported.20,21 However, the yields of these reactions were
generally low and occurred with limited substrate scope.
Moreover, the mechanisms of these reactions were not studied
in depth. Copper-catalyzed combinations of alkane
dehydrogenation and aziridination22 or epoxidation23 also
have been reported, but the epoxide and aziridine are just
one component of a mixture of products, and they formed with
a maximum of 3−4 turnovers. Thus, a high-yield combination
of dehydrogenation and C−H bond oxidation of an alkane to
form an allylic alcohol derivative that occurs with tolerance for
a wide range of functional groups is not known.
Herein, we report the copper-catalyzed oxidative dehydro-
genative carboxylation (ODC) of unactivated alkanes in the
presence of carboxylic acid derivatives to form the correspond-
ing allylic ester (Scheme 1). This reaction is related to the
classic Kharasch−Sosnovsky reaction,24 but the starting ma-
terial is an alkane, rather than an alkene. The reactions occur by
Received: October 1, 2014
© XXXX American Chemical Society
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Scheme 1
Table 1. Reaction Development of Catalytic ODC of
a
Cyclohexane
b
yield (%)
i
entry
catalyst
oxidant
A
B
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuCl
CuCl
CuCl
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
65
76
78
54
21
56
58
21
40
48
50
46
47
np
7
oxidative dehydrogenation of an alkane and oxidation of the
resulting allylic C−H bond. Detailed mechanistic studies show
that the tert-butoxy radical abstracts a C−H bond of
cyclohexane to generate a transient cyclohexyl radical, and
this radical is converted to cyclohexene by a copper−benzoate
complex. The cyclohexene is then oxidized to form the allylic
ester product. The relative rates for trapping of the radical by
the ligand on copper versus conversion of the radical to an
alkene control the selectivity for the formation of allylic vs alkyl
ester products.
c
d
e
f
4
4
5
16
5
CuCl2
CuI
e
15
16
15
17
20
16
17
np
[(phen)Cu]2(μ2-I)2
[(L1)CuCl]
g
10
11
12
13
14
[(BPI)CuCl]
h
[(BPI)CuCl]
[(BPI)CuCl]
RESULTS AND DISCUSSION
■
g
[(BPI)Cu(PPh3)2]
1. Development of Intermolecular ODC of Cyclo-
hexane. To extend our recently published copper-catalyzed
amidation of cyclohexane to the acetoxylation or benzyloxyl-
ation of cycloalkanes, we conducted the reaction of cyclohexane
with benzoic acid and tBuOOtBu in the presence of
[(phen)Cu](μ2-I)2 (phen = 1,10-phenanthroline).25 We
envisioned that the combination of the Cu(I) and tBuOOtBu
should generate tBuO•, which could generate cyclohexyl
radical, and this radical could combine with [(phen)Cu-
(O2CPh)2]26,27 to form cyclohexyl benzoate. Although benzoic
acid did react with cyclohexane and tBuOOtBu in the presence
of 2.5 mol% of [(phen)Cu](μ2-I)2, this combination of
materials yielded the allylic ester cyclohex-2-en-1-yl benzoate
(21%) and methyl benzoate (16%), not the alkyl benzoate
(Scheme 2). Cyclohexyl benzoate was not detected. Thus, the
a
Conditions: 0.5 mmol of acid, 5.0 mmol of cyclohexane, 0.025 mmol
b
of catalyst, 1.0 mmol of oxidant, 1 mL of C6H6 at 100 °C for 24 h. 1H
NMR yield with MeNO2 as the internal standard added after reaction.
3 equiv of tBuOOtBu. 4 equiv of tBuOOtBu. 10 mol%. 1 equiv of
tBuOOtBu. 2.5 mol%. 48 h. L1, Me2NCH2CH2NCH (2-OH-
C6H4); BPI, bis(2-pyridylimino)isoindole; phth, phthalimide. np = no
product.
c
d
e
f
g
h
i
transient tert-butoxy radical by Cu(I) to form Cu(II)-OtBu
species.29 The reaction requires both copper and oxidant (entry
14).
The reaction also occurred when catalyzed by Cu(I)
complexes containing neutral bidentate nitrogen ligands, such
as 4,7-dichloro-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-
phenanthroline, 1,10-phenanthroline, 4,7-dimethyl-1,10-phen-
anthroline, 4,5-diazafluoren-9-one, and 1,10-phenanthroline-
5,6-dione.30 The reactions catalyzed by these Cu(I) complexes
ligated by dative nitrogen ligands formed cyclohex-2-en-1-yl
benzoate (23−64%) in modest yields.30 Reactions catalyzed by
the well-defined [(L1)CuCl] (L1 = Me2NCH2CH2NCH(2-
O-C6H4), [(BPI)Cu(PPh3)2], and [(BPI)CuCl] (BPI = bis(2-
pyridylimino)isoindole) reproducibly produced the product in
40−50% yields (entries 9−13). The reactions catalyzed by
ligated copper complexes gave larger amounts of methyl
benzoate than did reactions with unligated copper.31 Consistent
with this observation, Kochi reported that nitrogen-ligated
Cu(II) complexes oxidize alkyl radicals to alkenes more slowly
than do simple Cu(II) salts.32,33 Although these reactions with
ligated copper occurred in lower yield than those with simple
copper halides, they did give substantial amounts of product
and were valuable for studying the mechanism of this reaction
(vide infra).
Scheme 2. Initial Studies of ODC of Cyclohexane
reaction of cyclohexane with benzoic acid and tBuOOtBu in the
presence of copper occurs by a combination of dehydrogen-
ation and C−H bond carboxylation.
To increase the yield of the allylic ester from this reaction, we
evaluated the reactivity of benzoic acid (0.5 mmol) and
cyclohexane (10 equiv) with a series of copper salts and
discrete copper complexes. The results of these experiments are
presented in Table 1. Simple Cu(I) and Cu(II) halides
catalyzed the coupling of benzoic acid and cyclohexane to
produce cyclohex-2-en-1-yl benzoate in moderate to good
yields (entries 1−7). For example, the combination of CuCl (5
mol%) and tBuOOtBu (3 equiv relative to benzoic acid) gave a
high yield of product (76%). Reactions conducted with a higher
10 mol% loading of Cu occurred in a lower yield (54%) than
did the reaction with 5 mol% copper (entry 4). A similar trend
of lower yield with higher loadings of catalyst was observed for
the copper-catalyzed amidation of cyclohexane.28 The lower
yield of product from reactions containing higher concen-
trations of copper presumably results from quenching of the
2. Scope of Intermolecular Oxidative Dehydrogen-
ative Carboxylations of Alkanes. The scope of the ODC of
cyclohexane with carboxylic acids to form allylic esters is
presented in Table 2. The yields of these reactions are based on
carboxylic acid. The mass balance consisted of unreacted
carboxylic acid and methyl benzoate, the origin of which will be
discussed later in the paper. The reaction is tolerant of halogens
on the benzoic acid 4-X-C6H4-CO2H (X = F (1a), Cl (2a), Br
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the catalytic reaction; cyclohex-2-en-1-yl 4-(methylthio)-
benzoate was produced in 69% yield.
Table 2. Intermolecular ODC Cyclic and Acyclic Alkanes to
Allylic Esters
a
The reactions with heteroaryl carboxylic acids, such as furan
(q) and thiophene (r), also gave substantial yields of allylic
esters; however, pyridine carboxylic acids did not yield allylic
oxidation products.
Finally, vinyl and aliphatic carboxylic acids reacted to form
allylic esters. Specifically, the ODC of cyclohexane with
cyclohexanecarboxylic acid (s), (E)-2-methyl-3-phenylacrylic
acid (t), octanoic acid (1u), and phenylacetic acid (2u) gave
cyclohex-2-en-1-yl cyclohexanecarboxylate (62%), cyclohex-2-
en-1-yl (E)-2-methyl-3-phenylacrylate (57%), cyclohex-2-en-1-
yl octanoate (69%), and cyclohex-2-en-1-yl 2-phenylacetate
(69%), respectively.
The reaction also occurred with smaller or larger cyclo-
alkanes and, to an extent, with acyclic alkanes. Reactions of
benzoic acids with cyclopentane and cycloheptane in the
presence of 5 mol% of CuCl yielded the corresponding
products in good yield (cyclopent-2-en-yl benzoate (1v, 75%),
cyclohept-2-en-yl benzoate (2v 75%)), but the reaction with
cyclooctane formed cyclooct-2-en-yl benzoate (3v, 12%) in
modest yield. In addition to reactions of cyclic alkanes,
reactions of linear alkanes (i.e., pentane) containing multiple
C−H bonds were performed to assess the selectivity of the
catalytic ODC. The reaction of pentane and benzoic acid in the
presence of 2.5 mol% of 1-PPh3 and tBuOOtBu produced two
products: pent-en-2-yl benzoate34 (1w, 26%) and pent-1-en-3-
yl benzoate35 (2w, 10%). The potential product of pen-2-en-1-
yl benzoate, which would be obtained from the oxidation of the
pent-2-ene intermediate at the primary C−H bond, was not
observed. This observation suggests that oxidation of a
secondary allylic C−H bond is favored over oxidation of a
primary allylic C−H bond. This relative reactivity is consistent
with the relative C−H bond dissociation energies.36 The
reaction of 2,2-dimethylpentane and benzoic acid produced 4,4-
dimethylpent-1-en-3-yl benzoate37 (y, 16%) and methyl
benzoate (80%) as the major byproduct.
3. Synthesis of Cu(I) and Cu(II) Complexes and
Determination of the Resting State of the Catalyst.
Although most of the catalytic reactions were performed with
CuCl as catalyst, copper complexes ligated by the imidobipyr-
idine ligand BPI did catalyze the reaction, and the molecular
complex [(BPI)Cu(O2CPh)] (1-O2CPh) was amenable to
isolation. The soluble, single-component Cu(II) species 1-
O2CPh was prepared in 80% yield as a green solid by salt
metathesis between [(BPI)CuCl] (1-Cl) and NaO2CPh in
MeOH at room temperature for 3 h (Scheme 3). Elemental
analysis of the product was consistent with the proposed atomic
composition for 1-O2CPh. We suspect that the molecular
structure of 1-O2CPh is similar to that of the derivatives of
a
1
Yields were determined by H NMR spectroscopy with MeNO2 as
internal standard, added after the reaction, and reported as an average
of two reactions. 1H NMR chemical shifts were compared to authentic
b
c
allylic ester products. 2.5 mol% of 1-PPh3. 5 mol% of 1-PPh3,
MeCN. phth = phthalimide.
Scheme 3. Syntheses of Cu(I) and Cu(II) Complexes
(3a)), forming the corresponding allylic esters in 57−79%
yields in these cases. The reaction is also tolerant of a halide
(1c, 2c), methoxy (4c), and acetyl group (5c) in the ortho
position. Carboxylic acids containing electron-donating sub-
stituents on the aromatic system, such as methyl (1b,d,e), tert-
butyl (2b), methoxy (1f), 4-phenoxy (2f), and phthalimido (l)
groups, generated the corresponding allylic ester products in
56−71% yields. Substrates containing electron-withdrawing
substituents, such as acetyl (m), trifluoromethyl (j), cyano (p),
and carboalkoxy (n) groups, also gave the corresponding
products in moderate to good yields (52−76%). Even a
thioether (h) is tolerated, despite the oxidizing conditions of
C
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[(BPI)CuX] (X = 2,6-dimethoxybenzoate and 3,4-dimethoxy-
benzoate) (vide infra). To assign the oxidation state of the
copper center, we performed X-band EPR measurement on 1-
O2CPh in toluene at 25 K. The X-band EPR spectrum of 1-
O2CPh revealed an axial pattern, consistent with a Cu(II) (S =
1/2) center.
Scheme 5. Stoichiometric Reaction of 1-O2CPh with
Cyclohexane with and without Peroxide
To isolate a discrete Cu(I) complex, [(PPh3)2Cu(OAc)]38
was allowed to react with NaBPI. The reaction in toluene at
room temperature formed [(BPI)Cu(PPh3)2] (1-PPh3) in 58%
yield as an orange crystalline solid (Scheme 3). Compound 1-
PPh3 was characterized by multinuclear (1H, 13C, 31P) NMR
spectroscopy, FT-IR spectroscopy, and elemental analysis. With
discrete Cu(I) and Cu(II) complexes in hand, we investigated
the resting state of the catalyst.
The resting state of the copper species in the reaction
between cyclohexane and benzoic acid catalyzed by 1-PPh3
with tBuOOtBu as oxidant was determined by UV−vis
spectroscopy, X-band EPR spectroscopy, and independent
synthesis of copper complexes.30 A mixture of benzoic acid,
cyclohexane, and tBuOOtBu with 5 mol% 1-PPh3 in benzene
was allowed to react for 2 h at 100 °C. The UV−vis spectrum
of this reaction mixture was identical to that of independently
synthesized 1-O2CPh recorded in benzene.30 Likewise, the X-
band EPR spectrum of the reaction mixture collected at 25 K
was identical to that of an authentic sample of 1-O2CPh.30
To assess the identity of this complex further, a
stoichiometric reaction of 1-PPh3 with benzoic acid (1.5
equiv) and tBuOOtBu in the absence of cyclohexane was
conducted at 100 °C for 0.5 h in benzene. This reaction
afforded 1-O2CPh in 64% isolated yield (Scheme 4), as
reactions of a cyclohexenyl radical and a methyl radical with 1-
O2CPh to produce cyclohex-2-en-1-yl benzoate and methyl
benzoate, respectively. The analogous reaction performed in
the absence of tBuOOtBu gave no product from reaction of the
cyclohexane. These results show that the copper−benzoate
does not react directly with the alkane. Instead, a species
generated from copper and tBuOOtBu reacts with the alkane.
To assess the sequence of bond-forming events in the
catalytic ODC of cyclohexane, we conducted the reaction of
cyclohexyl benzoate and cyclohexene (separately) (Scheme
6,A) with tBuOOtBu and the copper catalyst. These two
Scheme 6. Experiments To Test the Sequence of CC and
C−O Bond Formation
Scheme 4. Determination of the Catalyst Resting State
reactions reveal whether formation of the alkene occurs before
or after formation of the C−O bond. The reaction of cyclohexyl
benzoate, benzoic acid, and tBuOOtBu with 2.5 mol% of 1-
O2CPh at 100 °C for 24 h did not form cyclohex-2-en-1-yl
benzoate. Instead, this reaction generated methyl benzoate
(16%). The detection of methyl benzoate indicates that tert-
butoxy radical was generated from the reaction of tBuOOtBu
with copper, but that this radical reacts more slowly with the
cyclohexyl benzoate than it undergoes β-methyl scission to
generate the methyl radical (which reacts with the copper−
benzoate complex to form methyl benzoate).31
determined by FT-IR, X-band EPR spectroscopy, elemental
analysis, and comparison of the material to 1-O2CPh
synthesized independently from the salt metathesis reaction
of 1-Cl with NaO2CPh. These data from the spectroscopic
measurement of the copper species in the catalytic reactions
and of the species formed independently from stoichiometric
reactions strongly indicate that a copper(II)−benzoate complex
is the resting state of the catalyst.
4. Elucidation of the Mechanism by Stoichiometric
Reactions, Trapping Experiments, and Competition
Experiments. To assess the role of 1-O2CPh in the catalytic
reaction, we performed stoichiometric reactions of 1-O2CPh
with the reaction components. The reaction of 1-O2CPh with
cyclohexane was conducted in the presence of tBuOOtBu at
100 °C for 21 h in acetonitrile (Scheme 5). The products
consisted of cyclohex-2-en-1-yl benzoate (44%) and methyl
benzoate (49%). These results are consistent with competitive
In contrast to the reaction of cyclohexyl benzoate, the
reaction of cyclohexene with benzoic acid and tBuOOtBu in the
presence of 2.5 mol% 1-O2CPh generated the allylic ester. This
reaction formed cyclohex-2-en-1-yl benzoate in 58% yield and
methyl benzoate in 27% yield after 24 h at 100 °C (Scheme
6B). Moreover, the reaction of cyclohexane with tBuOOtBu in
the presence of 1 mol% of 1-O2CPh (based on tBuOOtBu) in
benzene-d6 at 100 °C for 20 h (Scheme 6C) formed
cyclohexene in 12% yield, with respect to cyclohexane, as
1
determined by H NMR spectroscopy. These results clearly
indicate that ODC of cyclohexane to cyclohex-2-en-1-yl
benzoate proceeds by initial conversion of the cycloalkane to
D
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the cycloalkene, followed by oxidation of the cycloalkene to the
final allylic ester product.
Scheme 8. Experiments To Probe the Intermediacy of tert-
Butoxy Radical
The mechanism for the initial conversion of cyclohexane to
cyclohexene likely proceeds by abstraction of a hydrogen atom
from cyclohexane by a tert-butoxy radical to generate a
cyclohexyl radical, which undergoes oxidation to the alkene.
The oxidation of alkyl radicals to olefins by copper−peroxide
systems has been studied by Kochi32,39 and Walling.40 Their
studies imply that oxidation of the cyclohexyl radical formed in
the current system likely generates cyclohexyl cation, which
undergoes deprotonation to form the alkene. The deproton-
ation could occur by the anionic Cu(I) complex [(BPI)Cu-
(O2CPh)]− (1-O2CPh*) (Scheme 7). The yield of allylic ester
would then be a function of the relative rate of oxidation of the
alkyl radical versus reaction of the alkyl radical with the copper
carboxylate.
Scheme 7. Proposed Mechanism for the Conversion of
Cyclohexane to Cyclohexene
radical,46 and in the presence of 9,10-dihydroanthracene, which
forms anthracene via hydrogen atom abstraction by alkoxy
radicals. The catalytic reaction of cyclohexane, benzoic acid, and
diphenylmethanol in the presence of 1-O2CPh produced
methyl benzoate (18%), benzophenone, and diphenylmethanol
in a ratio of 1:10:7.3 (Scheme 8B). The same reaction between
cyclohexane and benzoic acid at 100 °C for 24 h in the
presence of 9,10-dihydroanthracene produced anthracene as
the exclusive product from the hydrocarbon reactants (Scheme
8C). The formation of benzophenone and anthracene is
consistent with H-atom abstraction of the methine C−H bond
of diphenylmethanol and a methylene C−H bond of
dihydroanthracene by tert-butoxy radical to produce the organic
products. The detection of methyl benzoate as an additional
product, again, is consistent with β-methyl scission of a tert-
butoxy radical under the catalytic conditions.
After formation of cyclohexene, oxidation at the allylic
position to form cyclohex-2-en-1-yl benzoate would occur
through the mechanism of the Kharasch−Sosnovsky reac-
tion.8,9,24,40−44 In this pathway, the allylic hydrogen is
abstracted by a tert-butoxy radical, and the resulting allylic
radical reacts with the copper carboxylate to form the allylic
ester.
To detect for the possible formation of 1,3-cyclohexadiene or
benzene from cyclohexene through a series of steps involving
abstraction of the allylic hydrogen, oxidation of the allyl radical,
and deprotonation of the allyl cation, the catalytic reaction of
benzoic acid, cyclohexane, and tBuOOtBu in the presence of 1-
PPh3 (2.5 mol%) in d6-benzene (or d3-MeCN) at 100 °C for
To assess the potential intermediacy of a cyclohexyl radical,
the catalytic reaction of cyclohexane with benzoic acid was
performed in the presence of CBr4. This reaction exclusively
formed bromocyclohexane (Scheme 9). The observation of
1
16 h was monitored by H NMR spectroscopy. The result of
the reaction revealed only cyclohex-2-en-1-yl benzoate and
methyl benzoate as products in 40% and 14% yields, with
respect to benzoic acid. Cyclohexadiene and benzene that could
result from dehydrogenation of cyclohexene were not observed.
The stoichiometric and catalytic ODC of benzoic acid with
cyclohexane forms methyl benzoate as the major side product.
The observation of this product is consistent with the
intermediacy of tert-butoxy radical. β-Methyl scission of a tert-
butoxy radical is known to produce a methyl radical, and this
radical would react with the resting-state 1-O2CPh to give
methyl benzoate.
Scheme 9. Trapping of the Proposed Cyclohexyl Radical by
CBr4
To evaluate the potential generation of tert-butoxy radical in
the system, the standard catalytic reaction of benzoic acid in
C6D6 was performed in the absence of cyclohexane (Scheme
8A). Without a source of an alkyl radical besides the one
formed by β-methyl scission of •OtBu, the reaction produced a
quantitative yield of methyl benzoate and acetone (based on
benzoic acid as limiting reagent). This high-yield formation of
methyl benzoate from benzoic acid and tBuOOtBu in the
presence of 1-PPh3 further supports the intermediacy of a
transient tert-butoxy radical in the catalytic reaction.45
bromocyclohexane is further consistent with the formation of
cyclohexyl radical by abstraction of a hydrogen atom from
cyclohexane by a tert-butoxy radical in the catalytic reaction. In
this case, the radical reacts with CBr4 to form the alkyl
bromide.47−49
5. Kinetic Isotope Effect and Reactivity of the Alkyl
Radical with Copper−Amidate and Copper−Benzoate.
Parallel reactions were performed with cyclohexane and
cyclohexane-d12 to determine if cleavage of the C−H bond of
the alkane is the turnover-limiting step of the copper-catalyzed
ODC of cyclohexane. A comparison of the initial rates for
catalytic ODC of octanoic acid with cyclohexane and
cyclohexane-d12 in separate vessels revealed a KIE value of
As a final test of the potential intermediacy of tert-butoxy
radical in the catalytic process, we conducted reactions in the
presence of diphenylmethanol, a known trap for tert-butoxy
E
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2.8 0.2 (Scheme 10). This observed KIE value indicates that
C−H bond cleavage is the turnover-limiting step.
than the latter complex. Alternatively, the difference in relative
rates could arise from differences in the rates of reaction of alkyl
radicals with the Cu(II)−carboxylate and Cu(II)−amidate
complexes.
Scheme 10. Intermolecular ODC of Cyclohexane and
To reveal the origin of the difference in formation of alkyl
and allyl products with amide and carboxylic acid reagents we
conducted a series of reactions in which a methyl radical is
generated in the presence of a copper−carboxylate, amidate, or
imidate complex. First, the reaction of a source of methyl
radical (tBuOOtBu) with a combination of [(BPI)Cu(NHC-
(O)[heptyl]) (1-NHC(O)hept) and [(BPI)Cu(O2C[heptyl])]
(1-O2Chept) at 100 °C (Scheme 12A) was performed to assess
Cyclohexane-d12
Scheme 12. Competition Reaction of Methyl Radical with
Copper−Amidate and Copper−Carboxylate Complexes
In addition, a comparison of the rates of the catalytic reaction
of octanoic acid with cyclohexane and cyclohexene revealed
that the conversion of cyclohexene to cyclohex-2-en-1-yl
octanoate is faster than the conversion of cyclohexane.30
After 1 h, the reaction of octanoic acid and cyclohexene cleanly
produced 40% of cyclohex-2-en-1-yl octanoate, whereas the
reaction of octanoic acid with cyclohexane produced only 4% of
cyclohex-2-en-1-yl octanoate and 2% of methyl octanoate. This
result clearly indicates that abstraction of the C−H bond from
cyclohexane, not from cyclohexene, is the turnover-limiting step
in the catalytic ODC.
6. Effects of the Electronic Properties of Copper−
Benzoate and Copper−Amidate Complexes on the
Reaction of Alkyl Radicals. The roles of copper in the
catalytic ODC of cyclohexane are closely related to those of
copper in the catalytic amidation of cyclohexane we reported
recently.28 However, the two reactions form products
containing different hydrocarbyl groups (alkyl vs allylic), and
the difference between these groups likely stems from a
difference in relative rates for reaction of the alkyl radical with
the copper−benzoate and copper−amidate complexes. The
alkyl radical can undergo electron transfer, or it can combine
with a ligand at copper to form a product containing a new
carbon−heteroatom bond (Scheme 11). Apparently, oxidation
the ratio of products resulting from reactions of alkyl radicals
with Cu(II)−amidate and Cu(II)−carboxylate complexes
together. This reaction produced only MeNHC(O)[heptyl]
(52% at 24 h); MeO2C[heptyl] was not observed by GC. Thus,
the rate of reaction of methyl radical with 1-NHC(O)hept is
faster than that with 1-O2Chept. Analogous reactions of methyl
radical with a combination of 1-O2CPh and either [(BPI)Cu-
(NHC(O)Ph)] (1-NHC(O)Ph) or [(BPI)Cu(phth)] (1-
phth) in the presence of tBuOOtBu (20 equiv) in benzene at
100 °C also showed that the reaction of methyl radical with 1-
NHC(O)Ph and 1-phth is faster than that with 1-O2CPh.30
Second, a competition reaction was performed between
unligated [Cu(NHC(O)[heptyl])] and [Cu(O2C[heptyl])] in
the presence of tBuOOtBu at 100 °C in benzene (Scheme 12B)
to probe the effect of the BPI ancillary ligand on the rate of
reaction of the methyl radical with the Cu(II)−amidate and
Cu(II)−carboxylate complexes. Like the reactions with the
ligated copper complexes, the reaction of the unligated
complexes with the source of Me• produced higher yields of
MeNHC(O)[heptyl] than of MeO2C[heptyl] throughout the
reaction. The result of this experiment indicates that the rate of
reaction of a methyl radical with a ligandless copper−amidate is
faster than that with a ligandless copper−carboxylate.
Scheme 11. Ligand Transfer versus Electron Transfer of
Alkyl Radicals in Copper−Amidate or Copper−Benzoate
Third, a competition reaction was performed with 1-
O2Chept and 1-NHC(O)hept in the presence of cyclohexane
and tBuOOtBu at 100 °C in benzene (Scheme 13). Unlike a
methyl radical, a cyclohexyl radical can form a carbon−
heteroatom bond or convert to cyclohexene; carboxylation of
the resulting alkene then forms an allylic ester. The reaction of
the two copper complexes formed N-cyclohexyloctanamide in
92% yield and the allylic ester product cyclohex-2-en-1-yl
benzoate in 30% yield. This result is consistent with faster
reaction of an alkyl radical with a copper−amidate than with a
copper−benzoate, but the origin of the absence of product
of the alkyl radical by the copper−benzoate is faster than
reaction of the alkyl radical with the benzoate ligand, whereas
oxidation of the alkyl radical by the copper−amidate is slower
than reaction of the alkyl radical with the amidate ligand
(Scheme 11).
This difference in relative rates could arise from a difference
in redox potential of the benzoate and amidate complexes. A
Cu(II)−benzoate complex, presumably, is less electron-rich
than a Cu(II)−amidate complex. Therefore, the former
complex could oxidize the alkyl radical to an alkyl cation faster
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Scheme 13. Competitive Reaction of Cyclohexyl Radical
with Copper−Amidate and Copper−Benzoate Complexes
Scheme 15. Effect of Electronics on the Reactions of Methyl
Radical with Copper−Benzoate and Copper−Amidate
Complexes
from reaction of the allylic radical with the copper−amidate is
unclear. We also observed the ODC of cyclohexane to
cyclohex-2-en-1-yl benzoate only after an appreciable amount
of 1-NHC(O)hept is consumed because 1-NHC(O)hept
would react rapidly with the transient alkyl radical.
To investigate the effects of the nitrogen substituents on the
reactions with alkyl radicals, we conducted the reaction of 1-
NHC(O)Ph and 1-phth with tBuOOtBu (20 equiv) in
benzene at 100 °C for 24 h. This reaction formed higher
yields of the MeNHC(O)Ph (70%) than of Me-phth (53%)
(Scheme 14). The result of this competition experiment
electron-rich copper−benzoate and amidate complexes than
with the more electron-deficient copper−benzoate and amidate
complexes to form the corresponding N-alkyl and O-alkyl
products, respectively.
Scheme 14. Reaction of Methyl Radical with Copper−
Amidate and Copper−Imidate Complexes
7. Steric Effects on the Reaction of Alkyl Radicals with
Copper−Benzoates. To elucidate the steric effect of aromatic
ring of the carboxylate ligand in copper−benzoate complexes
on the reactivity, we performed reactions of cyclohexane and
tBuOOtBu in the presence of a series of copper−benzoates
containing methyl groups in the ortho, meta, and para
positions: [(BPI)CuX], with X = 2,6-dimethylbenzoate (2,6-
Me2), 2,4-dimethylbenzoate (2,4-Me2), and 3,4-dimethyl-
benzoate (3,4-Me2)). The results of these competition
experiments are summarized in Scheme 16. The reaction with
indicates that the reaction of the alkyl radical with 1-
NHC(O)Ph is faster than that with 1-phth. This trend is
consistent with faster reaction of an alkyl radical with the more
electron-rich anionic ligand on copper.
Scheme 16. Effect of Aromatic Substituents on Copper−
Benzoate Complexes on ODC of Cyclohexane
To gain more systematic data conerning the electronic effects
on the rates of reactions of alkyl radicals with the copper
complexes, we studied reactions with a series of substituted
benzoate complexes. Reactions of a methyl radical generated
from tBuOOtBu with a mixture of [(BPI)Cu(O2C[C6H4-4-
OMe]) (1-OMe) and [(BPI)Cu(O2C[C6H4-4-CN]) (1-CN)
were conducted at 100 °C in benzene (Scheme 15A). The
result showed that methyl radical reacted faster with the
electron-rich 1-OMe to produce the corresponding methyl 4-
methoxybenzoate than with the more electron-poor 1-CN to
produce methyl 4-cyanobenzoate. For example, at 24 h the
reaction produced methyl 4-methoxybenzoate in 76% yield and
methyl 4-cyanobenzoate in 10% yield.
To gain analogous information on the reaction of an alkyl
radical with copper−amidates, the analogous experiment was
conducted with [(BPI)Cu(NHC(O)[C6H4-4-OMe]) (1-
NHOMe) and [(BPI)Cu(NHC(O)[C6H4-4-CF3]) (1-
NHCF3). The reaction of tBuOOtBu with these complexes at
100 °C in benzene (Scheme 15B) showed that the methyl
radical reacts faster with the more electron-rich 1-NHOMe
than with the more electron-poor 1-NHCF3 to produce the
corresponding product of N-methyl-4-methoxybenzamide
(53%) at 24 h. The results of these competition reactions
clearly demonstrate that alkyl radicals react faster with the more
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the combination of 2,4-Me2 and 2,6-Me2 formed a higher yield
of cyclohex-2-en-1-yl 2,4-dimethylbenzoate than cyclohex-2-en-
1-yl 2,6-dimethylbenzoate (Scheme 16A′). The reaction with a
combination of 2,4-Me2 and 3,4-Me2 formed the correspond-
ing cyclohex-2-en-1-yl 3,4-dimethylbenzoate in higher yields
than it formed cyclohex-2-en-1-yl 2,4-dimethylbenzoate
(Scheme 16B′). Lastly, the reaction with the combination of
3,4-Me2 and 2,6-Me2 produced higher yield of cyclohex-2-en-1-
yl 3,4-dimethylbenzoate (40%) than of cyclohex-2-en-1-yl 2,6-
dimethylbenzoate (20%) at 24 h (Scheme 16C′). Similar results
were obtained from competition reactions between cyclohexane
and tBuOOtBu with a series of dimethoxybenzoate−Cu(II)
complexes.30
The difference in rates of reaction of the carboxylate
complexes as a function of the steric properties could result
from the effect on the conformation of these copper−benzoate
complexes and overlap of the aryl π system with the carbonyl
group. The molecular structures of 2,6-OMe2 and 3,4-OMe2
were determined by X-ray diffraction (Figure 1). The aryl ring
Scheme 17. Effect of Aromatic Substituents on the
Conformation of Copper−Benzoate Complexes
cyclohexane and copper-catalyzed amidation of cyclohexane is
the reaction of the transient cyclohexyl radical with a copper−
benzoate versus a copper−amidate or copper−imidate
intermediate. Specifically, alkyl radicals react faster with
copper−amidate and imidate complexes than they do with
copper−benzoates. Moreover, more electron-rich copper−
amidate and benzoate complexes react faster with alkyl radicals
than more electron-deficient copper−amidate and benzoate
complexes. Lastly, the slower rate of reactions of alkyl radicals
with copper−benzoate allows electron transfer to occur faster
than ligand transfer, unless the alkyl radical is not able to form
an alkene (i.e., a methyl radical). When the alkyl radical cannot
form an alkene, ligand transfer occurs to form an O-alkyl
product. Based on these hypotheses, we investigated copper-
catalyzed oxidative dehydrogenative amination (ODA) of
cyclohexane with electron-deficient amides. More electron-
deficient copper−amidate and imidate complexes would
undergo slower reactions with an alkyl radical and faster
electron transfer.
To this end, we conducted catalytic reactions of phthalimide
and cyclohexane (10 equiv) in the presence of 2.5 mol% of
[(phen)Cu(phth)], 1-PPh3, and [Cu(phth)] (Scheme 18).51
Scheme 18. Formation of Alkyl and Allylic Imidate from
Cyclohexane
Figure 1. Molecular structures of [(BPI)Cu(3,4-OMe2-C6H4)] (3,4-
OMe2) (top) and [(BPI)Cu(2,6-OMe2-C6H4)] (2,6-OMe2) (bottom)
are shown with 50% thermal ellipsoid. Hydrogen atoms are omitted
for clarity. Selected bond lengths (Å) and angles (°) for 3,4-OMe2:
Cu1−N1 = 2.019(2); Cu1−N3 = 1.892(2); Cu1−O1 = 1.9443(18);
N1−Cu1−N3 = 90.55(9); N3−Cu1−O1 = 168.23(9). Selected bond
lengths (Å) and angles (°) for 2,6-OMe2: Cu1′−N1′ = 2−0074(17);
Cu1′−N3′ = 1.9017(17); Cu1′−O1′ = 1.9721(14); N1′−Cu1′−N3′ =
90.94(7); N3′−Cu1′−O1′ = 167.63(7).
The reactions in the presence of 1-PPh3 and [Cu(phth)]
produced 18−25% of cyclohex-2-en-1-yl pthalimidate and
roughly 70% of N-cyclohexylphthalimide. The reactions
conducted with 1-PPh3 and [Cu(phth)] apparently occur by
competitive ligand transfer and electron transfer to form a
mixture of N-cyclohexylphthalimide and cyclohex-2-en-1-yl
pthalimidate, respectively. Conversely, the reaction catalyzed
by [(phen)Cu(phth)] formed N-cyclohexylphthalimide (63%)
and N-methylphthalimide (19%), and no cyclohex-2-en-1-yl
pthalimidate, as determined by gas chromatography, mass
of the 2,6-dimethoxybenzoate is nearly orthogonal to the
carbonyl group with a torsion angle of −76°, whereas the
benzene ring of the 3,4-dimethoxybenzoate lies nearly in plane
with the carbonyl group with a torsion angle of −163°. Thus,
the aryl ring of 3,4-OMe2 has more orbital overlap between the
carbonyl and benzene π-systems than does that of the 2,6-
dimethoxylbenzoate. This distortion from planarity of the 2,6-
disubstituted benzoate makes it less nucleophilic (Scheme
17).50 This reduced nucleophilicity is then responsible for the
difference in the reactivity of copper−benzoate with the allylic
radical to generate allylic benzoate products.
1
spectrometry, and H NMR spectroscopy.
The catalytic reaction in the presence of [(phen)Cu(phth)]
exclusively produced N-cyclohexylphthalimide and N-methyl-
phthalimide, presumably from reaction of the methyl and
cyclohexyl radicals with the resting-state species [(phen)Cu-
(phth)2].28 The preference of [(phen)Cu(phth)2] to react with
cyclohexyl radical by ligand-transfer is presumably because
[(phen)Cu(phth)2] is more electron-rich than the complexes
1-phth and [Cu(phth)2]n; thus, reaction of the alkyl radical
with [(phen)Cu(phth)2] occurs faster than electron transfer.
8. Observation of Oxidative Dehydrogenative Ami-
nation: Effect of Ligand and Nitrogen Source. The step
that distinguishes the reactivity of copper-catalyzed ODC of
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Previously, we reported the copper-catalyzed oxidative
coupling of p-toluenesulfonamide with cyclohexane to generate
the corresponding N-cyclohexyl-p-toluenesulfonamide.28 To
achieve ODA of cyclohexane, we reasoned that replacing p-
toluenesulfonamide with the more electron-deficient 4-CF3-
benzenesulfonamide should decrease the rate of reaction of the
alkyl radical with the ligand and increase the rate of oxidation of
the alkyl radical. The reaction of 4-CF3-benzenesulfonamide
with cyclohexane and tBuOOtBu in the presence of 2.5 mol%
of 1-PPh3 in acetonitrile produced N-cyclohexyl-4-CF3-
benzenesulfonamide (50%) and N-(cyclohex-2-en-1-yl)-4-CF3-
benzenesulfonamide (38%) (Scheme 19). This result demon-
strates that electron-deficient sulfonamides can form substantial
amount of product from ODA of cyclohexane by the electron-
transfer pathway.
Scheme 20. Proposed Catalytic Cycle of Cu-Catalyzed ODC
of Cyclohexane
Scheme 19. Catalytic ODA of Cyclohexane with an Electron-
Deficient Sulfonamide
cyclohexene and benzoic acid. The resulting cyclohexene would
then undergo a second C−H abstraction by a tert-butoxy radical
to give an allylic radical that reacts with 1-O2CPh to release the
allylic ester product and regenerate a (BPI)Cu(I) species to
complete the catalytic cycle. In a side reaction, the tert-butoxy
radical would decompose to a methyl radical and acetone. The
methyl radical would then combine with 1-O2CPh to produce
methyl benzoate and a (BPI)Cu(I) species. The catalytic cycle
for ODA of cyclohexane to form N-allyl products is presumably
analogous to that of the catalytic ODC. This catalytic cycle
would contain a copper−amidate resting state, based on
mechanistic investigations of a related copper-catalyzed amid-
ation of unactivated alkanes.28
The selectivity of the reaction of cyclohexane with CF3-4-
benzenesulfonamide in the presence of 1-PPh3 depended on
solvent and supporting ligand (Scheme 19). The reaction in
acetonitrile formed the mixture of alkyl and allylic amides just
described, but the reaction in benzene generated exclusively
cyclohexyl-4-CF3-benzenesulfonamide (57%). The distribution
of products from the reaction of CF3-4-benzenesulfonamide
and cyclohexane in the presence of “ligandless” copper
generated from [Cu(Mes)] also depended on solvent, but
with the opposite trend. The products of ODA were observed
in benzene, but not in acetonitrile (Scheme 19). Like the
reactions of phthalimide, the reactions of CF3-4-benzenesulfon-
amide with cyclohexane in the presence of phen-ligated copper
provided only the N-alkyl product (Scheme 19). This result
again highlights the effect of the electronic properties of the
supporting ligand on the relative rates to form N-alkyl and N-
allyl products. This effect of ligand (i.e., BPI vs phen) on this
selectivity reflects an opportunity to design ligands that favor
ODA of unactivated alkanes.
9. Proposed Mechanism for ODC of Cyclohexane. A
proposed mechanism for the catalytic ODC of cyclohexane to
cyclohex-2-en-1-yl benzoate is presented in Scheme 20. In this
pathway, catalysis is initiated by the decomposition of
tBuOOtBu by 1-PPh3 to produce a tert-butoxy radical and
[(BPI)CuOtBu], which rapidly reacts with benzoic acid to form
1-O2CPh and tBuOH. The tert-butoxy radical can undergo
reversible, secondary internal return to regenerate tBuOOtBu
or abstract a hydrogen atom from cyclohexane to generate a
cyclohexyl radical. To form the unsaturated product, 1-O2CPh
would oxidize the alkyl radical by one electron to form a
carbocation, and the carbocation would undergo deprotonation
by an anionic Cu(I) species [(BPI)Cu(O2CPh)]− to give
SUMMARY AND CONCLUSIONS
■
In summary, we have described a copper-catalyzed oxidative
dehydrogenative carboxylation (ODC) of unactivated alkanes
with a variety of benzoic acids to produce the corresponding
allylic ester products. A measurement of kinetic isotope effects
showed that the turnover-limiting step is C−H bond cleavage,
and experiments to trap radical intermediates revealed that a
transient tert-butoxy radical cleaves the C−H bond of the
alkane to generate an alkyl radical. Reactions of alkyl radicals
with a combination of Cu(II)−amidates and Cu(II)−benzoates
revealed that the alkyl radical reacts faster with a Cu(II)−
amidate than with a Cu(II)−benzoate to form N-alkyl products.
Additional mechanistic investigations indicated that the
electronic properties of the Cu(II)−X (X = amidate, benzoate)
resting state contributes to the partitioning of the alkyl radical
between ligand transfer to form the alkyl−heteroatom bond
and electron transfer to oxidize the alkyl radical to an olefin,
followed by oxidative carboxylation to produce an allylic ester.
The reaction of the alkyl radical with a Cu(II)−amidate versus
a Cu(II)−benzoate is the step that distinguishes copper-
catalyzed amidation and copper-catalyzed ODC of the alkane.
This insight into the mechanism of ODC of cyclohexane led
to preliminary observations of copper-catalyzed oxidative
dehydrogenative amination of cyclohexane with electron-
deficient nitrogen sources (i.e., phthalimide and an electron-
deficient sulfonamide) to form N-allyl products. Current efforts
are underway to discover reaction conditions to suppress ligand
transfer and favor electron transfer to achieve high selectivity
for a copper-catalyzed ODA of unactivated alkanes.
I
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(26) Devereux, M.; O’Shea, D.; Kellet, A.; McCann, M.; Walsh, M.;
ASSOCIATED CONTENT
■
Egan, D.; Deegan, C.; Kędziora, K.; Rosair, G.; Muller-Bunz, H. J.
̈
S
* Supporting Information
Inorg. Biochem. 2007, 101, 881.
Experimental procedures, characterization of compounds, and
spectroscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
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15, 3326.
AUTHOR INFORMATION
■
Corresponding Author
jhartwig@berkeley.edu
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Einstein Foundation Berlin
(J.F.H.), the NIH-NIGMS (R29-55382 to J.F.H), and the
Cluster of Excellence UniCat (financed by the DFG and
administered by the TU Berlin to M.D.) for research support.
We thank Dr. Ruchira Chatterjee (LBNL) for access to EPR
spectroscopy. We acknowledge Dr. Antonio DiPasquale and
NIH Shared Instrumentation Grant S10-RR027172 for X-ray
diffraction support. B.L.T. thank Dr. Bijie Li for checking the
procedure.
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