Copper-catalyzed intermolecular amidation and imidation of unactivated alkanes

Article abstract of DOI:10.1021/ja411912p

We report a set of rare copper-catalyzed reactions of alkanes with simple amides, sulfonamides, and imides (i.e., benzamides, tosylamides, carbamates, and phthalimide) to form the corresponding N-alkyl products. The reactions lead to functionalization at secondary C-H bonds over tertiary C-H bonds and even occur at primary C-H bonds. [(phen)Cu(phth)] (1-phth) and [(phen)Cu(phth)₂] (1-phth₂), which are potential intermediates in the reaction, have been isolated and fully characterized. The stoichiometric reactions of 1-phth and 1-phth₂ with alkanes, alkyl radicals, and radical probes were investigated to elucidate the mechanism of the amidation. The catalytic and stoichiometric reactions require both copper and tBuOOtBu for the generation of N-alkyl product. Neither 1-phth nor 1-phth₂ reacted with excess cyclohexane at 100 C without tBuOOtBu. However, the reactions of 1-phth and 1-phth₂ with tBuOOtBu afforded N-cyclohexylphthalimide (Cy-phth), N-methylphthalimide, and tert-butoxycyclohexane (Cy-OtBu) in approximate ratios of 70:20:30, respectively. Reactions with radical traps support the intermediacy of a tert-butoxy radical, which forms an alkyl radical intermediate. The intermediacy of an alkyl radical was evidenced by the catalytic reaction of cyclohexane with benzamide in the presence of CBr₄, which formed exclusively bromocyclohexane. Furthermore, stoichiometric reactions of [(phen)Cu(phth)₂] with tBuOOtBu and (Ph(Me)₂CO) ₂ at 100 C without cyclohexane afforded N-methylphthalimide (Me-phth) from β-Me scission of the alkoxy radicals to form a methyl radical. Separate reactions of cyclohexane and d₁₂-cyclohexane with benzamide showed that the turnover-limiting step in the catalytic reaction is the C-H cleavage of cyclohexane by a tert-butoxy radical. These mechanistic data imply that the tert-butoxy radical reacts with the C-H bonds of alkanes, and the subsequent alkyl radical combines with 1-phth₂ to form the corresponding N-alkyl imide product.

Full text of DOI:10.1021/ja411912p

Article
pubs.acs.org/JACS
Copper-Catalyzed Intermolecular Amidation and Imidation of
Unactivated Alkanes
Ba L. Tran,†,‡,§ Bijie Li,†,‡,§ Matthias Driess,‡ and John F. Hartwig*,†
†Department of Chemistry, University of California, Berkeley, California 94720, United States
‡Department of Chemistry: Metalorganics and Inorganic Materials, Technische Universitat Berlin, Strasse des 17. Juni 135, Sekr. C2,
̈
10623 Berlin, Germany
S
* Supporting Information
ABSTRACT: We report a set of rare copper-catalyzed
reactions of alkanes with simple amides, sulfonamides, and
imides (i.e., benzamides, tosylamides, carbamates, and
phthalimide) to form the corresponding N-alkyl products.
The reactions lead to functionalization at secondary C−H
bonds over tertiary C−H bonds and even occur at primary C−
H bonds. [(phen)Cu(phth)] (1-phth) and [(phen)Cu-
(phth)2] (1-phth2), which are potential intermediates in the
reaction, have been isolated and fully characterized. The
stoichiometric reactions of 1-phth and 1-phth2 with alkanes, alkyl radicals, and radical probes were investigated to elucidate the
mechanism of the amidation. The catalytic and stoichiometric reactions require both copper and tBuOOtBu for the generation of
N-alkyl product. Neither 1-phth nor 1-phth2 reacted with excess cyclohexane at 100 °C without tBuOOtBu. However, the
reactions of 1-phth and 1-phth2 with tBuOOtBu afforded N-cyclohexylphthalimide (Cy-phth), N-methylphthalimide, and tert-
butoxycyclohexane (Cy-OtBu) in approximate ratios of 70:20:30, respectively. Reactions with radical traps support the
intermediacy of a tert-butoxy radical, which forms an alkyl radical intermediate. The intermediacy of an alkyl radical was
evidenced by the catalytic reaction of cyclohexane with benzamide in the presence of CBr4, which formed exclusively
bromocyclohexane. Furthermore, stoichiometric reactions of [(phen)Cu(phth)2] with tBuOOtBu and (Ph(Me)2CO)2 at 100 °C
without cyclohexane afforded N-methylphthalimide (Me-phth) from β-Me scission of the alkoxy radicals to form a methyl
radical. Separate reactions of cyclohexane and d12-cyclohexane with benzamide showed that the turnover-limiting step in the
catalytic reaction is the C−H cleavage of cyclohexane by a tert-butoxy radical. These mechanistic data imply that the tert-butoxy
radical reacts with the C−H bonds of alkanes, and the subsequent alkyl radical combines with 1-phth2 to form the corresponding
N-alkyl imide product.
for the synthesis of complex molecules.15,27 Although
remarkable developments and applications have been reported
for intramolecular reactions, intermolecular reactions are more
limited. The selectivity of these reactions depends on the
INTRODUCTION
■
Amination reactions are crucial to the synthesis of medicinally
important compounds. The amination of C−H bonds provides
a route to N-alkyl and N-aryl amine derivatives that avoids
electron density at the C−H bond of the substrate, such that
typical functional group interconversions and reactants
the preferred sites of reactions are tertiary, benzylic, and
containing a functional group already present at the position
secondary C−H bonds.14,28 When a nitrene is the reactive
where a C−N bond is desired. Intermolecular reactions that
intermediate, the nitrogen-based reagent is limited to those
convert unactivated C−H bonds to C−N bonds are particularly
challenging to achieve, but such reactions could directly modify
complex molecules, create chemical feedstocks, or create
containing just one substituent.
We sought an alternative route to the intermolecular
functionalized polymers.1,2 Methods for the oxidation of
alkanes by the combination of peroxides and iron complexes
have been developed,3−12 but intermolecular functionalization
of purely unactivated C−H bonds with reagents that form
products containing common nitrogen-based functionality are
rare.13 Most intermolecular amidations of C−H bonds have
been catalyzed by copper complexes and occur at benzylic or
allylic positions.
functionalization of alkyl C−H bonds that could form N-alkyl
amides, carbamates, and imides, in addition to the formation of
sulfonamides. Amides, carbamates, and imides are more
common synthetic intermediates or final products than those
generated by prior copper-catalyzed reactions with alkyl C−H
bonds.29 We also sought to conduct these transformations with
readily accessible complexes of first-row metals. Although
copper-catalyzed reactions at allylic and benzylic C−H bonds
A few intermolecular aminations of C−H bonds occur with
nitrene precursors to form sulfonamides.14−26 Reactions
catalyzed by dirhodium complexes are the most developed
Received: November 22, 2013
© XXXX American Chemical Society
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with carboxylic acids and sulfonamides in the presence of
peroxides is well-known (Karasch-Sosnovsky reaction),30−35
and the mechanism of these reactions has been studied,34,36−40
the amidation of C−H bonds with such reagents has been
limited to reactions at benzylic C−H bonds.32,33
We report the reactions of common amides, carbamates, and
imides with alkanes to form N-alkyl derivatives with simple
copper catalysts and a peroxide (Scheme 1). The amidation of
higher 36% yield. Reactions catalyzed by the well-defined
[(L1)CuCl] precatalyst (entry 8) (L1 = (((2-(dimethylamino)-
ethyl)imino) methyl)phenoxide) provided 83% of N-cyclo-
hexylbenzamide. Finally, we found that the reaction of
benzamide with cyclohexane catalyzed by the simple combina-
tion of phenanthroline (phen) (entry 6) or 4,7-dimethoxy-
phenantronline ((MeO)2phen) (entry 7) and CuI formed N-
cyclohexylbenzamide in nearly quantitative yield.
2. Scope and Selectivity of Intermolecular Amidation.
The scope of benzamides that undergo this C−H bond
amination reaction is summarized in Table 2. Benzamides
containing electron-withdrawing groups, such as Cl, Br, F, and
CF3 (a−d), underwent the reaction to give good yields of the
corresponding amidation product (73−82%). Benzamides
Scheme 1. Conversion of Alkanes to N-Alkyl Products
t
containing electron-donating groups, such as Me, Bu, and
OMe (e−k), also underwent the amidation process, but the
isolated yields of the amidation products were slightly lower
(55−78%) than those of the benzamides containing electron-
withdrawing groups. Heteroaromatic amides, such as 2-
thienylamide (m) and 2-pyridylamide (l), also underwent the
oxidative coupling with cyclohexane to give the corresponding
N-alkyl products. The reaction of the 2-pyridylamide is
noteworthy because the 2-pyridylamide product could form a
strong chelating ligand that would prevent catalysis. The
position of the substituent on the benzamide (ortho, meta, or
para) did not have a pronounced effect on the reaction yields.
The reactions of cyclohexane with primary and secondary
alkyl amides, carbamates and imides also occurred (Table 2).
The yields of the reactions of cyclohexane with acetamide (n),
tert-butylcarbamate (o), and toluenesulfonamide (p) to form
N-cyclohexylacetamide, tert-butyl-N-cyclohexylcarbamate, and
N-cyclohexyltoluenesulfonamide (38%, 42%, and 55%, respec-
tively) were lower than those that formed N-alkyl benzamides.
However, the reaction of tert-butylcarbamate, with excess
tBuOOtBu (4 equiv) gave tert-butyl-N-cyclohexylcarbamate in
75% yield.
alkanes under our catalytic conditions preferentially forms the
products from amidation at secondary sites over tertiary sites
and even leads to the functionalization of primary C−H bonds
in some cases. Mechanistic data from the stoichiometric
reactions of isolated copper amidate or imidate complexes
indicate that the transformation of alkanes to N-alkyl products
likely occurs by the reactions of a alkyl radicals with copper(II)
amidate and imidate complexes.
RESULTS AND DISCUSSION
■
1. Reaction Development of Intermolecular Amida-
tion. To identify effective precatalysts and conditions for
intermolecular amidation of unactivated C−H bonds, we
evaluated the reactivity of benzamide (0.5 mmol) and
cyclohexane (10 equiv) with 2.5−5.0 mol % of various copper
precatalysts and oxidants. Results for the copper-catalyzed
amidation of cyclohexane with benzamide are presented in
Table 1. The combination of copper and tBuOOtBu was crucial
for catalysis; other peroxide-based oxidants and redox-active 3d
transition metals did not yield the amidation product.41
The reactions catalyzed by Cu(I) and Cu(II) salts without
ligand gave the N-cyclohexylbenzamide in low yields (entry 1−
4, 10−27%). However, the reactions catalyzed by Cu(I) and
bipyridine (bipy), gave N-cyclohexylbenzamide in a measurably
The reactions of cyclohexane with secondary nitrogen
sources (N-methylbenzamide, phthalimide, pyrrolidinone, and
N-Me-p-toluenesulfonamide) also occurred to form the
a
Table 1. Development of the Catalytic Amidation of Cyclohexane
b
entry
catalyst
Cu(OAc)2
ligand
oxidant
yield (%)
1
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOtBu
tBuOOAc
tBuOOH
10
2
CuCl2
22
3
CuCl
24
4
CuI
27
5
CuI
bipy
36
6
CuI
phen
95
7
CuI
(MeO)2Phen
99 (76)
c
8
(L1)CuCl
83
c
9
[(phen)CuCl]2(μ2-Cl)2
83
10
11
12
13
CuI
CuI
CuI
(MeO)2Phen
(MeO)2Phen
(MeO)2Phen
(MeO)2Phen
<5
<5
<5
<5
H2O2
tBuOOtBu
a
Conditions: 0.5 mmol of benzamide, 5.0 mmol of cyclohexane, 0.0125 mmol of catalyst, 0.0125 mmol of ligand, 1.0 mmol of oxidant, 1 mL of PhH
b
c
at 100 °C for 24 h. GC yield with n-dodecane as the internal standard. Isolated yield in parentheses. 5 mol %. L1 = Me2NCH2CH2NCH(2-
HO−C6H4).
B
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a
Table 2. Amidation of Cyclohexane with Various Amides
and Imides
Table 3. Selectivity for Amidation of Alkanes
a
a
Conditions: 0.5 mmol of benzamide, 1 mL of alkane (10−17 equiv),
0.0125 mmol CuI, 0.0125 mmol of (MeO)2Phen, 2.0 mmol of
tBuOOtBu, 1 mL of o-C6H4Cl2 at 100 °C for 36 h. Regioselectivity
a
Conditions: 0.5 mmol of amide, 5.0 mmol of cyclohexane, 0.0125
b
mmol of CuI, 0.0125 mmol of (MeO)2Phen, 1.0 mmol of tBuOOtBu,
determined by crude 1H NMR. Yield for the reaction with t-
b
1 mL of PhH at 100 °C for 24 h. Four equivalents of oxidant.
butylcarbamate.
c
Reaction performed in o-C6H4Cl2 as solvent.
corresponding N-alkyl products. The yields of these reactions
were variable (10−75%) (q−t), but they do demonstrate that
the mechanism cannot involve a nitrene intermediate. The
reaction of phthalimide was improved from 20% to 75% by
changing the solvent from benzene to 1,2-dichlorobenzene to
increase the solubility of the reagent.
3. Isolation and Characterization of Copper(I) and
Copper(II) Imidate and Amidate Intermediates. To assess
whether copper-amidate and copper-imidate complexes with
Cu in the oxidation state of +1 and +2 are intermediates in the
catalytic amidation reactions, we synthesized and characterized
a variety of these amidate and imidate complexes supported by
phen and 2-(dimethylamino)ethyl)imino)methyl) phenoxide
(L1) (Scheme 2). Salt-metathesis reactions of [(phen)-
CuCl]2(μ-Cl)2 with potassium phthalimide (Kphth) or a
combination of NaOtBu and H2NSO2Ph or H2NCOPh in
THF at room temperature yielded air- and moisture-stable
[(phen)Cu(phth)2] (1-phth2), [(phen)Cu(NHSO2Ph)2] (2),
and [(phen)Cu(NHCOPh)2] (3), respectively.
The selectivities for amidation of various alkanes with
benzamide are presented in Table 3. The amidations of alkanes
containing secondary and tertiary C−H bonds formed products
from functionalization at the secondary C−H bonds (entry 1−
5). For example, the major products of the reactions of
benzamide with trans- and cis-1,4-dimethylcyclohexane (entry
1,2) resulted from amidation of secondary C−H bonds, while
the minor products resulted from the amidation of primary C−
H bonds. No product was formed from amidation of the
tertiary C−H bond. Likewise, the reaction of 3-ethylpentane
(entry 5) occurred preferentially at secondary and primary C−
H bonds over tertiary C−H bonds. The reaction of 2,4-
dimethylpentane (entry 7), in which the secondary C−H bond
is hindered, occurred exclusively at the primary C−H bond.
This product distribution contrasts that of most C−H
oxidations by a radical mechanism.42,43 For reactions of
cycloalkanes ranging from cyclopentane to cyclododecane, the
ring size did not affect the yield of the corresponding N-alkyl
products (69−80%) (entry 8).
Phen-ligated Cu(I) complexes containing benzamidate and
benzenesulfonamidate ligands were isolated from the reaction
of [Cu(Mes)]n with phen, followed by the addition of
benzenesulfonamide and benzamide to produce the corre-
sponding products [(phen)2Cu][Cu(NHSO2Ph)2] (4) and
[(phen)2Cu][Cu(NHCOPh)2] (5). The complex [(phen)Cu-
(phth)] (1-phth) was prepared by methods described
previously.44
Salt-metathesis reactions of [(L1)CuCl]41 with phthalimide
(Hphth), benzenesulfonamide, and benzamide produced the
corresponding Cu(II) complexes of [(L1)Cu(phth)] (6),
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All pertinent bond distances and angles for these complexes are
listed in the caption of Figure 1. Phen-ligated Cu(II)
phthalimidate 1-phth2 is mononuclear in the solid state with
a square planar geometry around the Cu(II) ion (Figure 1).
In contrast, the copper(I) compounds were ion pairs in the
solid state. The structure of phen-ligated benzenesulfonamidate
4 is an ion pair consisting of the cationic [(phen)2Cu]+, in
which Cu(I) is ligated by two phen ligands in a distorted
tetrahedral environment, and the linear anion [Cu-
(NHSO2Ph)2]− (Figure 1).
Scheme 2. Syntheses of Copper(I) and Copper(II) Amidate
and Imidate Complexes
In contrast to the diverse molecular structures of phen-
ligated copper species, complexes 6 and 7 containing the
tridentate amino imine phenoxide ligands are mononuclear
Cu(II) species with square-planar geometries in the solid state
(Figure 1). These structures are also mononuclear in solution,
as evidenced by X-Band EPR spectroscopy recorded at 20 K in
CH2Cl2 indicating an axial environment.41
To determine whether the structures of 1-phth2 and 4 in
solution differ from those in the solid state44 we measured the
conductivities of 1-phth2, and 4 in DMSO. These measure-
ments distinguish between ionic and neutral forms. The
conductivities of 1-phth2, and 4 (1.0 mM in DMSO, 25 °C)
were compared to those of a 1.0 mM (DMSO) solution of
ferrocene (0.2 Ω−1 cm2 mol−1) and N(Bu)4Cl (11.1 Ω−1 cm2
mol−1). The conductivity of the solutions of Cu(I) complexes 4
and 5 in DMSO (1.0 mM) were 33.0 and 23.1 Ω−1 cm2 mol−1,
respectively. These values are similar to the reported values for
related (phen)Cu(I) amidate and imidate complexes.44 In
contrast, the conductivity of the solution of 1-phth2 was 0.0
Ω−1 cm2 mol−1, showing that 1-phth2 retains its neutral,
mononuclear structure in DMSO. Moreover, the results for
conductivity of 6 (0.0 Ω−1 cm2 mol−1) and 7 (0.1 Ω−1 cm2
mol−1) also revealed that these complexes are neutral molecules
in solution. Unfortunately, the insolubility of 1-phth2 and 4 in
benzene prevented the measurement of their conductivities in a
less polar solvent.
[(L1)Cu(NHSO2Ph)] (7), and [(L1)CuNHCOPh] (8)
(Scheme 2).
Previous structural characterizations of phen-ligated copper-
(I) amidate and imidate complexes revealed that these
complexes can exist as mononuclear or ion-pair species.
Therefore, we assessed the atomic connectivity of 1-phth2
and 4 by single crystal X-ray diffraction (XRD) analysis.44 The
solid-state structures of 1-phth2 and 4 are shown in Figure 1.
4. Catalytic and Stoichiometric Reactivity of Copper-
Amidate and -Imidate Complexes. To gain information on
the mechanism of the catalytic amidation of alkanes, we
conducted catalytic and stoichiometric reactions with isolated
[(phen)Cu(phth)n] (n = 1, 2) complexes. These well-defined
complexes contain a reactive phthalimidate group bound to
copper in the oxidation states of +1 and +2.
First, we investigated the effect of the oxidation state of the
metal in the copper complexes lying on the catalytic reaction.
The reactions of cyclohexane with Hphth catalyzed by 2.5 mol
% of 1-phth2 and 2.5 mol % of 1-phth produced N-
cyclohexylphthalimide (Cy-phth) in 54% and 80% yield,
respectively (Scheme 3). N-Methylphthalimide (Me-phth)
was observed in 13% and 20% yields in the reactions catalyzed
by 1-phth2 and 1-phth, respectively. The observation of this
side-product implies the intermediacy of a tert-butoxy radical
because this radical is known to undergo β-Me scission to
generate a methyl radical.42 This methyl radical can then
combine with 1-phth2 to form Me-phth (Scheme 3).45 The
observation of this side product suggests that the N-
cyclohexylphthalimide forms from a reaction between 1-phth2
and a cyclohexyl radical generated from hydrogen atom
abstraction of cyclohexane by a tert-butoxy radical.
Figure 1. Molecular structures of [(phen)Cu(phth)2] (1-phth2),
[(phen)2Cu] [Cu(NHSO2Ph)2] (4), [(L1)Cu(phth)] (6), and
[(L1)Cu(NHSO2Ph)] (7) shown with 50% thermal ellipsoid. Selected
bond lengths (Å) and angles (°) of 1-phth2: Cu1−N1 = 2.0480(14);
Cu1−N2 = 2.0363(14); Cu1−N3 = 1.9667(14); N1−Cu1−N3 =
170.29(5); N1−Cu1−N2 = 93.45(5); N1−Cu1−O1 = 92.5(3).
Selected bond lengths (Å) and angles (o) of 4: Cu1−N1 =
1.9920(15); Cu1−N2 = 2.1079(16); Cu1−N3 = 1.8553(17); N1−
Cu1−N2 = 81.75(6); N3−Cu1−N3′ = 178.92(10). Selected bond
lengths (Å) and angles (o) of 6: Cu1−N1 = 1.938(7); Cu1−N2 =
2.045(7); Cu1−N3 = 1.958(7); Cu1−O1 = 1.919(6); N1−Cu1−N3 =
175.2(3); N1−Cu1−N2 = 83.4(3); N1−Cu1−O1 = 92.5(3). Selected
bond lengths (Å) and angles (o) of 7: Cu1−N1 = 1.956(6); Cu1−N2
= 2.104(6); Cu1−N3 = 1.972(6); Cu1−O1 = 1.993(5); N1−Cu1−N3
= 170.0(2); N1−Cu1−N2 = 83.7(2); N1−Cu1−O1 = 91.2(2).
In the reaction catalyzed by 1-phth, the orange solution of 1-
phth rapidly transformed to a light-blue suspension. A similar
light-blue suspension was also observed in the reaction
catalyzed by 1-phth2. Moreover, 1-phth2 was isolated from a
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complexes are capable of abstracting a hydrogen atom from
cyclohexane. The reaction of 1-phth or 1-phth2 with
cyclohexane (80 equiv) in MeCN or benzene without
tBuOOtBu at 100 °C for 24−72 h produced no Cy-phth
detectable by GC (Scheme 5, A). The absence of any Cy-phth
Scheme 3. Catalytic C−H Amidation of Cyclohexane with 1-
phth2 and 1-phth
Scheme 5. Stoichiometric Reactions of 1-phth2 and 1-phth
with Cyclohexane
reaction of 1-phth, tBuOOtBu, and Hphth in benzene at 100
°C for 0.5 h (Scheme 4). The identity of 1-phth2 was
Scheme 4. Isolation of 1-phth2 from 1-phth
product from these reactions rules out a mechanism involving
hydrogen atom abstraction by the Cu(I) or Cu(II)
phthalimidates and combination of the resulting alkyl radical
with the copper complexes.29
However, the stoichiometric reaction of 1-phth2 with
cyclohexane and tBuOOtBu (16 equiv) for 24 h produced
Cy-phth (70% yield based on copper), Me-phth, and Cy-OtBu
in a 70:25:35 ratio (Scheme 5, B). The analogous reaction of 1-
phth with cyclohexane and tBuOOtBu (16 equiv) also
produced Cy-phth (73% yield based on copper), Me-phth,
and Cy-OtBu in a 73:21:32 ratio (Scheme 5, C). Formation of
the ether product has been observed from Cu(I)-catalyzed
decomposition of tBuOOtBu and recombination of a cyclo-
hexyl radical with a Cu−OtBu functionality.48 Moreover, the
observation of Cy-OtBu suggests that [(phen)Cu(phth)-
(OtBu)] is a likely intermediate in these reactions lacking
free phthalimide; reaction of the cyclohexyl radical with this
complex would form Cy-phth and Cy-OtBu.
The formation of N-alkyl amides in the presence of
tBuOOtBu, but not in the absence of tBuOOtBu, was observed
for copper complexes 1-phth2 or 1-phth. Complexes 2−6 also
reacted with cyclohexane to produce their corresponding N-
alkyl products in the presence of tBuOOtBu, but not in the
absence of tBuOOtBu.41 These studies provide further evidence
that tBuOOtBu leads to formation of tert-butoxy radical, which
cleaves the alkane C−H bond.
confirmed by comparison of its IR spectrum to that of the
authentic sample of 1-phth2, prepared by the method in
Scheme 2, and by elemental analysis. The isolation of 1-phth2
from the reaction catalyzed by 1-phth clearly demonstrates that
a Cu(I)-imidate or amidate is a short-lived species in the
presence of excess oxidant and imide or amide under catalytic
conditions. Therefore, under the catalytic condition, the
predominant species in the system is a Cu(II)-amidate or
imidate complex.
Second, we investigated the role of oxidant in the catalytic
reaction by conducting a series of stoichiometric reactions with
1-phth and 1-phth2 in the presence and absence of tBuOOtBu.
C−H bond amidations of cyclohexane by copper complexes
have been proposed to occur by insertion of a copper-nitrene
intermediate into a C−H bond or by hydrogen atom
abstraction. In one study, a copper-nitrene species stabilized
by Sc3+ and an isolated bridging copper-nitrene complex were
shown to undergo stoichiometric reactions with cyclohexane to
form N-cyclohexyl-4-methylbenzenesulfonamide and N-cyclo-
hexyladamantane, respectively.46,47 In another study, an
isolated, three-coordinate Cu(II)-NHAd (Ad = adamantane)
complex was shown to react with cyclohexane to form N-
cyclohexyladamantane; this reaction was proposed to occur by
abstraction of a hydrogen atom from cyclohexane and capture
of the cyclohexyl radical by Cu(II).29 A mechanism involving a
nitrene intermediate in our system is ruled out by the reaction
of secondary nitrogen reagents (i.e., phthalimide) with
cyclohexane to form the corresponding N-alkyl product, but
reaction of the amidate and imidate complexes with the alkane
could occur.
To investigate if the Cu(II) complex 1-phth2 and the Cu(I)
complex 1-phth react by a common pathway, we measured the
kinetic isotope effect of the amination reactions catalyzed by
these two complexes. Reactions of the combination of
cyclohexane and cyclohexane-d12 in a single vessel containing
phth, tBuOOtBu, and 2.5 mol % 1-phth2 occurred with a
primary KIE of 2.7 0.1. The reaction of 1-phth under the
same experimental conditions occurred with a primary KIE of
3.0
0.3. The similarity of these values is consistent with
Thus, we tested the potential reactions of the copper amidate
and imidate complexes with cyclohexane. To do so, we
performed stoichiometric reactions of 1-phth and 1-phth2 with
cyclohexane. These reactions would assess whether these
reaction of Cu(I) and Cu(II) complexes through the same C−
H bond cleavage step. Furthermore, the catalytic reaction of
cyclohexane and cyclohexane-d12 in the same vessel with
benzamide and 2.5 mol % of the phen-ligated Cu(II)
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benzamidate complex 5 occurred with a primary KIE value of
Scheme 7. Trapping of the Putative Alkyl Radical
2.8
0.4. These results imply that the same C−H bond
cleavage step occurs for reactions of the different copper-
amidate complexes.
5. Trapping of Proposed Radical Intermediates.
Results from the stoichiometric and catalytic reactions of 1-
phth2 and 1-phth strongly suggest that a tert-butoxy radical is
responsible for the C−H abstraction of cyclohexane. To assess
this hypothesis further, we performed experiments that would
trap the tert-butoxy and alkyl radicals.
First, we conducted the catalytic reaction in the presence of
diphenylmethanol (2.5 equiv) (Scheme 6, A), a common probe
Scheme 6. Trapping of tert-Butoxy Radical
This result is consistent with the intermediacy of a cyclohexyl
radical in the catalytic reaction.53,54
The analogous reaction of trans-1,4-dimethylcyclohexane was
conducted. The reaction of this alkane in the presence of CBr4
and 2.5 mol % CuI/(MeO)2Phen in benzene at 100 °C for 24 h
(Scheme 7, B) formed the products from bromination at the
tertiary and the secondary sites: cis- and trans-1-bromo-1,4-
dimethylcyclohexane and cis- and trans-2-bromo-1,4-dimethyl-
cyclohexane. The two sets of constitutional isomers formed in a
ratio of 1.7:1 and a combined 86% yield based on CBr4. The 1-
bromo-1,4-dimethylcyclohexane diastereomers were obtained
as a 1.2:1 mixture, indicating that the transient tertiary radical
formed under this condition undergoes facile racemization.55
To investigate whether an alkyl radical would react with the
copper imidates to form an N-alkyl product, we conducted
reactions of the phthalimidate complex 1-phth2 with precursors
to alkyl radicals. We chose to use peroxides as the precursors to
alkyl radicals, and we performed these reactions with 1-phth2
instead of 1-phth because our data indicate that 1-phth2 is the
predominant complex under catalytic conditions. The reaction
of 1-phth2 with tBuOOtBu and (Ph(Me)2CO)2 at 100 °C for
18 h generated Me-phth in 64% and 81% yield based on
copper, respectively (Scheme 8). The rate of β-Me scission of
for tert-butoxyl radical.45,49 This alcohol can react with an
alkoxy radical by abstraction of the C−H hydrogen atom from
Cu(II)-diphenylmethoxide to form a Cu(II)-ketyl radical that is
then oxidized to form benzophenone to regenerate Cu(I).50
Alternatively, an alkoxy radical abstracts the C−H bond of
diphenylmethanol to form a ketyl radical. This ketyl radical
undergoes another hydrogen atom abstraction at the OH group
by another alkoxy radical to form benzophenone.51 Consistent
with the generation of an alkoxy radical, the catalytic reaction
conducted in the presence of diphenylmethanol formed the N-
cyclohexyl benzamide product in only 47% yield, based on
benzamide. Instead of the N-cyclohexyl amide, a large amount
of benzophenone (2.4:1.0 ratio of benzophenone to N-
cyclohexyl benzamide) formed. This reaction to form
benzophenone decreases the amount of available tert-butoxy
radical for hydrogen atom abstraction of cyclohexane and thus
decreased the yield of the N-cyclohexyl benzamide product.
Second, we probed for the formation of tert-butoxy radical by
conducting the reaction in the presence of the hydrogen atom
donor 9,10-dihydroanthracene. The tert-butoxy radical should
abstract the weak C−H bond of 9,10-dihydroanthracene over
the stronger C−H bonds in cyclohexane. Indeed, the catalytic
reaction of benzamide with cyclohexane conducted under the
standard conditions, except for the addition of 3 equiv of 9,10-
dihydroanthracene, yielded anthracene as the only organic
product besides tert-butanol (Scheme 6, B).
Scheme 8. Trapping of the Putative Alkyl Radical with 1-
phth2
the cumyloxide radical is faster than that of the tert-butoxy
radical. Thus, the higher yield of N-alkyl product from the
reaction of dicumyl peroxide than from the reaction of
tBuOOtBu is consistent with the rate of generation of the
methyl radical.52,56
Finally, to probe for a transient cyclohexyl radical in the
reaction, we performed the catalytic reaction in the presence of
CBr4 (Scheme 7, A), which would trap a cyclohexyl radical to
form bromocyclohexane.52−54 The reaction of benzamide with
cyclohexane and tBuOOtBu at 100 °C for 24 h did not form
any product from the amidation of cyclohexane. Instead,
bromocyclohexane formed in 90% yield, based on benzamide.
These results with radical probes and alkyl radicals provide
strong evidence that an alkoxy radical generates an alkyl radical
by hydrogen atom abstraction and that the alkyl radical
combines with a copper(II)-amidate and -imidate species to
produce the amidation and imidation products. The formation
of products from halogenation at the tertiary C−H bond of the
dimethylcyclohexane indicates that the absence of the products
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from amination at the tertiary C−H bonds results from the
ability of these radicals to form the C−N bond (vide infra).
Reactions in acetonitrile provide evidence against a
carbocationic intermediate that could form by oxidation of
the radical and combination of the cation with the copper
amide or imidates.57 Acetonitrile is well known to trap
carbocations by a Ritter-type reaction.4,57,58 The amidation of
cyclohexane with Hphth in wet acetonitrile (Scheme 3)
produced Me-phth (80%), and this result argues against a
transient carbocation in our system.
6. Determination of the Turnover-Limiting Step and
Order of Reagents. Additional measurements of KIE values
were conducted to determine the turnover-limiting step (TLS)
of the catalytic reaction. The KIE determined from
independent measurements of the rates of amidation of
cyclohexane and cyclohexane-d12 catalyzed by 10 mol % of 3
was 2.9 0.1.41 This primary KIE indicates that hydrogen atom
abstraction of cyclohexane by a tert-butoxy radical is the
turnover-limiting step in the catalytic process.
To identify the TLS and to explain the observed primary
KIE, we determined the order of the reaction in each
component. We obtained the kinetic data by measuring the
concentration of cyclohexylbenzamide and N-methylbenzamide
versus time by the method of initial rates with varied
concentrations of oxidant, cyclohexane, and benzamide.41 At
copper concentrations of 23 mM, the reaction was found to be
first-order in oxidant, first-order in cyclohexane, and zero-order
in benzamide. The reaction order of oxidant and cyclohexane is
consistent with turnover-limiting C−H abstraction of cyclo-
hexane by a tert-butoxy radical. The dependence of the reaction
rate on the concentration of oxidant and cyclohexane was lower
for reactions conducted with higher concentrations of these two
reagents. When the concentration of oxidant and cyclohexane
exceeded 1.0 M, there was little dependence of the rate of
cyclohexane amidation on the concentration of these two
species.41
The order of Cu is complex; our data indicates that the
reaction rate is positively dependent on the concentration of
Cu. However, the order of the reaction in the concentration of
copper varied between first-order and essentially zeroth-
order.41 A similar dependence of reaction rate on the
concentration of copper was reported for copper-catalyzed
allylic oxidation of cyclohexene by tert-butyl perbenzoate in
benzene.59 At low concentration of copper, the rate of allylic
oxidation increased with increasing concentration of copper;
however, the rate of this reaction was less dependent on the
concentration at higher concentrations of copper.40,59
The tert-butoxy radical is known to undergo multiple
nonproductive pathways: (1) β-Me scission for the methylation
of the bound Cu(II)-amidate; (2) coupling of methyl radicals;60
and (3) reaction of tert-butoxy radical with Cu(I) to form
Cu(II)-OtBu.42,48 The quenching of the tert-butoxy radical at
high concentration of copper offers one possible explanation for
the lower yield of product at high loading of Cu(I) compared to
low loading of Cu(I) and the lower order in copper.
Regardless of the origin of the effect of the concentration of
copper on yield, a copper complex does not directly participate
in the C−H bond cleavage of cyclohexane. Several pieces of
data provide evidence that copper is not required for C−H
cleavage of cyclohexane. For example, in the absence of copper,
the reaction of adamantane with tBuOOtBu and CBr4 at 100
°C for 24 h produced a mixture of 1-bromoadamantane and 2-
bromoadamantane in a ratio of 2.6:1, respectively.41 The same
reaction conducted in the presence of copper, formed a mixture
of products containing 1-bromoadamantane and 2-bromoada-
mantane in a 2:1 ratio. The similarity of the ratio of products in
the presence and absence of copper suggest that copper is not
directly involved in the C−H cleavage step.
Thus, copper appears to play two roles in our system. First,
copper catalyzes the decomposition of tBuOOtBu to generate
tert-butoxy radical, which is the species that cleaves the C−H
bond of the alkanes. Specifically, reaction of 1-phth with
tBuOOtBu and Hphth in the absence of a hydrogen atom
donor (i.e., cyclohexane) leads to rapid oxidation of 1-phth to
1-phth2 and exclusive formation of Me-phth, in which the
methyl radical is derived from tert-butoxy radical by β-Me
scission.42 Additional evidence for copper-catalyzed formation
of tert-butoxy radical is the observation of benzophenone from
diphenylmethanol under catalytic conditions.45 Second, copper
participates in the events after the turnover-limiting step of C−
H activation by tert-butoxy radical to form the N-alkyl product.
This proposal is corroborated by the reaction of methyl
radicals, derived from the tertiary alkoxy radical precursors RO-
OR (R = tBu, Ph(Me)2C), with 1-phth2 to generate the Me-
phth product.
7. Proposed Mechanism for Amidation of Cyclo-
hexane. Our proposed mechanism for C−H amidation of
cyclohexane by 1-phth is summarized in Scheme 9. An
analogous cycle is assumed to operate for the amidation with
benzamide. Our proposed mechanism begins with the
decomposition of tBuOOtBu initiated by 1-phth to produce a
tert-butoxy radical and a potential intermediate containing an
alkoxide and a phthalimidate ligand [(phen)Cu(phth)-
In addition to the difference in dependence of the rate on the
concentration of copper, we observed a difference in yield of
the amination products as a function of the concentration of
copper. Reactions conducted with a higher mol % of the Cu
catalyst formed the N-alkyl amide product in lower yields than
the reactions conducted with a lower loading of the Cu catalyst.
Specifically, reactions of cyclohexane conducted with 2.84−17.0
mM 5 yielded 94−99% of the N-cyclohexy benzamide product,
while those conducted with 34.0−45.5 mM 5 gave the N-
cyclohexyl benzamide product in 76% yield, along with
MeNHCOPh (10%) and unreacted benzamide. Perhaps, at
higher loading of Cu(I), faster decomposition of peroxide leads
to a higher concentration of tert-butoxy radical, relative to the
concentration of copper complex, and the tert-butoxy radical
undergoes processes that do not lead to the N-alkyl amide
product.
Scheme 9. Proposed Mechanism of Copper-Catalyzed
Intermolecular Amidation of Cyclohexane
G
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(OtBu)].29,61 This complex would react rapidly with Hphth to
generate 1-phth2. The tert-butoxy radical can regenerate
tBuOOtBu by secondary geminate recombination or can
abstract a hydrogen atom from an alkane to form an alkyl
radical.62 In this case, the turnover-limiting step is abstraction of
a hydrogen atom from cyclohexane by a tert-butoxy radical to
produce a cyclohexyl radical, which recombines with 1-phth2 to
expel Cy-phth and regenerate 1-phth to close the cycle.
The identity of the species that forms the C−N bond is not
defined by our studies. This species could be a transient Cu(III)
intermediate ligated by a cyclohexyl and amidate ligand. Such a
species could undergo rapid reductive elimination to release the
N-alkyl product and to regenerate Cu(I).63,64 Prior mechanistic
and DFT investigations of the Kharasch-Sosnovsky reaction
have led to the conclusion that these oxidative reactions occur
by formation of a Cu(III) species, which forms the C−O bond
by reductive elimination.34,36,38,39,65 Conversely, DFT calcu-
lations on the combination of a cyclohexyl radical with the
three-coordinate [(nacnac)Cu(II)-OtBu] (nacnac− = [ArNC-
(Me)]2CH; Ar = 2,6-Cl2C6H3) to form Cy-OtBu suggest that
capture of the alkyl radical at the oxygen atom of the OtBu
ligand is thermodynamically favorable (ΔG = −13.4 kcal/mol),
whereas combination of the alkyl radical at Cu(II) to form the
square planar complex [(nacnac)Cu(III)(Cy)(OtBu)] is
thermodynamically disfavored (ΔG = +14.9 kcal/mol).48
Thus, it is possible that the alkyl radical reacts directly with
the imidate or amidate ligands to form the N-alkyl imide and
amide products.
The selectivity of secondary (2°) and primary sites (1°) over
tertiary (3°) sites for the amidation of alkanes by this copper
system is different from the selectivity of 3° > 2° > 1° for
hydrogen abstraction by a tert-butoxy radical.43 This selectivity
for secondary over primary and tertiary sites has been observed
in the copper-catalyzed amidation of benzylic C−H bonds, and
the rationale for such selectivity was based on steric effects.33
We propose that the selectivity for the amidation of secondary
over tertiary C−H bonds results from the recombination of
alkyl radicals with phen-ligated Cu(II) amidate and imidate
complexes; we propose that the tertiary radical is too hindered
to recombine with phen-ligated Cu(II) amidate and imidate
complexes and the alkyl radical undergoes decomposition.
To address this proposal, we determined the mass balance of
the reaction. This information would provide insight into the
fate of all the alkyl radicals that could form. The amidation of
adamantane afforded a ratio of 1.6 N-(adamantan-1-yl)-
benzamide to 1.0 N-(adamantan-2-yl)benzamide and 1-phenyl-
adamantane. The 1-phenyladamantane product likely results
from the direct reaction of 1-adamantyl radical with benzene.66
The observation of 1-phenyladamantane reveals another
pathway by which tertiary alkyl radicals decompose in the
reaction. Moreover, the amidation of trans-1,4-dimethylcyclo-
hexane that produced trans-2,5-dimethylcyclohexyl benzamide
also produced 1,4-dimethylcyclohex-1-ene.41 The alkene likely
forms from the decomposition of the tertiary radical, and this
decomposition likely occurs because the combination of the
tertiary radical with the phen copper amidate or imidate is
sterically disfavored.
from amidation at secondary sites over tertiary sites. The
amidation of primary C−H bonds to form N-alkyl products is
observed when the secondary C−H bonds are hindered.
Potential Cu(II)-amidate and -imidate intermediates were
isolated, characterized, and demonstrated to be intermediates
for C−H amidation of cyclohexane. Our mechanistic data imply
that the tert-butoxy radical, not a copper-nitrene or copper-
aminyl species, leads to the activation of aliphatic C−H bonds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization of new compounds,
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
■
Author Contributions
§B.L.T. and B.L. contributed equally to the work presented.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support by 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 Paula Nixdorf and Dr. Antonio DiPasquale
for assistance with XRD. We thank Dr. Ruchira Chatterjee
(LBNL) for access and assistance with EPR spectroscopy.
REFERENCES
■
(1) Sac
̀
hez, C.; Men
̀
dez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23,
1007.
(2) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed.
2012, 51, 8960.
(3) Li, Z.; Capretto, D. A.; Rahaman, R.; He, C. Angew. Chem., Int.
Ed. 2007, 119, 5276.
(4) Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012,
2012, 2547.
(5) Liang, C.; Collet, F.; Robert-Peillard, F.; Muller, P.; Dodd, R. H.;
̈
Dauban, P. J. Am. Chem. Soc. 2008, 130, 343.
(6) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(7) Chen, M. S.; White, M. C. Science 2007, 318, 783.
(8) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2013, 135,
14052.
(9) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(10) Gomez, L.; Canta, M.; Font, D.; Prat, I.; Ribas, X.; Costas, M. J.
́
Org. Chem. 2013, 78, 1421.
(11) Barton, D. H. R.; Doller, D. Acc. Chem. Res. 1992, 25, 504.
(12) Barton, D. H. R.; Bev
50, 2665.
(13) Díaz-Requejo, M. M.; Per
(14) Roizen, J. L.; Harvey, M. E.; Bois, J. D. Acc. Chem. Res. 2012, 45,
911.
́ ̀
iere, S. D.; Hill, D. R. Tetrahedron 1994,
́
ez, P. J. Chem. Rev. 2008, 108, 3379.
(15) Dequirez, G.; Pons, V.; Dauban, P. Angew. Chem., Int. Ed. 2012,
51, 7384.
(16) Gephart, R.; Warren, T. H. Organometallics 2012, 31, 7728.
(17) Barman, D. N.; Nicholas, K. M. Eur. J. Org. Chem. 2011, 908.
(18) Barman, D. N.; Liu, P.; Houk, K. N.; Nicholas, K. M.
Organometallics 2010, 29, 3404.
(19) Srivastava, R. S.; Tarver, N. R.; Nicholas, K. M. J. Am. Chem. Soc.
2007, 129, 15250.
SUMMARY AND CONCLUSIONS
■
In summary, we have described a copper-catalyzed amidation of
unactivated alkanes by benzamide, sulfonamide, carbamate,
phthalimide, and their derivatives. The amidation of alkanes
under our catalytic conditions preferentially forms the products
H
dx.doi.org/10.1021/ja411912p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(20) Yu, X.-Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Org. Lett. 2000,
2, 2233.
(21) Liu, Y.; Guan, X.; Wong, E. L.-M.; Liu, P.; Huang, J.-S.; Che, C.-
(63) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.;
Ribas, X. Chem. Sci 2010, 1, 326.
(64) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196.
(65) Andrus, M. B.; Argade, A. B.; Chen, X.; Pamment, M. G.
Tetrahedron Lett. 1995, 36, 2945.
M. J. Am. Chem. Soc. 2013, 135, 7194.
(22) Lebel, H.; Trudel, C.; Spitz, C. Chem. Commun. 2012, 48, 7799.
(23) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198.
(66) Stavropoulos, P.; C
Res. 2001, 34, 745.
̧elenligil-Çetin, R.; Tapper, A. E. Acc. Chem.
(24) Lu, H.; Hu, Y.; Jiang, H.; Wojtas, L.; Zhang, X. P. Org. Lett.
2012, 14, 5158.
(25) Lyaskovskyy, V.; Suarez, A. I. O.; Lu, H.; Jiang, H.; Zhang, X. P.;
Bruin, B. d. J. Am. Chem. Soc. 2011, 133, 12264.
(26) Paradine, S. M.; White, M. C. J. Am. Chem. Soc. 2012, 134, 2036.
(27) Zalatan, D. N.; Bois, J. D. Top. Curr. Chem. 2009, 292, 347.
(28) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Bois, J. D.
Tetrahedron 2009, 65, 3042.
(29) Wiese, S.; Badiei, Y. M.; Gephart, R. T.; Mossin, S.; Varonka, M.
S.; Melzer, M. M.; Meyer, K.; Cundari, T. R.; Warren, T. H. Angew.
Chem., Int. Ed. 2010, 49, 8850.
(30) Kharasch, M. S.; Sosnovsky, G. J. Am. Chem. Soc. 1958, 80, 756.
(31) Kohmura, Y.; Kawasaki, K.-i.; Katsuki, T. Synlett 1997, 1456.
(32) Pelletier, G.; Powell, D. A. Org. Lett. 2006, 8, 6031.
(33) Powell, D. A.; Fan, H. J. Org. Chem. 2010, 75, 2726.
(34) Andrus, M. B.; Lashley, J. C. Tetrahedron 2002, 58, 845.
(35) Eames, J.; Watkison, M. Angew. Chem., Int. Ed. 2001, 40, 3567.
(36) Beckwith, A. L. J.; Zavitsas, A. A. J. Am. Chem. Soc. 1986, 108,
8230.
(37) Kochi, J. K.; Mains, H. E. J. Org. Chem. 1965, 30, 1862.
(38) Smith, K.; Hupp, C. D.; Allen, K. L.; Slough, G. A.
Organometallics 2005, 24, 1747.
(39) Mayoral, J. A.; Rodríguez-Rodríguez, S.; Salvatella, L. Chem.
Eur. J. 2008, 14, 9274.
(40) Walling, C.; Zavitsas, A. A. J. Am. Chem. Soc. 1963, 85, 2084.
(41) See the Supporting Information.
(42) Walling, C. Free Radicals in Solution; Wiley: New York, 1957.
(43) Walling, C.; Jacknow, B. B. J. Am. Chem. Soc. 1960, 82, 6108.
(44) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J.
F. J. Am. Chem. Soc. 2008, 130, 9971.
(45) Paul, H.; R. D. Small, J.; Scaiano, J. C. J. Am. Chem. Soc. 1978,
100, 4520.
(46) Kundu, S.; Miceli, E.; Farquhar, E.; Pfaff, F. F.; Kuhlmann, U.;
Hildebrandt, P.; Braun, B.; Greco, C.; Ray, K. J. Am. Chem. Soc. 2012,
134, 14710.
(47) Badiei, Y. M.; Dinescu, A.; Dai, X.; Palomino, R. M.;
Heinemann, F. W.; Cundari, T. R.; Warren, T. H. Angew. Chem., Int.
Ed. 2008, 47, 9961.
(48) Gephart, R. T.; McMullin, C. L.; Sapiezynski, N. G.; Jang, E. S.;
Aguila, M. J. B.; Cundari, T. R.; Warren, T. H. J. Am. Chem. Soc. 2012,
134, 17350.
(49) Finn, M.; Friedline, R.; Suleman, N. K.; Wohl, C. J.; Tanko, J.
M. J. Am. Chem. Soc. 2004, 126, 7578.
(50) Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742.
(51) Konaka, R.; Terabe, S.; Kuruma, K. J. Org. Chem. 1969, 34,
1334.
(52) Avila, D. V.; Brown, C. E.; Ingold, K. U.; Lusztyk, J. J. Am. Chem.
Soc. 1993, 115, 466.
(53) MacFaul, P. A.; Ingold, K. U.; Wayner, D. D. M.; Que, L. J. Am.
Chem. Soc. 1997, 119, 10594.
(54) Zavitsas, A. A.; Ehrenson, S. J. Am. Chem. Soc. 1965, 87, 2841.
(55) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th
ed.; Springer: New York, 2007.
(56) Kochi, J. K. Tetrahedron 1962, 18, 483.
(57) Kochi, J. K. J. Am. Chem. Soc. 1962, 84, 3271.
(58) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045.
(59) Barnard, P. W. C.; Yang, N. C. Chem. Ind. 1961, 1573.
(60) Xia, Q.; Liu, X.; Zhang, Y.; Chen, C.; Chen, W. Org. Lett. 2013,
15, 3326.
(61) Kochi, J. K. J. Am. Chem. Soc. 1961, 83, 3162.
(62) Niki, E.; Kamiya, Y. J. Am. Chem. Soc. 1974, 96, 2129.
I
dx.doi.org/10.1021/ja411912p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX