Evidence for alkene cis-aminocupration, an aminooxygenation case study: Kinetics, EPR spectroscopy, and DFT calculations

Article abstract of DOI:10.1002/chem.201101703

Alkene difunctionalization reactions are important in organic synthesis. We have recently shown that copper(II) complexes can promote and catalyze intramolecular alkene aminooxygenation, carboamination, and diamination reactions. In this contribution, we

Full text of DOI:10.1002/chem.201101703

FULL PAPER
DOI: 10.1002/chem.201101703
Evidence for Alkene cis-Aminocupration, an Aminooxygenation Case Study:
Kinetics, EPR Spectroscopy, and DFT Calculations
Monissa C. Paderes,[a] Lee Belding,[b] Branden Fanovic,[b] Travis Dudding,*[b]
Jerome B. Keister,*[a] and Sherry R. Chemler*[a]
ꢀ
Abstract: Alkene difunctionalization
reactions are important in organic syn-
thesis. We have recently shown that
copper(II) complexes can promote and
catalyze intramolecular alkene amino-
oxygenation, carboamination, and dia-
mination reactions. In this contribution,
we report a combined experimental
and theoretical examination of the
mechanism of the copper(II)-promoted
olefin aminooxygenation reaction. Ki-
netics experiments revealed a mecha-
nistic pathway involving an equilibrium
reaction between a copper(II) carbox-
ylate complex and the g-alkenyl sulfo-
namide substrate and a rate-limiting in-
kinetically competent N Cu intermedi-
ate with a CuII oxidation state. Due to
the highly similar stereochemical and
reactivity trends among the CuII-pro-
moted and catalyzed alkene difunction-
alization reactions we have developed,
the cis-aminocupration mechanism can
reasonably be generalized across the
reaction class. The methods and find-
ings disclosed in this report should also
prove valuable to the mechanism anal-
ysis and optimization of other copper(-
II) carboxylate promoted reactions, es-
pecially those that take place in aprotic
organic solvents.
ꢀ
tramolecular cis-addition of N Cu
across the olefin. Kinetic isotope effect
studies support that the cis-aminocup-
ration is the rate-determining step.
UV/Vis spectra support a role for the
base in the break-up of copper(II) car-
boxylate dimer to monomeric species.
Electron
paramagnetic
resonance
(EPR) spectra provide evidence for a
Keywords: alkenes
· aminocupra-
tion · copper · EPR spectroscopy ·
kinetics · reaction mechanisms
Introduction
actions that provide useful nitrogen heterocycles functional-
ized at the 2-position, for example, indolines and pyrroli-
dines, in good to excellent yield and high diastereoselectivity
in many instances.[2] These reactions have been rendered
catalytic with the use of ligands and oxidants [MnO2,
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and O2],
and when chiral ligands are employed, asymmetric catalytic
reactions can result [e.g., Eq. (2)].[23,25–27]
The discovery and development of copper-catalyzed and
-promoted difunctionalizations of unactivated alkenes is a
burgeoning area of chemical research.[1–15] The alkene func-
tional group is ubiquitous, the resulting products are useful,
and copper is a versatile and relatively inexpensive reagent
and catalyst. A number of mechanistic pathways and inter-
mediates are feasible and the precise pathway depends on
the copper oxidation state (Cu0, CuI, CuII, or CuIII) and the
reaction components.[16] Copper can serve as a Lewis acid, a
p-acid, and an oxidant, and organometallic mechanisms as
well as redox mechanisms have been implicated in its mode
of action.
Copper(II) carboxylate promoted, intramolecular alkene
aminofunctionalization reactions, carboamination,[17–20] dia-
mination[21–23] and aminooxygenation [Eq. (1), PMBS=para-
methoxybenzenesulfonyl],[24] are a growing class of such re-
[a] M. C. Paderes, Prof. J. B. Keister, Prof. S. R. Chemler
Department of Chemistry
In our initial mechanistic examination of these three reac-
The State University of New York at Buffalo
Buffalo, New York 14260 (USA)
Fax : (+1)716-645-6963
[22]
ꢀ
tions, evidence for both organocopper (C Cu) and carbon
[18,19,22,26,27]
C
radical (R )
intermediates was found. For exam-
E-mail: schemler@buffalo.edu
ꢀ
ple, the formation of the terminal C N bond in the diamina-
tion reaction is most consistent with a Kharash–Sosnovsky-
[b] L. Belding, B. Fanovic, Prof. T. Dudding
Department of Chemistry, Brock University
St.Catherines, Ontario, L2S 3 A1 (Canada)
type CuIII mechanism,[28–30] which involves addition of a
II
ꢀ
carbon radical to an R2N Cu complex followed by reduc-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101703.
tive elimination (Scheme 1). Conversely, formation of the
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ꢀ
ꢀ
Scheme 1. Proposed mechanisms for C C, C N, and C O bond forma-
tions.
Scheme 2. Proposed mechanism for the diastereoselective, copper-pro-
moted, aminooxygenation of substituted alkenyl sulfonamides.
ꢀ
ꢀ
C C and C O bonds in the carboamination and aminooxy-
genation reactions is most consistent with direct addition of
a carbon radical to a p-bond or to the stable TEMPO radi-
cal, respectively (Scheme 1).[18,19,22,26,27]
Despite this prior analysis, a number of key questions re-
mained. Detailed structures and direct analytical evidence
for the individual copper species involved in the reaction
were not available from our initial investigations, but might
be obtained by UV/Vis and EPR spectroscopy. The ligand
environment, geometry, and charge of the copper in the ste-
reochemistry-determining transition state were also poorly
understood, but might be analyzed by DFT calculations. In
addition, the rate-limiting step for this reaction had yet to
be confirmed, but could be probed by kinetics and kinetic
isotope effects as well as DFT calculations. Finally, we be-
lieved a detailed understanding of the role and localization
of the unpaired electron brought to the reaction by CuII and
the degree of charge transfer occurring between the nitro-
gen-containing substrate and the copper(II) promoter might
be assessed by EPR spectroscopy and spin analysis of DFT
calculated intermediates and transition states.
In this article, we report 1) the kinetics studies conducted
to determine the kinetic order in each component of the
aminooxygenation reaction, 2) the kinetic isotope effect
studies that aid in determining the rate-limiting step, 3) the
UV/Vis and EPR spectra of relevant observable [Cu] spe-
cies, 4) evidence for the direct carbon radical trapping with
TEMPO (provided by a deuterium labeling experiment)
and 5) DFT calculations of intermediates and transition
states along the reaction coordinate.
We have studied the mechanisms of these reactions using
stereochemical and regiochemical trends, isotopic labeling,
and radical trapping agents.[18,19,22,26,27] These methods have
provided a working mechanistic model that aids in product
prediction, but we sought a more rigorous understanding of
the nature and structure of the discrete reaction intermedi-
ates and the relative energies of the steps on the reaction
coordinate. Due to its high efficiency and apparently least
complicated reaction sequence, we selected the copper(II)
carboxylate promoted, intramolecular aminooxygenation re-
action[24] as the first subject for detailed reaction kinetics,
isotope effects, and molecular modeling studies. The fact
that the soluble TEMPO radical can serve as sole oxidant
and oxygen source in the copper-catalyzed aminooxygena-
tion of some substrates[26] also made this a practical choice
for comparison with future follow-up studies of the catalytic
reaction.
Initial mechanism proposal: A comparison[18] of the high
2,5-cis-pyrrolidine stereoselectivity in the copper(II) carbox-
ylate promoted, alkene aminooxygenation[24] of a-substitut-
ed-g-alkenylsulfonamides [Eq. (1), vide supra] with analo-
gous intramolecular alkene amination reactions that proceed
via trans-aminometallation[18,31,32] (outer sphere) and cis-ami-
nometallation[18,33–36] (inner sphere) mechanisms led us to
postulate that, stereochemically, the copper-promoted reac-
tion is more similar to reactions that proceed through cis-
aminometallation mechanisms than to those that proceed
through trans-aminometallations. We proposed that the re-
Results and Discussion
Experimental mechanistic investigations: N-Tosyl-o-allylani-
line (1) was chosen as the model substrate for kinetics stud-
ies due to its high reactivity and efficiency in both the stoi-
chiometric and catalytic aminooxygenation reactions.[18,24,26]
ꢀ
sulting organocopper(II) intermediate underwent C Cu ho-
molysis[29,37–39] to generate the carbon radical, and direct
trapping of the radical with TEMPO[40,41] provided the ob-
served aminooxygenation product (Scheme 2). We proposed
Substrate 1 was initially shown to undergo CuACTHGUNETRNNU(G OAc)2 pro-
moted aminooxygenation in DMF,[18] but subsequent studies
with other substrates have shown that the aminooxygenation
reaction can be carried out in less polar solvents.[24,26] Thus,
several solvents were screened for the copper(II) 2-ethyl-
hexanoate, (Cu(eh)2), promoted aminooxygenation of 1. As
shown in Table 1(entries 1–3), toluene, CF3Ph, and xylenes
are suitable solvents for the aminooxygenation reaction. As
Cu(eh)2 has the highest solubility in toluene and owing to
the fact that toluene is the most widely used of these organic
solvents, it was selected as the solvent of choice for the ki-
netics study.
ꢀ
that the cis-pyrrolidine stereochemistry resulted from N C
bond formation through either a chair- or boatlike transition
state, both of which place the sterically demanding a- and
N-substituents on opposite sides of the ring.[18]
An uncoordinated, “naked” nitrogen radical mechanism
(the result of N Cu homolysis) was disfavored, because in-
tramolecular alkene additions that proceed by means of ni-
trogen radical mechanisms show poor stereoselectivity or se-
lectivity for the 2,5-trans-pyrrolidines.[18,42–44]
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Alkene cis-Aminocupration
FULL PAPER
Table 1. Aminooxygenation reaction of N-tosyl-o-allylaniline using dif-
ferent solvents and bases.
Entry
Solvent
Base
Yield [%][a]
1
2
3
4
5
6
7
CF3Ph
CH3Ph
xylenes
CH3Ph
CH3Ph
CH3Ph
CH3Ph
Cs2CO3
Cs2CO3
Cs2CO3
proton sponge
NBu4OAc
2,5-di-tBu-4-Me-pyridine
–
85
87
90
57
96
83
70
[a] Yield refers to amount of 2 isolated after flash chromatography.
In our previously reported aminooxygenation reac-
tions,[24,26] we used Cs2CO3 or K2CO3 as base. The poor solu-
bility of these bases in toluene prompted us to examine
more soluble bases for greater control of concentration in
our kinetics experiments. Use of a proton sponge gave poor
yield, while the use of NBu4OAc or 2,5-di-tert-butyl-4-meth-
ylpyridine gave excellent yields (Table 1, entries 4–6). The
reaction was less efficient without use of a base (entry 7,
Table 1). Since NBu4OAc gave a higher yield, we used it in
our kinetics study. The analogy of this soluble base to the
less soluble bases K2CO3 and Cs2CO3 was further explored
by UV/Vis spectroscopy (vide infra). From these studies we
could conclude that NBu4OAc is a reasonably good model
for Cs2CO3, the base of choice for the CuII-promoted reac-
tions.[17–24]
Figure 1. A linear plot of 2[1]0.5 versus time showing half-order depend-
ence in substrate 1.
tained from the slope of the plot of 2[1]0.5 against time (see
Supporting Information). The plot of kobs against concentra-
tion of NBu4OAc revealed that the observed rate constant
increases to a maximum (kobs =(0.62ꢂ0.05) mm0.5 minꢀ1) at
an OAcꢀ concentration of approximately 150–200 mm,
which is about half the concentration of Cu(eh)2, and then
decreases at higher concentrations of NBu4OAc (Figure 2).
This 2:1 [Cu(eh)2]/ACTHNUTRGNEUNG
[OAcꢀ] ratio appears to be optimal for
this reaction. At a NBu4OAc concentration of zero, the ex-
trapolated rate constant is equal to 0.090 mm0.5 minꢀ1, which
indicates that the reaction occurs in the absence of
NBu4OAc, but at a slower rate. One interpretation of these
observations is that the OAcꢀ complexes with the copper(2-
Kinetic order of the reaction: We determined the kinetic
order of the aminooxygenation reaction of N-tosyl-o-allyla-
niline (1) in each of the reaction components. Under
pseudo-first-order conditions, we first examined the order in
the alkene substrate by combining substrate 1 (50 mm) and
300 mm each of Cu(eh)2, NBu4OAc and TEMPO in toluene
at 1008C. The progress of the reaction was monitored up to
80–90% conversion by using high-performance liquid chro-
matography (see Supporting Information for detailed de-
scription).
Initial rate data suggested that the order in concentration
of sulfonamide 1 was half-order. The integrated rate law for
such a reaction is given in Equation (3).
0:5
0:5
ð3Þ
2 ½1ꢁ ¼ 2 ½1t¼0
ꢁ
ꢀkobs
t
As shown in Figure 1, a linear plot of 2[1]0.5 versus time
was obtained, confirming half-order dependence in the
alkene substrate.
We next determined the effect of NBu4OAc on the rate of
the reaction using 1 (50 mm), 300 mm each of Cu(eh)2 and
TEMPO and varying concentrations of NBu4OAc (12 to
500 mm) in toluene at 1008C. The value of the observed rate
constant, kobs at each concentration of NBu4OAc was ob-
Figure 2. Plot of kobs against [NBu4OAc] showing the effect of increasing
the concentration of NBu4OAc on the rate of the reaction. The rate con-
stant is optimum at 2:1 ratio between [Cu] and [OAcꢀ] (kobs =0.62ꢂ
0.05 mm0.5 minꢀ1).
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S. R. Chemler, J. B. Keister, T. Dudding et al.
ethylhexanoate) dimer to form a more active species. This
hypothesis was further examined using UV/Vis spectroscopy
(vide infra).
A number of literature reports have demonstrated that
copper(II) carboxylates exist in the crystalline phase as car-
boxylate-bridged dimers.[45–48] Crystallographic evidence
exists for the binuclear structure of many of these com-
pounds, and their dimeric structures persist in many nonaqu-
eous solvents.[49,50] Of all the binuclear copper(II) complexes,
cupric acetate monohydrate, [Cu2ACHTUNTGRENNUG(OCOCH3)4AHCUTNGTRENN(UGN H2O)2], has
been extensively studied.[46] It has a dimeric structure in
which the copper ions are bridged by the acetate groups and
the axial positions are occupied
by water molecules (Figure 3).
X-ray crystallographic analyses
of various adducts of dimeric
copper(II)
acetate,
[Cu2-
ACHTUNGTRENNUNG(OCOCH3)4(L)2], have also
been reported.[46,51,52] Some of
the ligands used are methanol,
acetic acid, N,N-dimethylforma-
mide, and pyridine. These li-
Figure 4. Plot of ln (kobs) versus ln [Cu(eh)2]. The order in Cu(eh)2 was
obtained from the slope of the plot, 0.52ꢂ0.03.
Figure 3. Structure of dimeric
copper(II) acetate adducts
with R=CH3 and L could be
H2O, MeOH, acetic acid,
gands were shown to occupy the DMF, pyridine.
Added acetate affects the value of kobs, increasing it five-
axial position of the dimeric
fold from 25CuT:1 acetate to a maximum at a 2 CuT:1 ace-
copper acetate complexes.
tate ratio and then decreasing. At this 2:1 ratio kobs
=
Based on the NBu4OAc rate information, the order in
Cu(eh)2 was determined using a 2:1 ratio of Cu(eh)2 and
NBu4OAc. N-Tosyl-2-allylaniline (1) (50 mm), TEMPO
(300 mm) and varying concentrations of Cu(eh)2 (300 to
1000 mm) and NBu4OAc (150 to 500 mm), at a constant 2:1
Cu(eh)2:NBu4OAc ratio, were combined in toluene at
1008C. Using an analogous procedure, the disappearance of
1 was monitored and the rate constant at each Cu(eh)2 con-
centration was determined from the slope of the plot of
2[1]0.5 against time (see Supporting Information). The order
in copper was determined by non-linear least squares fit to
the equation, kobs =k[Cu(eh)2]n. From the slope of the plot
of ln(kobs) versus ln[Cu(eh)2], the order was determined to
be (0.52ꢂ0.03) (Figure 4). This suggests that the rate law is
half-order in total concentration of copper ion, [CuT].
Finally, the determination of order in TEMPO was carried
out by using sulfonamide 1 (50 mm), 300 mm of Cu(eh)2 and
150 mm of NBu4OAc and varying concentrations of TEMPO
(200 to 400 mm) in toluene at 1008C. Rate constants were
obtained from the slope of the plot of 2[1]0.5 against time
(see Supporting Information). The data from the experi-
ments showed no change in the rate constant upon changing
the concentration of TEMPO, which indicates zero-order ki-
netic dependence in TEMPO. This suggests that TEMPO is
not present in the rate-determining step.
(0.036ꢂ0.002) minꢀ1 at 1008C.
A mechanistic interpretation of the kinetics study is pre-
sented in Scheme 3. An equilibrium between sulfonamide 1
and the complex resulting from the Cu(eh)2 dimer and
Bu4NOAc (possibly 3) results in monomers 4 and 5. The
ꢀ
monomer–substrate intermediate 5 is the active Cu N inter-
mediate that undergoes the cis-aminocupration step to form
the organocopper intermediate 6 via the transition state A.
Carbon radical species 7 is formed by the homolysis of inter-
mediate 6, which is then trapped by TEMPO to give the
aminooxygenation product 2. The reaction kinetics indicate
The above results are consistent with the rate law given in
Equation (4), in which [CuT] is the molar concentration of
copper ions, without regard to the nature of the com-
plex(es).
Scheme 3. Proposed mechanism for the copper(II)-promoted aminooxy-
genation of alkenes.
0:5
0:5
ð4Þ
ꢀd½1ꢁ=dt ¼ kobs½1ꢁ ½CuTꢁ
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Alkene cis-Aminocupration
FULL PAPER
that k3, radical trapping with TEMPO, is not rate-limiting.
An alternative to 5, 6 and A, in which RCO2H has been dis-
sociated, is also viable (see the section on calculations, for
further discussion).
Effect of NBu4OAc : From the kinetic plot of kobs versus
[NBu4OAc] (Figure 2), we were able to conclude that 1) the
OAcꢀ serves to activate Cu(eh)2 rather than as a base to de-
protonate the sulfonamide and 2) a 2:1 Cu:OAcꢀ ratio gave
the optimum kobs. Kochi and Subramanian reported that the
addition of acetate salts to a solution of cupric acetate in
acetic acid effects the dissociation of the dimer [Eq. (5)].[53]
Tri- (m=1) and tetracetatocuprate (m=2) are the anionic
species formed; the former is the preferred species and the
latter is only available at high concentrations of acetate.[54]
The disappearance of the dimer upon the addition of the
acetate salts has been qualitatively studied by UV/Vis ab-
sorption spectroscopy.[53] Cupric acetate in glacial acetic acid
exhibits characteristic absorption bands at 690 and 375 nm.
It appears as a green solution due to the broad absorption
at 690 nm and the weak absorption band at 375 nm has been
attributed to the dimer.[53,55,56] Its color changes to blue
when acetate salt is added. At constant copper concentra-
tion, the intensity of both bands decreases with increasing
amount of acetate salts. This observation indicates the disap-
pearance of the dimer. At 578C the dimer–monomer equi-
librium constant in glacial acetic acid in the absence of ace-
tate is 5ꢁ10ꢀ4; addition of 0.23m sodium acetate increases
this to 3.2ꢁ10ꢀ3 and at 1.04m lithium acetate the dimer com-
pletely dissociates. Therefore, the acetate adducts of the
dimer have greater dissociation equilibrium constants than
the adducts of acetic acid.
Figure 5. UV/Vis spectra of a series of Cu(eh)2 (A) solution titrated with
NBu4OAc (B), K2CO3 and Cs2CO3.
ing reaction (coordination with copper) between OAcꢀ and
the sulfonamide substrate 1. It is on the basis of this
Cu:OAcꢀ ratio that we propose dimer 3 as a potential struc-
ture for the formed complex. We examined the similarity of
the 2:1 Cu:OAcꢀ ratio spectra with the spectra obtained
from the same ratio with the less soluble bases, K2CO3 and
Cs2CO3. As seen in Figure 5, both bases affect the spectra,
but the more soluble Cs2CO3 gives a spectrum more similar
to that with Bu4NOAc, indicating it is playing a larger role
in CuII carboxylate dimer break up. From this data we can
conclude that Bu4NOAc is a reasonable soluble base model
for Cs2CO3, the base of choice in the majority of our CuII
carboxylate promoted reactions [e.g., Eq. (1) vide supra].[2]
½Cu2ðOAcÞ4ðHOAcÞ2ꢁ þ n OAcꢀ Ð2 CuðOAcÞ2þmmꢀ þ 2 HOAc
n ¼ 2m ¼ 2,4
ð5Þ
Dimeric copper complex 3: Our kinetics results together
with literature precedents have led us to postulate that
dimer 3 combines with substrate 1 and dissociates to form
the active monomeric copper species 5 (Scheme 3). The
dimer complex 3 is proposed to contain two copper ions
bridged together by 2-ethylhexanoate groups, with one ace-
tate (from NBu4OAc) and an open coordination site on its
remaining axial position. This proposed structure is consis-
tent with the ratio that gave the optimum rate constant (2:1
Cu/OAcꢀ). We envisioned that the coordination of substrate
1 with dimer 3 and the breaking down of the resulting inter-
mediate into 4 and 5 is occurring simultaneously. The ob-
tained half-order kinetic dependence in substrate 1 and in
copper supports this mechanism (Figures 1 and 4).[57]
To support our hypothesis that the OAcꢀ mediates in the
dissociation of copper(II) 2-ethylhexanoate, we ran UV/Vis
spectra of a series of solutions of Cu(eh)2 in toluene titrated
with increasing amount of NBu4OAc (Figure 5). When
NBu4OAc was added to a solution of Cu(eh)2, its color
turned from green to blue.[53] The spectrum of a solution of
Cu(eh)2 in toluene displayed absorption bands at 670 and
380 nm. Changes in the absorption spectra were observed
when 6 and 12 mm of NBu4OAc were added to a 12 mm so-
lution of Cu(eh)2. No further decrease in the absorbance
was observed upon the addition of more than 12 mm of
NBu4OAc. We interpet the spectral changes to indicate for-
mation of first the 2:1 Cu/acetate adduct NBu4[{Cu(eh)2}2-
A
and
then
CHTUNGTRENNUNG
the
1:1
Cu/acetate
adduct
Kinetic isotope effects and rate-limiting step analysis: To gain
further insight into the nature of the rate-limiting step of
this aminooxygenation reaction, we investigated the primary
and secondary kinetic isotope effects (kH/kD). The primary
kinetic isotope effect was determined by comparing the rate
constants for the reaction of 1 and [D]-1a. As shown in
The maximum rate constant, kobs was observed at a
Cu:OAcꢀ ratio of 2:1. At OAcꢀ concentration higher than
200 mm, kobs starts to decrease, presumably due to compet-
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S. R. Chemler, J. B. Keister, T. Dudding et al.
Equations (6) and (7), the measured kH/kD was equal to
(0.98ꢂ0.07) (see Supporting Information for details). This
kH/kD is not significant compared to the maximum theoreti-
cal KIE of 8.5 (258C), based on nNH of 3100 cmꢀ1.[58,59] The
observed lack of primary isotope effect implies that the
amine deprotonation is not the rate-limiting step, thus sup-
Competition experiment: The cis-aminocupration step, for
example, transition state A (Scheme 3), involves a steric and
an electronic component. Sterically, addition to a more sub-
stituted alkene should be disfavored. Electronically, addition
to a terminally substituted alkene would be more favorable
if the transition state held a significant amount of radical
character, such that a secondary benzylic carbon radical
would be more favored than a primary radical.[61] To ascer-
tain the importance of such electronic stabilization, we ran a
competition experiment between terminal alkene 8 and in-
ternal alkene 9. Equimolar amounts of 8 and 9 were treated
with Cu(eh)2 (1 equiv), NBu4OAc (1 equiv) and TEMPO
(3 equiv) in toluene and the solution was heated to 1208C.
After 24 h, 70% of the adduct 10 was isolated, while only
14% of 11 was obtained [Eq. (11)]. Thus, the terminal olefin
is more reactive than the internal olefin. Therefore, we con-
ꢀ
porting our depiction of the formation of the N Cu inter-
mediate 5 as an equilibrium rather than a rate-limiting pro-
cess (Scheme 3).
ꢀ
clude that the addition of N Cu to the alkene is more domi-
nated by sterics than electronics. This result disfavors an al-
ternative nitrogen radical mechanism, since it is more favor-
able for a radical to add to a styrene, to form a benzylic rad-
ical, than to add to a terminal alkene to form a primary rad-
ical.[61,62] This result is also most supportive of a rate-limiting
ꢀ
To determine the secondary isotope effect, a mixture of
substrates 1 and [D]-1b was subjected to the aminooxygena-
tion reaction under typical reaction conditions [Eq. (8)].
The isotopic ratio before and after the reaction were deter-
mined by mass spectrometry and fractional conversion was
determined by HPLC analysis (see Supporting Information).
The measured inverse secondary kinetic isotope effect (kH/
addition of N Cu across the alkene versus a rate-limiting
ꢀ
C Cu homolysis, which would be more favorable for forma-
tion of a secondary benzylic carbon radical than a primary
carbon radical.
ꢀ
kD =(0.90ꢂ0.03)) supports the addition of N Cu bond
across the olefin (k1, Scheme 3) as the rate-determining step.
The inverse nature of the kinetic isotope effect is interpret-
ed as arising from the change in hybridization of the alkene
carbon from sp2 to sp3 in the transition state.[60]
ꢀ
Mechanistic analysis of C O bond formation: The existence
of a primary carbon radical intermediate in our copper(II)-
catalyzed and -promoted reactions has been supported by
isotopic labeling studies and regioselectivity trends.[18,22,26,27]
In order to differentiate a mechanism involving direct
carbon radical trapping with TEMPO versus a potential
alkyl copper(II) oxidation with TEMPO to an alkyl copper-
Rate equation: If the cis-aminocupration is the rate-limiting
step (Scheme 3) as suggested by the secondary kinetic iso-
tope effect, the reaction rate for the aminooxygenation can
be expressed as Equation (9). After derivation, it can fur-
ther be expressed as Equation (10), which accounts for the
observed rate law.
AHCTUNGTREG(NNUN III) complex followed by reductive elimination (Scheme 4),
ð9Þ
rate ¼k1½5ꢁ
K1 ¼
½4ꢁ½5ꢁ
½1ꢁ½3ꢁ
; x ¼ ½4ꢁ ¼ ½5ꢁ
x2
K1 ¼
; x2 ¼ K1½1ꢁ½3ꢁ
½1ꢁ½3ꢁ
1=2
x ¼ ½5ꢁ ¼ ðK1½1ꢁ½3ꢁÞ
Scheme 4. Evidence for direct capture of the carbon radical with
TEMPO.
1=2
ð10Þ
rate ¼ k1ðK1½1ꢁ½3ꢁÞ
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Alkene cis-Aminocupration
FULL PAPER
we performed a deuterium-labeling experiment. When the
deuterioalkene [D]-12 was treated with the standard amino-
oxygenation reaction conditions under partial conversion,
41% of the unscrambled starting material was recovered
and 57% of a 1:1 mixture of aminooxygenation product dia-
stereomers was obtained [Eq. (12)].
analogous to the proposed intermediate and to determine
its ability to undergo aminooxygenation. Electron paramag-
netic resonance (EPR) spectroscopy was used to detect an
ꢀ
[N Cu] intermediate. The EPR spectra were collected at
the X-band at 100 K (Figure 6).
The EPR spectrum of the [Cu2(eh)4] dimer (frozen glass
in toluene, 100 K) is very weak and broad (EPR silent), in-
dicating a strong degree of CuII–CuII spin coupling due to
the dimer structure. In contrast, Figure 6a shows the spec-
trum of Cu(eh)2 and Bu4NOAc (2:1 ratio) in frozen toluene
Cu
glass and has the parameters gk =2.33, g? =2.07, Ak
=
The observed 1:1 mixture of diastereomers [D]-13 implies
that a direct capture of an sp2-hybridized carbon radical in-
termediate is most likely operative in this reaction
(Scheme 4, mechanism 1). This is not surprising as the direct
ꢀ
carbon radical trapping with TEMPO is an efficient C O
bond-forming process.[40,41,63,64] If the reaction proceeds
through mechanism 2, which is the reductive elimination
from an alkyl copperACTHNUTRGNE(NUG III) intermediate, then a single (or
major) diastereomer would have been observed. This obser-
vation is consistent with previous reports in which TEMPO
has been used as a catalytic or stoichiometric oxidant in
copper-catalyzed cross-coupling and oxidation reactions.[65,66]
ꢀ
In each of these reactions, C O reductive elimination of
TEMPO and an alkyl/aryl ligand on copper has never been
suggested or observed. Although a mechanism involving an
II
ꢀ
initial C Cu homolysis and the subsequent recombination
of the carbon radical with a TEMPO-coordinated CuII, fol-
lowed by reductive elimination cannot be entirely ruled out,
this mechanism is more complicated and there is no appar-
ent driving force given that the combination of carbon radi-
cals with TEMPO occurs spontaneously in so many instan-
ces.[40,41,63,64] Isolation of the starting material g-alkenyl sulfo-
namide with complete retention of alkene geometry indi-
cates that the carbon radical intermediate does not revert
ꢀ
back to the alkene, implying the N C bond formation is not
ꢀ
reversible after C Cu homolysis.
This isotope-labeling experiment also rules out a mecha-
nism involving a concerted two-electron electrophilic addi-
tion[67,68] of TEMPO (either as a copper-complexed reagent
or a oxoammonium ion [O=NR2]+, formed from oxidation
of TEMPO by CuII) and the sulfonamide amine to the
alkene, as one diastereomer of [D]-13 would also be expect-
ed in such a mechanism. The half-order dependence on [Cu]
and substrate and, most importantly, zero-order dependence
on TEMPO, determined by our reaction kinetics, also rule
out such a mechanistic alternative.
ꢀ
Detection of an [N Cu] intermediate by EPR spectroscopy
and kinetics of the intermediate: The proposed mechanism in
Scheme 3 postulates the intermediacy of a mononuclear
copper–amido complex. To test the viability of such an inter-
mediate we sought to independently synthesize a complex
Figure 6. EPR spectra of solutions of a) Cu(eh)2 and Bu4NOAc, b)
Cu(eh)2, Bu4NOAc and sulfonamide 1 (heated at 508C for 15 min) and c)
Cu(eh)2 and deprotonated sulfonamide 1 in toluene at 100 K.
Chem. Eur. J. 2012, 18, 1711 – 1726
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1717

S. R. Chemler, J. B. Keister, T. Dudding et al.
157 MHz and A?Cu =19 MHz. The strong signal indicates
the unpaired electron of CuII is being observed. No change
in the EPR spectrum was observed when sulfonamide 1 was
added to the Cu(eh)2/Bu4NOAc mixture (Figure 6b; 1/
ꢀ
Cu(eh)2/BuNOAc=2:2:1) which indicates that no [N Cu]
intermediate is detectable as a component of the equilibri-
um reaction under these conditions (Scheme 3). A change in
the EPR spectrum was observed (Figure 6c), however, when
the Li amide of 1, formed from the deprotonation of 1 with
nBuLi, was added to a solution of Cu(eh)2 in toluene
(R2NLi/Cu(eh)2 =1:1). The EPR spectrum of the R2NLi/
Cu(eh)2 product (Figure 6c) exhibits the typical four-line
pattern expected for a single CuII center with N Cu super-
ꢀ
hyperfine splitting (ACu =35 MHz and AN =4 MHz). This
spectrum (Figure 6c) is clearly different from the others
(Figure 6a and b).[69] The broadness of some peaks in spec-
trum (Figure 6c) may be due to the presence of more than
one species (for example, R2NCu(eh)2Li and R2NCu(eh)).
ꢀ
Figure 7. Kinetic plot of the conversion of [N Cu] complex to 2.
ꢀ
The small N Cu superhyperfine splitting indicates a low
spin density located on the nitrogen (DFT calculated spin
densities of the proposed observed intermediate are in
agreement, see Supporting Information for a discussion and
ꢀ
reactive than the deprotonated [R2N Cu] complex. None-
calculations). The spectra resemble EPR spectra recorded
theless, the EPR spectrum and the kinetic behavior of the
II
for other N Cu species[70,71] and do not indicate a signifi-
[R2N Cu] intermediate support the cis-aminocupration
mechanism and suggest it is the rate-determining step. Cal-
culated relative aminocupration activation energies of the
respective [R2N Cu] intermediates involved in these reac-
tions (Scheme 6, vide infra) are consistent with the finding
that the intermediate formed from R2NLi and Cu(OR)2 is
less reactive (vide infra).
ꢀ
ꢀ
I
ꢀ
cant degree of aminal-radical Cu character (due to internal
redox).[72] The EPR spectrum (Figure 6c) indicates the
[R2N-CuII] species under observation is more isotropic than
would be expected of a square-planar CuII complex (lack of
significant gk signals).
ꢀ
ꢀ
We demonstrated that the [R2N Cu] intermediate ob-
served in Figure 6c was kinetically competent. Upon the ad-
dition of TEMPO and subsequent heating of the solution to
1108C the aminooxygenation product was produced in 89%
yield [Eq. (13)].
Theoretical investigation of the aminooxygenation reaction
mechanism: Calculations were carried out at the Kohn–
Sham hybrid-DFT B3LYP[73,74] level of theory using the
Gaussian 09[75] and GaussView v5.0.8 programs. The
GenECP method was employed with a 6-31G(d) basis set
applied to all atoms (i.e., H, C, N, O, S) except copper,
which was computed using the Los Alamos LAN2DZ[76–79]
basis set. This combination was used because the sole use of
the 6-31G(d) basis set resulted in exaggerated basis set su-
perposition error (BSSE), while sole use of the LanL2DZ
basis set did not properly account for the hypervalent
nature of sulfur. For ease of calculations, CuACTHUNRGTNEUNG(OAc)2 was
ꢀ
The kinetics of the transformation of this [R2N Cu] com-
plex to aminooxygenation product 2 were determined at
1008C. A linear plot of ln[1] against time indicates that the
used instead of Cu(eh)2. The calculations (in vacuo) were
carried out at the temperatures most relevant to the reac-
tion being studied. These calculations were performed in
vacuo owing to lower computational time required com-
pared to use of an implicit solvation model. This is largely a
reasonable simplification due to the low dielectric constant
of toluene (e=2.38) and our use of relative energies for
comparison of mechanistic scenarios. Introduction of error
from this simplification would have most impact on species
with a large charge separation. See the Supporting Informa-
tion for a brief comparison of calculated relative energies
using in vacuo versus implicit solvation models.
ꢀ
reaction is first-order in the [R2N Cu] complex (Figure 7).
Neither excess of Cu(eh)2 nor TEMPO had an effect on the
observed rate constant (kobs =(1.6ꢂ0.1)ꢁ10ꢀ2 minꢀ1).
ꢀ
The rate of the reaction of the [R2N Cu] complex at an
initial concentration of 50 mm (0.75 mmminꢀ1) is about half
the rate of the reaction of 1 promoted by the 2:1 [Cu(e-
h)2]/ACHTUNGTRENNUNG
[OAcꢀ] ratio at 50 mm concentrations of 1 and [CuT]
(1.8 mmminꢀ1 based on the experimentally determined rate
law and rate constant). Therefore, the intermediate in the
[Cu(eh)2]/
non-detectable equilibrium concentrations) must be more
ACHTUNGTRENNUNG
[OAcꢀ]-promoted reaction (which is present in
1718
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Alkene cis-Aminocupration
FULL PAPER
Scheme 5. Mechanistic alternative for copper(II)-promoted alkene aminoxygenation.
of coordinated acetate ligands. Path A starts from
[(R1R2N)Cu (HOAc)] (I-5; R1 =tosyl (Ts), R2 =2-al-
(OAc)
A
ACHTUNGTRENNUNG
lylphenyl) and is the two-acetate, neutral path. Path B starts
from [(R1R2N)CuOAc] (I-1B) + HOAc and is the one-ace-
tate, neutral path. We found that one-acetate-ligand mecha-
nism, path B, has a lower aminocupration activation barrier
than the two-acetate neutral mechanism, path A, by about
1.2 kcalmolꢀ1 (Figure 8 and Scheme 5). (The early steps of a
two-acetate anionic pathway were considered briefly but
deemed less likely due to a much higher relative aminocup-
ration activation barrier, see Supporting Information for fur-
ther discussion and calculations.)
We also calculated the activation barrier for the amino-
Scheme 6. Cation effects on relative energies of aminocupration activa-
tion energy. Relative energies only are being compared since different
cupration starting from the [(R1R2N)Cu
ACHTNUTRGNE(UNG OAc)2Li] inter-
atoms are involved in each path. GTS(C–A) =2.8 kcalmolꢀ1
.
mediate (most relevant to Figure 7, vide supra) and found it
was 2.8 kcalmolꢀ1 higher than the activation barrier for tran-
sition state A, path A at 1008C, the temperature the kinetics
experiments were run at (compare aminocupration paths A
and C, Scheme 6). This is consistent with experimental find-
ings that the reaction involving 1 deprotonated with nBuLi
is half the rate of the reaction involving 1 and Bu4NOAc
(vide supra). The fact that there is a difference in rates be-
tween the two series indicates that the copper centers in
each intermediate are not likely to lose an acetate ligand to
Calculations of aminooxygenation reaction mechanism possi-
bilities: Detailed mechanistic alternatives for the Cu(OAc)2/
AHCTUNGTRENNUNG
Bu4NOAc-promoted aminooxygenation reaction of N-tosyl-
2-allylaniline (1) were calculated (1108C) and the optimized
transition states were confirmed to be first-order saddle
points by the appearance of a single imaginary frequency (i).
Furthermore, the respective product complexes immediately
following from the transition
states were located using the in-
trinsic
reaction
coordinate
(IRC)[80–82] method and con-
firmed to be minima by the ap-
pearance of only real vibrational
modes. Thereafter, each inter-
mediate shown was located by
optimization to the lowest
energy minima of the corre-
sponding geometry.
Two mechanistic scenarios
(pathways A and B) were envi-
sioned for this aminooxygena-
tion reaction (Scheme 5). The
two mechanisms differ in their
Figure 8. Potential energy landscapes for the two-acetate-ligand neutral path A (blue diamond) and the one-
ꢀ
acetate-ligand path B (red square) at 1108C. Energy scale in kcalmolꢀ1. GTSA =17.2 kcalmolꢀ1, GTSB =16.0 kcal
possible starting [N Cu] com-
plexes, in particular, the number molꢀ1
.
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1719

S. R. Chemler, J. B. Keister, T. Dudding et al.
ꢀ
form intermediate I-1B (path B, Scheme 5), since then the
rates would be expected to be the same.
cause the C Cu homolysis transition states were difficult
and in most cases impossible to locate.[83,84]
Upon further investigation of reaction coordinates A and
B (Scheme 5 and Figure 8), a dramatic ligand effect is ob-
served. The most stable aminocopper intermediate to
The calculated aminocupration transition states TS-A
(path A) and TS-B (path B) have distorted square-planar
copper geometries (Figure 9). Spin density analysis of transi-
ꢀ
emerge from TS-B is I-2B, which still maintains N Cu coor-
dination. Loss of this coordination and homolysis to carbon
radical I-7 and CuOAc resulted in a 26.5 kcalmolꢀ1 higher
energy state. The majority of the energy cost appears to be
ꢀ1
ꢀ
ꢀ
loss of the C Cu bond (17.5 kcalmol ), but loss of the N
Cu bond is also endothermic (9.0 kcalmolꢀ1). The organo-
copper intermediate emerging from TS-A is I-2A, which
ꢀ
ꢀ
also maintains N Cu coordination. Loss of N Cu coordina-
ꢀ
tion generates a re-oriented minimized C Cu intermediate,
I-6, which has an acetate and HOAc ligand bound to it. In
the path A series, the re-oriented intermediate I-6 is actually
lower in energy than I-2A by 2.0 kcalmolꢀ1. The different
ꢀ
relative change in energy between the two C Cu intermedi-
ates in the two series might be explained by the formal
charge on Cu in the two series. In series A, I-2A has a Cu
with a formal charge of ꢀ2, so when it releases the N
ligand, it becomes Cu with a formal charge of ꢀ1, and this
change in formal charge on Cu is apparently favorable even
though the Cu becomes tricoordinate in going to I-6. In ser-
ies B, I-2B has a formal charge of ꢀ1, so when it releases
the N ligand to yield I-3B, it becomes Cu with formal
charge of 0. This is apparently not as beneficial a change
ꢀ
compared to becoming the tricoordinate C Cu intermediate
I-3B (the acetate is bidentate), so I-2B to I-3B is an endo-
thermic process. Homolysis of I-6 to give the carbon radical
I-7 and CuACHTUNGTRENNUNG(OAc)ACHTUNGTRENNUNG(HOAc) is exothermic, but by only 1.0 kcal
molꢀ1 (it is possible this step is actually slightly endothermic
if solvation is taken into account, see supporting information
for further discussion). Trapping of the carbon radicals with
TEMPO was found to be highly exothermic, resulting in the
optimized aminooxygenation product 2 and the respective
CuI salt (Figure 8 and Scheme 5).
The large difference in product energies between paths A
and B is the result of the copper(I) species, Cu
HOAc in the one-acetate-ligand path B, and Cu
ACHTUNGTRENNUNG(HOAc) for the two-acetate-ligand path A. Thus, it appears
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
the ligation of the second acetate greatly stabilizes the CuI
homolysis product, thereby impacting the overall reaction
profile. It is thus proposed that the two-acetate-ligand (neu-
tral) mechanism (path A, blue diamond, Figure 8) is overall
lower in energy and thus a reasonable mechanism. Another
mechanistic possibility, however, would be a “cross-over”
mechanism in which aminocupration proceeds through the
one-acetate-ligand pathway (path B, red square, Figure 8)
ꢀ
resulting in the [C Cu] complex I-2B, which then picks up
an acetate (as HOAc to maintain overall neutrality) to gen-
erate intermediate I-6. At this point, the two-ligand, neutral
ꢀ
mechanism (path A) is embarked upon whereby C Cu ho-
molysis is followed by capture of the resulting carbon radi-
Figure 9. Optimized structures of aminocupration transition states, the re-
ꢀ
sulting C Cu intermediates, and spin density analysis thereof. C(1)=in-
cal I-7 by TEMPO to yield the exothermic aminooxygean-
ternal (alkene) carbon, C(2)=terminal (alkene) carbon. a) Transition
state TS-A, b) intermediate I-6, c) transition state TS-B, d) intermediate
I-2B.
tion product 2 and the respective CuI
A
ACHTUNGTRENUN(NG HOAc) salt.
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Alkene cis-Aminocupration
FULL PAPER
tion states TS-A and TS-B indicate the majority of spin den-
sity resides on Cu and little increase in nitrogen spin from
ground state to transition state is observed. The spin on ni-
trogen never exceeds 15% and thus the nitrogen does not
possess significant radical character. Wiberg bond indi-
ces[85–89] were analyzed to quantify the extent to which the
ꢀ
ꢀ
N C and Cu C bonds are formed at the transition states.
ꢀ
Accordingly, the Cu C bond is 73% formed in TS-A, while
ꢀ
ꢀ
the N C bond is only 49% formed. Similarly, the Cu C
bond is 71% formed at TS-B, while the N C bond is only
49% formed. This indicates the alkene amincupration is
ꢀ
ꢀ
being led by Cu p-bond activation. In the most stable C Cu
intermediates, I-6 and I-2B, significant spin density, 40 and
36%, respectively, resides on the terminal carbon, which
leads to the prediction that this carbon will behave like a
radical, which it subsequently does.
An alternative aminooxygenation mechanism involving a
ꢀ
nitrogen radical pathway, by means of homolysis of the N
Cu bond of I-5, was also considered. This pathway was cal-
culated to be significantly higher in energy compared to
pathway A, and thus was not considered competitive. See
Supporting Information for a discussion and the calculation
data.
Theoretical treatment of observed reaction diastereoselectiv-
ity: The Cu(eh)2 promoted aminooxygenation reaction of a-
methyl-g-alkenyl sulfonamide 14 occurred in about 83%
yield and >20:1 cis/trans diastereoselectivity irrespective of
whether Cs2CO3 or Bu4NOAc was used [Eq. (14)]. This 2,5-
cis selectivity is consistent for a number of substrates.[18,24]
We calculated eight possible aminocupration transition
states for this reaction, four that lead to the observed 2,5-
cis-pyrrolidine 15 and four that lead to the 2,5-trans-pyrroli-
dine 16.
Figure 10. Path D transition states: a) cis-chair TS, relative energy=
0 kcalmolꢀ1; b) trans-chair TS, relative energy=3.5 kcalmolꢀ1; c) cis-boat
TS, relative energy=0.2 kcalmolꢀ1; d) trans-boat TS, relative energy=
2.7 kcalmolꢀ1. C(1)=internal carbon, C(2)=terminal carbon.
The four potential aminocupration transition states for
the two-ligand, neutral path D are shown in Figure 10a–d.
Transition states cis-TS-Dch and cis-TS-Dbt (ch=chair, bt=
boat) are favored (lower in energy by at least 2.5 kcalmolꢀ1)
in which the steric interaction is minimized between the
methyl substituent and the tosyl group, leading to the 2,5-
cis-product. The relative energies are shown in Figure 10(see
Supporting Information for a potential energy landscape for
the four possible path D transition states). The lowest
energy transition state, cis-TS-Dch, most closely resembles a
chairlike geometry, but it is within 0.2 kcalmolꢀ1 of the cis-
TS-Dbt transition state, which has a boatlike geometry.
favoured due to the lower energy (lower by at least 3.1 kcal
molꢀ1) of transition states of cis-TS-Ech and cis-TS-Ebt com-
pared with trans-TS-Ech and trans-TS-Ebt. The relative ener-
gies are shown in Figure 11 (see Supporting Information for
a potential energy landscape for the four possible path E
transition states). The lowest energy transition state is the
cis-TS-Ebt, which is boatlike, and lower in energy than the
chairlike cis-TS-Dch transition state by 0.2 kcalmolꢀ1.
The finding that both the boat and chair transition states
that lead to the 2,5-cis-pyrrolidines are within 0.2 kcalmolꢀ1
is not consequential to the diastereoselectivity of the reac-
tion since both lead to the same product. However, if this
trend is similar with CuII catalysts coordinated by chiral bi-
The aminocupration transition states for the one ligand
pathway E are shown in Figure 11a–d. The cis-product is
Chem. Eur. J. 2012, 18, 1711 – 1726
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1721

S. R. Chemler, J. B. Keister, T. Dudding et al.
mented by three additional minima on the energy landscape.
The one-ligand mechanism (path E) is calculated to have a
lower activation energy for aminocupration by 3.1 kcal
molꢀ1. The one-ligand mechanism, however, is disfavoured
ꢀ
to undergo C Cu homolysis due to the higher energy state
of the CuIOAc species. Again, a crossover mechanism may
be active wherein aminocupration occurs with one ligand
bound to copper, followed by coordination of a free HOAc
ligand to facilitate homolysis.
Taken together, it is important to note that despite having
a higher activation energy for aminocupration, overall, the
two-ligand, neutral mechanism (pathway D) is favored over
the one-acetate-ligand mechanism (pathway E) due to the
ꢀ
relative energetics of the C Cu homolysis step.
The two-acetate, neutral pathway D for the a-methyl-g-al-
kenylsulfonamide 14 (Scheme 7 and Figure 12) closely re-
sembles the analogous path A for the 2-allylaniline sulfona-
ꢀ
mide 1 (Scheme 5 and Figure 8). The C Cu homolysis in
each of these reactions is exothermic by about 1 kcalmolꢀ1.
The homolysis mechanism for the one-acetate neutral path-
way E for the a-methyl-g-alkenylsulfonamide 14 (Scheme 7
and Figure 12) is also quite similar to the analogous path B
for the 2-allylaniline sulfonamide 1 (Scheme 5 and Figure 8).
ꢀ
Breaking the N Cu interaction in the initial aminocupration
product to give the re-oriented intermediate, for example, I-
2E to I-3E in the a-methyl series is endothermic by 7.0 kcal
molꢀ1. Likewise, in the aniline series, the conversion of I-2B
ꢀ1
ꢀ
to I-3B is endothermic by 9.0 kcalmol . Similarly, C Cu ho-
molysis is endothermic in both series (I-3E to I-4D/E,
+16.7 kcalmolꢀ1; I-3B to I-7, +17.5 kcalmolꢀ1). The energy
differences I-2B to I-7 [+CuACHTGNUTRENNUNG
D/E [+Cu
G
ꢀ1
ꢀ
mol ); C Cu homolysis through pathways B and E are en-
ergetically unfavorable and thus not reasonable mecha-
nisms.
In practice, the N-tosyl-2-allylaniline substrate 1 is more
reactive than the a-methyl-g-alkenyl sulfonamide 14 (1
reacts at 1108C, while 14 requires heating to 1308C). This
trend in reactivity is better reflected by the two-acetate neu-
tral pathways (paths A and D, DGTS =17.2 and 17.9 kcal
molꢀ1, respectively) than the one-acetate pathways (paths B
and E, DGTS =16.0 and 14.8 kcalmolꢀ1, respectively). Thus,
it is possible that paths A and D more closely resemble the
actual reaction mechanism, even in the aminocupration step.
Additionally, since the diastereoselectivity is determined in
the aminocupration step and the major diastereomer of the
aminooxygenation, diamination and carboamination reac-
tions [Eqs. (1) and (14), Scheme 1] are the same irrespective
of base and ligands or conditions (catalytic versus stoichio-
metric copper catalyst),[24,90] we can infer that the cis-amino-
cupration mechanism is relevant to all reactions in the class.
Figure 11. Path E transition states: a) cis-chair TS, relative energy=
0.2 kcalmolꢀ1; b) trans-chair TS, relative energy=3.3 kcalmolꢀ1; c) cis-
boat TS, relative energy=0 kcalmolꢀ1; d) trans-boat TS, relative energy=
4.9 kcalmolꢀ1. C(1)=internal carbon, C(2)=terminal carbon.
s(oxazoline) ligands, it could translate to low levels of enan-
tioselectivity in some reactions (e.g., substrates with a-sub-
stituents). In point of fact, this has actually been observed in
a recently performed attempted desymmetrization reac-
tion.[90]
Conclusion
A comparison between the two mechanistic paths, D and
E, is depicted in Figure 12 and Scheme 7, in which the
lowest energy aminocupration transition states are supple-
In this study we report mechanistically rigorous evidence for
a rate-limiting cis-aminocupration step in the CuII-promoted
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Alkene cis-Aminocupration
FULL PAPER
steps of the reactions mecha-
nism. Isotopic-labeling studies
ꢀ
support C O bond formation
through carbon radical trapping
with TEMPO and rule out
more concerted reaction pro-
cesses.
In this study we have also ob-
served an interesting and unex-
pected role of acetate ion in the
break-up of copper(II) carbox-
ylate dimer in a pre-equilibrium
step. The prominence of this
pre-equilibrium is established
by the observed half-order ki-
netics in [CuT] and in [sub-
strate]. This under-recognized
role of CuII carboxylates as ac-
ceptors of acetate ions may ex-
Figure 12. Potential energy landscape for the two possible pathways for the aminooxygenation of -methyl–al-
kenylsulfonamide 14 at 1308C (energy scale in kcalmolꢀ1).
alkene aminooxygenation/cyclization. Although we had pre-
viously proposed this mechanism based on empirical obser-
vations, this study, involving reaction kinetics, EPR spectros-
copy, and DFT calculations, has given much stronger experi-
mental evidence for the proposed mechanism. A detailed
understanding of alkene aminometallation is required to fur-
ther develop stereoselective metal-promoted alkene addi-
tion reactions. While significant work has been conducted to
study the mechanism of alkene aminopalladation[91–93] and
aminoauration,[94,95] few rigorous mechanistic studies have
been conducted with respect to the alkene aminocupra-
tion.[18] Our reaction kinetics and observed secondary kinetic
isotope effect support a rate-limiting, cis-aminocupration
step. The cis-aminocupration mechanism is also supported
plain their ability to facilitate a variety of reactions that re-
quire CuII additives.[96–98] To the best of our knowledge, this
is also the first study that documents kinetic order to illus-
trate the importance of copper(II) carboxylate dimer break-
up on the rate of a copper(II) carboxylate promoted reac-
tion. Although half-order [CuT] kinetics would be expected
when starting from dimeric copper(II) carboxylates, the
half-order substrate kinetics, which indicates the substrate is
involved in the break-up of the CuII dimer, is more unusual.
There is some evidence that a dimer break-up step may be
important in other copper(II) carboxylate promoted reac-
tions, for example, the known Chan–Lam CuACTHNURGTNEUNG(OAc)2-pro-
moted cross-coupling reaction of amines and organoboronic
acids.[99,100]
ꢀ
by the kinetic competency of a pre-formed [N Cu] inter-
We further document for the first time a copper(II) car-
boxylate promoted reaction in which the rate of the reaction
can be dependent upon the ratio of copper(II) carboxylate
to added base or nucleophile, in this case, acetate ion. This
finding may also be relevant to other copper(II) carboxylate
promoted reactions. For example, Lam has indicated in a
recent review of the Chan–Lam coupling reaction, that
while solubility and color changes are observed upon addi-
mediate with a first-order kinetic profile. Competition ex-
periments further support aminocupration as the alkene ad-
dition mode and help rule out an aminyl radical mechanism.
The EPR experiments and DFT calculations directly ad-
dressed the possible contribution of nitrogen radical chemis-
try in the mechanism and we were able to conclusively elim-
inate the involvement of a nitrogen radical in the productive
Scheme 7. Potential reaction coordinates for the cis-pyrrolidine selective aminooxygenation reaction. Path D involves a two-acetate neutral copper(II)
complex and Path E involves a one-acetate neutral copper(II) complex.
Chem. Eur. J. 2012, 18, 1711 – 1726
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1723

S. R. Chemler, J. B. Keister, T. Dudding et al.
tion of nucleophiles to CuACTHNUTRGNE(NUG OAc)2 solutions, further insight
Experimental Section
into the influence of nucleophiles and ligands on the identity
of the copper(II) catalyst is needed.[99] Reaction kinetics
have recently been investigated in the Chan–Lam cou-
pling.[16, 101] In these studies, the reaction conditions for the
kinetic study were catalytic in CuII and performed in alcohol
solvent.[16, 101] The majority of Chan–Lam couplings, howev-
er, are performed by using a stoichiometric amount of Cu-
ACHTUNGTRENNUNG(OAc)2 in aprotic, organic solvents, much like our reac-
tions.[98,99,102] Thus, the methods of reaction study disclosed
herein may be useful in the kinetic study of other CuII car-
boxylate promoted reactions that take place in aprotic, or-
ganic solvents. Furthermore, although numerous copper(II)
carboxylate promoted reactions have been developed, the
role of the dimeric nature of the copper(II) carboxylate salt
is rarely considered in mechanism discussions.[98,99,102–104] Our
studies indicate that consideration of the dimeric state of
copper(II) carboxylates could lead to a more rational reac-
tion optimization approach in some cases. Reaction kinetics
of copper(II) carboxylate promoted reactions that take
place in aprotic organic solvent are rare, perhaps due to the
N-(2-Allyl-2-[D1]-phenyl)-4-methylbenzenesulfonamide ([D]-1b): A solu-
tion of LiAlD4 (3.6 g, 85.6 mmol, 1.6 equiv) in dry Et2O (285 mL) was
cooled to ꢀ108C and a solution of propargyl alcohol (3.0 g, 53.5 mmol,
1 equiv) in Et2O (33 mL) was added through an addition funnel over
30 min. The resulting solution was warmed to room temperature and
stirred for 14 h. The mixture was cooled to 08C and was quenched slowly
with H2O (4.0 mL). The solution was stirred for another 15 min and then
15% aqueous NaOH solution (4.0 mL) and H2O (4.0 mL) were added.
The white slurry was filtered through a short pad of Celite and was
washed with Et2O (300 mL). The filtrate was concentrated in vacuo to
give the crude allyl-2-d1 alcohol4 as
a
yellow oil (3.0 g). 1H NMR
(500 MHz, CDCl3): d=5.22 (s, 1H), 5.09 (s, 1H), 4.08 (s, 2H), 3.0 ppm
(brs, 1H).
difficulties associated with CuACHTNUGTRENUNG(OAc)2 solubility. We propose
that Cu(2-ethylhexanoate)2 can be used in the kinetic analy-
sis of any reaction previously run with the less soluble Cu-
ACHTUNGTRENNUNG
The crude allyl-2-[D1] alcohol (3.0 g, 50.8 mmol, 1 equiv) was added to a
stirring solution of PBr3 (2.4 mL, 25.5 mmol, 0.5 equiv) in Et2O (21 mL)
dropwise at 08C. The resulting solution was stirred at 08C for 1 h and
then carefully quenched by the addition of brine (12 mL). The layers
were separated and the combined organic extracts were washed with a
saturated solution of NaHCO3, brine and dried over Na2SO4. Excess sol-
vent was removed via careful distillation (45–508C). The crude allyl-2-
[D1] bromide was obtained as colorless liquid (2.1 g, 32% yield over 2
steps).[5] 1H NMR (500 MHz, CDCl3): d=5.31 (s, 1H), 5.14 (s, 1H),
3.94 ppm (s, 2H).
with the experimental results and also indicate a further role
for the acetate ligands throughout the reaction coordinate.
In our calculations we have found a strong ligand effect on
II
ꢀ
the energies of ligand dissociation and C Cu homolysis.
II
[84]
ꢀ
There are few theoretical studies of C Cu homolysis and
a ligand effect on bond dissociation energy has not previous-
ly been noted, although calculated ligand effects on single
electron transfer involving copper complexes have been re-
cently reported.[105]
Into an oven-dried round bottom flask were added the crude allyl-2-[D1]
bromide (1.5 mL, 12.5 mmol, 1.0 equiv), aniline (4.5 mL, 37.0 mmol,
3.0 equiv), K2CO3 (5.0 g, 37.0 mmol, 3.0 equiv) and DMF (20 mL).[6] The
flask was equipped with a stopper and the reaction mixture was heated
to 708C overnight. The mixture was allowed to cool to room temperature
and was washed with water (20 mL). The aqueous phase was extracted
with Et2O (3ꢁ20 mL). The combined organic layers were washed with
brine, dried with Na2SO4 and concentrated in vacuo. Purification by flash
chromatography on SiO2 (10% EtOAc in hexanes) gave compound N-
allyl-2-[D1] aniline (0.7 g, 45% yield). Data: 1H NMR (500 MHz,
CDCl3): d=7.18 (t, J=7.5 Hz, 2H), 6.72 (t, J=7.5 Hz, 1H), 6.64 (d, J=
8.0 Hz, 2H), 5.29 (s, 1H), 5.17 (s, 1H), 3.78 ppm (s, 2H); 13C NMR
(75 Hz, CDCl3): d=148.0, 135.1 (t, J=23.0 Hz), 129.2, 117.5, 116.1, 112.9,
46.4 ppm; HRMS (ESI): m/z calcd for [M]+ C9H11DN1: 135.1027, found:
135.1022.
The mechanistic work described in this paper sets the
stage for a subsequent detailed mechanistic analysis of our
recently reported enantioselective Cu-catalyzed aminooxy-
genation of alkenes, which can open the door to a more de-
tailed understanding of catalytic, enantioselective, Cu-cata-
lyzed, alkene amination reactions.[26] While we do not
expect the reaction kinetics to be identical, since we start
from monomeric rather than dimeric copper complexes in
the enantioselective reaction,[26] the stereochemical trends
(diastereoselectivity) of the reactions[24,90] are similar enough
for us to anticipate similar kinetic isotope effects and rate-
limiting step. Although CuII-promoted and -catalyzed alkene
amination reactions are relatively novel, the attractive quali-
ties CuII salts have to offer with respect to low expense, high
versatility, and stereoselectivity ensure this reaction class
will grow, thus a detailed mechanistic understanding as de-
scribed in this paper should aid in the rational development
of this class of reactions.
To an oven-dried pressure tube were added N-allyl-2-[D1] aniline (0.7 g,
5.2 mmol, 1 equiv) and xylenes (13 mL). The solution was cooled to
ꢀ788C and BF3·Et2O (1.3 mL, 10.4 mmol, 2.0 equiv) was added dropwise.
The resulting solution was warmed to room temperature and was heated
to 1608C for 4 h.[7] The reaction mixture was then cooled to room tem-
perature and was placed in an ice–water bath and was quenched with 2m
NaOH (6 mL). The organic layer was separated and aqueous layer was
extracted with Et2O (3ꢁ10 mL). The organics were combined, dried with
Na2SO4, filtered and concentrated in vacuo. Purification by flash chroma-
tography on SiO2 (10% EtOAc in hexanes) gave o-allyl-2-[D1] aniline
(0.5 g, 70% yield). 1H NMR (500 MHz, CDCl3): d=7.05 (t, J=8.0 Hz,
2H), 6.75 (t, J=7.5 Hz, 1H), 6.64 (d, J=8.0 Hz, 1H), 5.12 (s, 1H), 5.10 s,
1H), 3.66 (brs, 2H), 3.30 ppm (s, 2H); HRMS (ESI): m/z calcd for [M+
H]+ C9H11DN1: 135.1012, found: 135.1009.
The o-allyl-2-[D1] aniline (0.5 g, 3.7 mmol, 1 equiv) was dissolved in dry
CH2Cl2 (20 mL) and the solution was treated with pyridine (1.18 mL,
1724
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1711 – 1726

Alkene cis-Aminocupration
FULL PAPER
14.9 mmol, 4 equiv) followed by p-toluenesulfonyl chloride (0.85 g,
4.5 mmol, 1.2 equiv). The mixture was stirred at room temperature for
24 h, washed with 1n HCl (15 mL) and extracted with CH2Cl2 (3ꢁ
15 mL). The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. Flash chromatography of the result-
ing crude compound on SiO2 (5–10% EtOAc in hexanes) afforded com-
pound [D]-1b as white solid (1.0 g, 96% yield). M.p. 62–658C; 1H NMR
(500 MHz, CDCl3): d=7.61 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H),
7.23 (d, J=8.5 Hz, 2H), 7.19 (m, 1H), 7.13–7.05 (m, 2H), 6.55 (b. s., 1H),
5.11 (s, 1H), 4.93 (s, 1H), 3.00 (s, 2H), 2.39 ppm (s, 3H); 13C NMR
(75 Hz, CDCl3): d=143.7, 136.7, 135.2 (t, J=24 Hz), 134.9, 131.9, 130.4,
129.5, 127.6, 127.0, 126.2, 124.4, 116.9, 36.0, 21.5 ppm; IR (neat): n˜ =3266,
3076, 3030, 2967, 2913, 2849, 2243, 1922, 1623, 1596, 1492, 1451, 1401,
1333, 1161, 1089, 1039, 1016, 921, 817, 754, 663 cmꢀ1; HRMS (ESI): m/z
calcd for [M]+ C16H16DO2N1S1: 288.1037, found: 288.1036.
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Received: June 3, 2011
Published online: January 11, 2012
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