The Mechanism of Rhodium-Catalyzed Allylic C-H Amination

Article abstract of DOI:10.1021/jacs.0c01069

Herein, the mechanism of catalytic allylic C-H amination reactions promoted by Cp*Rh complexes is reported. Reaction kinetics experiments, stoichiometric studies, and DFT calculations demonstrate that the allylic C-H activation to generate a Cp*Rh(π-allyl) complex is viable under mild reaction conditions. The role of external oxidants in the catalytic cycle is elucidated. Quantum mechanical calculations, stoichiometric reactions, and cyclic voltammetry experiments concomitantly support an oxidatively induced reductive elimination process of the allyl fragment with an acetate ligand proceeding through a Rh(IV) intermediate. Stoichiometric oxidation and bulk electrolysis of the proposed π-allyl intermediate are also reported to support these analyses. Lastly, evidence supporting the amination of an allylic acetate intermediate is presented. We show that Cp*Rh(III)²⁺ behaves as a Lewis acid catalyst to complete the allylic amination reaction.

Full text of DOI:10.1021/jacs.0c01069

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Article
The Mechanism of Rhodium Catalyzed Allylic C–H Amination
Robert J Harris, Jiyong Park, Taylor A. F. Nelson, Nafees Iqbal, Daniel C.
Salgueiro, John Bacsa, Cora E. MacBeth, Mu-Hyun Baik, and Simon B. Blakey
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Mar 2020
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The Mechanism of Rhodium Catalyzed Allylic C–H Amination
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,
‡ §
,
‡ §
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Robert J. Harris, Jiyong Park, Taylor A. F. Nelson, Nafees Iqbal, Daniel C. Salgueiro, John
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Bacsa, Cora E. MacBeth, Mu-Hyun Baik* and Simon B. Blakey*
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Department of Chemistry, Emory University, Atlanta, GA, 30322, U.S.A.
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‡
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon
34141, Republic of Korea
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Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141,
Republic of Korea
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ABSTRACT
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Herein the mechanism of catalytic allylic C–H amination reactions promoted by Cp*Rh complexes is
reported. Reaction kinetics experiments, stoichiometric studies, and DFT calculations demonstrate that
the allylic C–H activation to generate a Cp*Rh(π-allyl) complex is viable under mild reaction conditions.
The role of external oxidants in the catalytic cycle is elucidated. Quantum mechanical calculations,
stoichiometric reactions, and cyclic voltammetry experiments concomitantly support an oxidatively
induced reductive elimination process of the allyl fragment with an acetate ligand proceeding through a
Rh(IV) intermediate. Stoichiometric oxidation and bulk electrolysis of the proposed π-allyl intermediate
are also reported to support these analyses. Lastly, evidence supporting the amination of an allylic acetate
intermediate is presented. We show that Cp*Rh(III)2+ behaves as a Lewis acid catalyst to complete the
allylic amination reaction.
Keywords: Density Functional Theory, C–H amination, Rhodium, Allylic functionalization,
Mechanism
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INTRODUCTION
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Transition-metal-mediated direct activation of C(sp3)–H bonds to install C–X (X = C, N, and O)
functionalities has become an indispensable method in modern synthetic strategy. Precisely controlling
the regio- and diastereoselectivities in these reactions is a key challenge that has been achieved using
directing groups1 or by taking advantage of the inherent reactivities of the C–H bonds.2 Direct and efficient
synthetic protocols that afford desired selectivities continue to be actively sought after. For many years,
palladium catalyzed C–H allylic functionalization has been studied with simple olefins.3 In 2004, White
and co-workers reported the catalytic allylic C–H acetoxylation of terminal olefins in complex settings
catalyzed by palladium.4 In a series of reports that followed, Pd(π-allyl) intermediates were intercepted
with a variety of stabilized carbon, nitrogen, and oxygen nucleophiles (Scheme 1A).5 Cossy and co-
workers subsequently reported the use of a Cp*Rh precatalyst to catalyze the intramolecular cyclization
of aminoalkenes by allylic C–H functionalization, as illustrated in Scheme 1B.6 More recently our group
disclosed the intermolecular allylic C–H amination of internal olefins with primary and secondary amines
bearing only one electron withdrawing group (Scheme 1C).7 This foundational study paved the way for
additional rhodium and iridium catalyzed allylic C–H functionalization protocols, including etherification,
arylation, and amidation reactions.8
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Scheme 1. Transition metal catalyzed allylic C–H amination
The development of catalytic methods for C(sp3)–H functionalization has exceeded our
mechanistic understanding of these transformations. In the case of rhodium catalyzed allylic C–H
functionalization, Cossy suggested that a plausible mechanism would involve an allylic C–H insertion to
generate a Rh(π–allyl) complex followed by N–metallation and reductive elimination from a Rh(III)
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intermediate to generate the allylic amine and a Rh(I) species that would be reoxidized to Rh(III) to
complete the catalytic cycle (see supplemental Scheme S1). The proposed mechanism is in accord with
reports on the rhodium catalyzed allylic substitution with phosphine and phosphite supporting ligands.9
Similar catalytic reactions involving Rh(III/I) have also been proposed for C(sp2)–H bond activations that
utilize cyclopentadienyl supporting ligands.10 However, we note that higher oxidation states of rhodium
have also been proposed in Cp*Rh catalyzed C(sp2)–H activation.11
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Providing additional complexity to the mechanistic picture, the synthesis and reactivity of several
group IX π–allyl complexes similar to those invoked by Cossy and our group in the Cp*Rh catalyzed
allylic C–H amination have been reported. Bergman isolated and characterized the Cp*Rh(π–allyl)
complex I (Figure 1A)12 and Stryker subsequently determined the structures of the exo and endo isomers
of IrCp*(π–allyl) complex II (Figure 1B).13 In each case, the exo–isomers of the π–allyl complexes react
with hard nucleophiles at the central carbon to generate metallocyclobutane products. Additionally,
Tanaka reported the isolation and characterization of the CpERh(III)(π–allyl) complex III bearing a
pendent tosyl amine nucleophile (Figure 1C) (CpE = 1,3-diethylester-2,4,5-trimethylcyclopentadiene, see
Figure 1C).14 When complex III was treated with AgSbF6 to abstract the chloride and generate a vacant
coordination site for N–metallation, the expected cyclization product was not observed. When complex
III was treated with both AgSbF6 and Cu(OAc)2, the expected amination product was observed in 51%
yield. The authors did not postulate specific roles of Cu(OAc)2 in this transformation. However, Jones and
coworkers have reported the use of a copper salt as an oxidant to induce reductive elimination of a C(sp2)–
N(sp2) bond from a Cp*Rh(III) complex.11b In 2017, Chang and Baik reported a detailed mechanistic
study of a C–H arylation reaction catalyzed by Cp*Ir, in which a strong oxidant facilitates the C–H
arylation by oxidizing the metalated complex via an oxidatively induced reductive elimination (Figure
1D).15 The reactivities of III are largely inconsistent with the previously proposed Rh(III/I) mechanism
for Cp*Rh catalyzed allylic C–H amination.
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Figure 1. Previously reported reactions of group IX π–allyl complexes
Herein, we describe a detailed mechanistic study of allylic C–H aminations via a Cp*Rh(III)(π-
allyl) intermediate, combining experimental observations including kinetic analysis, isolation and
subsequent characterizations of putative intermediates and their reactivities. These experimental findings
were corroborated with cyclic voltammetry measurements and quantum mechanical calculations, to
elucidate the mechanistic details of the Rh-catalyzed C(sp3)–H activations that afford allylic amination
products.
RESULTS AND DISCUSSION
Kinetic Analysis
To obtain experimental data to facilitate a deeper understanding of the mechanism for the rhodium
catalyzed allylic C–H amination, we targeted 1,3-diphenylpropene 1 as a simple model substrate, in which
complications caused by regioselectivity are not present (Scheme 2). We note that our initial attempt to
monitor the reaction progress using p-toluenesulfonamide as a nucleophile was complicated due to its
insolubility, leading us to choose benzyl carbamate as the nucleophile.
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Scheme 2. Reaction scheme for allylic C–H amination for kinetic analysis
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Analysis of initial rates of reactions of diphenylpropene 1 with carbamate 2 catalyzed by
[Cp*RhCl2]2/AgBF4 showed that allylic amine production was linearly dependent on the concentrations
of the Rh, alkene, and 1/carbamate with slopes of k1 = 2.4 ± 0.4 × 10–4 s–1, k2 = 1.5 ± 0.1 × 10–5 s–1 and k3
= 1.4 ± 0.2 × 10–6 M2 s–1 respectively (Figures S1-S6). These data indicate the reaction is first-order in
rhodium and alkene concentrations. Also, an inverse rate constant for the carbamate concentration was
observed, that is consistent with the carbamate nucleophile binding to the rhodium catalyst in an off–cycle
equilibrium (Scheme S2).
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Kinetic isotope experiments provide insight into the rate determining step (RDS). A 1:1 mixture
of 1 and 1–d2 (0.2 M) in DCE was treated with carbamate 2 (0.49 M), [Cp*RhCl2]2 ([Rh] = 12 mM),
AgBF4 (26 mM), and AgOAc (2.1 equiv). The reaction was stopped after 2 hours (~10% conversion), and
allylic amine 3 was isolated in 5% yield (Figure 2). Analysis of the 1H NMR of 3 established deuterium
incorporation in 28 % of the product, with the label observed equally at both C1 and C3. This observation
is consistent with a primary KIE of kH/kD = 2.6, and the intermediacy of a symmetrical -allyl complex.
In our original disclosure of the rhodium catalyzed allylic C–H amination, we showed that C–H cleavage
was irreversible.7 Taken together, these observations along with the first order dependence of rate on 1,
establish that C–H cleavage is rate-determining.16
H
H
[Cp*RhCl2]2 ([Rh] = 12 mM)
AgBF4 (26 mM)
H
H
D
NHCbz
Ph
NHCbz
Ph
H
D
NHCbz
Ph
H
Ph
Ph
Ph
AgOAc (2.1 equiv)
CbzNH2
(0.49 M)
1
+
+
+
Ph
Ph
Ph
DCE (0.2 M), 60 °C, 2 h
D
D
3c
3b
3a
Ph
1-d2
3a:3b:3c = 5.2:1:1
at 10% conversion
Figure 2. Amination of a 1:1 mixture of 1 and 1–d2 with benzyl carbamate catalyzed by
[Cp*RhCl2]2
Synthesis, Characterization, and Reactivity of Rhodium π-allyl Complexes
The kinetic data presented above are consistent with the notion that C–H activation is rate limiting.
Consequently, overall reaction kinetics cannot be used to probe the mechanism of C–N bond formation or
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catalyst regeneration. In order to gain insight into this sequence in the catalytic cycle, we synthesized
plausible intermediates in the catalytic cycle and examined their reactivities. Analogous to Tanaka’s
synthesis of CpERh(π–allyl) complex III, we attempted to synthesize a Rh(π–allyl) complex with a Cp*
supporting ligand. Initial attempts to make a Cp*Rh(π–allyl) complex starting from [Cp*RhCl2]2 in the
presence of AgSbF6 were unsuccessful and led to a complex mixture of products. However, stirring
[Cp*Rh(MeCN)3](SbF6)2 with cesium acetate (1.5 equiv) and 4-phenyl-1-butene (2 equiv) in DCM at
room temperature for 16 h followed by the addition of tetraethylammonium chloride, led to the isolation
of a mixture of Rh(π–allyl) complexes IV and V in 53% yield (9:1 ratio, Figure 3A). By using 1,2–DCE
as a solvent and heating the reaction to 80 °C we were able to isolate complex V exclusively as the
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thermodynamic product in 61% yield (Figure 3B).
A)
Me
Me
Me
Me
[Cp*Rh(MeCN)3](SbF6)2
+
Me
Me
Me
Me
Me
Me
1. CsOAc (1.5 equiv)
DCM, 40 °C, 16 h
Rh
Rh
2. Et4NCl (2 equiv)
DCM, 23 °C, 30 min
Ph
Cl
Cl
Ph
Ph
Me
H
V
IV
(2 equiv)
53%, 9 : 1
B)
Me
[Cp*Rh(MeCN)3](SbF6)2
+
Me
Me
Me
1. CsOAc (1.5 equiv)
1,2-DCE, 80 °C, 16 h
Me
2. Et4NCl (2 equiv)
DCM, 23 °C, 30 min
Rh
Ph
Ph
Cl
Me
H
V
(2 equiv)
V, 61%
C)
OAc
Me
Me
Me
Ph
Me
Me
CbzNH2 (1.1 equiv)
AgSbF6 (2.2 equiv)
AgOAc (1.5 equiv)
4, 31%
Me
+
Rh
Ph
Cl
DCM, 23 °C
80 min
NHCbz
Me
Me
Ph
V
5, 43%
Figure 3. Synthesis and structure of Cp*Rh(π–allyl)Cl complex. A) Synthesis of a mixture of
internal (IV) and terminal (V) RhCp*(π-allyl) complexes. B) Synthesis for selectively forming the
terminal Cp*Rh(π-allyl)Cl complex V. C) Stoichiometric reactivity of complex V in catalytic
reaction conditions. ORTEP diagram of V depicted with ellipsoids shown at the 50% probability
level and hydrogen atoms omitted for clarity
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Complex V was fully characterized by H and C NMR spectroscopy and single crystal X-ray
diffraction. The 1H NMR spectrum of V displayed a characteristic triplet of doublets at δ = 4.55 ppm with
coupling constants JHH = 10.7 Hz and JRhH = 2.0 Hz corresponding to the proton attached to the central
carbon of the π-allyl ligand. Vapor diffusion of pentane into a concentrated ether solution of V at 25 °C
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provided crystals suitable for X-ray analysis (Figure 3B, inset). The allyl ligand of complex V adopts a
near planar geometry with dihedral angles C1–C2–C3–C5 = 173.8° and C4–C1–C2–C3 = 178.6°. The
Rh–C1 and Rh–C3 bond distances are approximately equal with bond lengths of 2.203(2)Å and
2.219(2)Å, respectively, while the Rh–C2 bond length is significantly shorter with a bond length of
2.133(2) Å.
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With complex V in hand, we began to investigate the reactivities of Cp*Rh(π-allyl) complexes
towards nucleophiles. In an initial experiment, complex V was treated with a single equivalent of
carbamate 2 in DCMat 23 °C. Unsurprisingly, even after 48 h, complex V remained unreacted. However,
when complex V was treated with benzylcarbamate (2, 1.1 equiv) in the presence of AgSbF6 (2.2 equiv,
as a halide abstractor) and AgOAc (1.5 equiv) in DCM at 23 °C to mimic the reaction conditions that
yielded aminated products, both allylic acetate 4 and the expected allylic amine 5 were generated in 31%
and 43% yield respectively (Figure 3C). This result suggests that while V is likely not a catalytically
relevant species, the cationic complex generated from abstracting a chloride from V could be. Also, this
result indicated that silver additives are essential for the activation of the Rh(π-allyl) complex V. Lastly,
the significant quantities of allylic acetate 4 observed in the reaction lead us to consider the possibility
that the amination reaction might proceed through an allylic acetate intermediate.
Figure 4. Synthesis of Cp*Rh(III)(π-allyl) complexes bearing A) acetonitrile, B) tosyl amine, and
C) acetate ligands
To further probe these possibilities, we synthesized the cationic [Cp*Rh(π–allyl)(MeCN)](SbF6)
complex VI (Figure 4A), the Cp*Rh(π–allyl)(NHTs) complex VII (Figure 4B) and the Cp*Rh(π–
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allyl)(OAc) complex VIII (Figure 4C). Complexes VI, VII and VIII were characterized by H and C
NMR spectroscopy and single crystal X-ray diffraction (see supplemental for full XRD data).
Dichloroethane solutions of complex VII and complex VIII were heated to 60 °C and both compounds
were stable over a 6-hour period. The isolation and stability of complexes VII and VIII unambiguously
rules out the possibility that allylic C–N or C–O bond formation by reductive elimination from these
Rh(III) species is possible under the catalytic conditions. Furthermore, the fact that no allylic amine or
allylic acetate product was observed during the synthesis of complexes suggests that outer-sphere
nucleophilic attack of these nucleophiles on cationic Rh(III)(π–allyl) complexes is not a plausible
explanation for product formation in the catalytic reaction.
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This conclusion is further supported by the observation that no allylic amine was observed, even
after cationic complex VI was reacted with benzylcarbamate at 40°C for 14 h. Instead, Cp*Rh(π–allyl)Cl
complex V was recovered in 92% yield after a chloride quench (Figure 5A). To investigate the potential
for an oxidatively induced reductive elimination mechanism to be operating, we exposed both Cp*Rh(π–
allyl)(NHTs) complex VII and Cp*Rh(π–allyl)(OAc) complex VIII to two equivalents AgSbF6. In the
reaction of Cp*Rh(π–allyl)(NHTs) complex VII, two equivalents of benzenesulfonamide were included
allowing us to probe both an oxidatively induced inner-sphere reductive elimination, and an oxidatively
induced outer-sphere nucleophilic attack. In this reaction, only 10% combined yield of allylic amine
products (6 and 7) was observed. No rhodium(π-allyl) complexes could be recovered (Figure 5B). In
contrast, when the Cp*Rh(π-allyl)(OAc) complex VIII was oxidized with two equivalents AgSbF6, clean
conversion to the allylic acetate product 4 was observed (Figure 5C). These observations suggest that the
catalytic allylic amination reaction proceeds through an allylic acetate intermediate, obtained by an
oxidatively induced reductive elimination mechanism.
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Figure 5. Reactivity of Cp*Rh(III)(π-allyl) complexes demonstrating the feasibility of oxidatively
induced reductive elimination of an allyl acetate. A) Reaction scheme of benzyl carbamate
reactivity with complex VI.B) Reaction scheme of benzene sulfonamide with complex VII. C)
Reaction scheme of complex VIII with AgSbF6 as an oxidant resulting in clean conversion to
acetate 4. Yields were determined by H NMR analysis of the reaction mixture using 1,4-
dinitrobenzene as an internal standard.
a
1
To complete our experimental investigation, we demonstrated that allylic acetate 4 is readily
converted to allylic amine 5 in the presence of the Lewis acid components present in the catalytic reactions
(Table 1). Both AgSbF6 and AgBF4 were found to be competent Lewis acid catalysts providing product
in 91% and 76% yield, respectively. We also confirmed that [Cp*Rh(MeCN)3](SbF6)2 and (Cp*RhCl2)2
are competent Lewis acid catalysts after halide abstraction, affording 5 in at 73 % and 84 %, respectively.
In the absence of either silver cation or Cp*Rh, the allylic acetate remained unchanged. We note that the
Ag(I) and Cp*Rh(III) catalyzed allylic amination of allylic acetate 8 proceeds readily even at reduced
temperatures (Table 1, entry 6 to 8). Time course studies of Ag(I) and Cp*Rh(III) also provided insight
into the relative rates of catalysis (Figures S11-S12). We noted that at 0 ºC Ag(I) catalysis proceeded to
completion in 2.5 h, while Cp*Rh(III) proceeded to completion in seconds. These data strongly supported
a plausible mechanistic hypothesis toward the completion of the allylic amination catalytic cycle via
Cp*Rh(III) catalyzed allylic substitution which will be discussed further.
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Table 1. Reactivity of allylic acetate and benzyl carbamate in the presence of Ag(I) or Rh(III) as
3
4
a catalyst.
5
6
7
8
9
entry
Time
3 h
R
Temp (ºC)
Catalyst
AgSbF6
Yield
91%a
76%a
73%a
84%a
0%a,d
97%b
47%b
90%b
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1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Ph
60
60
60
60
60
0
3 h
AgBF4
c
3 h
[Cp*RhCl2]2/AgSbF6
3 h
[Cp*Rh(MeCN)3](SbF6)2
none
3 h
5 min
5 min
2.5 h
[Cp*Rh(MeCN)3](SbF6)2
AgSbF6
Ph
0
Ph
0
AgSbF6
aReactions were performed in 1,2-DCE and yield determined by crude reaction analysis by proton 1H NMR
against 1,4-dinitrobenzene. bReactions were performed in DCM and yield determined by GC analysis against
nonane as internal standard (see supplemental for full time course) c[Cp*RhCl2]2 (25 mM) and AgSbF6 (40
mM) were stirred in DCM with benzyl carbamate (2) at 60 °C for 30 min before allylic acetate 4 was added
to be sure that there was no Ag+ in solution. dAllylic amine was not observed by 1H NMR.
Computational Investigation of the Key Steps in the Catalytic Cycle
Density functional theory (DFT) calculations were carried out to construct a catalytic mechanism
incorporating the experimental observations mentioned above. Using 1,3-diphenylpropene as the
substrate, we compared the activation barriers of the reductive elimination from the three relevant
oxidation states Rh(III), Rh(IV) and Rh(V), as illustrated in Figure 6. The reductive elimination initiated
from the Rh(III) intermediate to give Rh(I) is not viable, as the computed activation barrier of 38.4
kcal/mol corresponds to an Eyring rate of 4.8×1010/s or equivalently 0.7×10-8 mol/day at 313 K (Figure
6a). As expected, the oxidation of the metal center to Rh(IV) lowers the activation barrier notably by more
than 21 kcal/mol to 17.6 kcal/mol (Figure 6b), which suggests an acceleration of the reaction by more than
1010 fold compared to the Rh(III) intermediate. Our calculations suggest that a second oxidation to access
the Rh(V) center does not enhance the reaction rate further, as the calculated barrier increases to 19.5
kcal/mol (Figure 6c).
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Figure 6. Calculated energy profiles for reductive elimination from the a) Rh(III)–, b) Rh(IV)–,
and c) Rh(V)–π-allyl intermediates, leading to the Rh(I), Rh(II), and Rh(III) products, respectively.
The detailed molecular structure of each TS is shown as well. The unit of energy is kcal/mol and
of bond length is Å.
A closer inspection of the transition structures reveals that the two oxygen atoms of the acetate
introduce a slight variation in the transition states. During the reductive elimination from the Rh(III)–
center, the C–O bond is formed by the acetate–oxygen that is directly bound to the metal, as illustrated in
Figure 6a. The Rh–O bond elongates from 2.121 to 2.211 Å as the transition state IX-TS is traversed with
the C–O distance being 1.839 Å. This bond forming event is best conceptualized by considering that the
allylic fragment formally donates two electrons to the Rh-center to accomplish the reductive part of the
reductive elimination step. Consequently, it becomes a positively polarized electrophile that can engage
the acetate and form the C–O bond. Of course, these two processes are concerted in reality, but it is
instructive to visualize them separately. When the metal is oxidized to Rh(IV) or Rh(V), it is the distal
oxygen of the acetate that attacks the allylic carbon and the Rh–O bond is mostly maintained with the Rh–
O bond lengths being 2.110 (XI-TS) and 2.100 Å (XIII-TS), respectively, as illustrated in Figures 6b and
6c. On the contrary, reductive coupling of the oxygen atom bonded to the metal center is energetically
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less favorable, for the oxidized metal centers (Rh(IV) and Rh(V)). When traversing the Rh(IV)-Rh(II)
cycle, the activation barrier is elevated to 24.9 kcal/mol (XI-TS’ in Figure S15) and for the Rh(V)-Rh(III)
cycle, the corresponding barrier is 22.6 kcal/mol (XIII-TS’ in Figure S15). Thus, whereas the Rh(III)
center carries out a classical reductive elimination, the other higher valent metal centers prefer to
reductively couple the acetate with the allyl functionality without eliminating the acetate. This subtle
change in mechanism is easy to understand considering that the Rh–O bond becomes much stronger in
Rh(IV) and Rh(V) compared to Rh(III). As the acetate acts as a nucleophile in this step, the higher
oxidation state at the metal decreases its nucleophilicity and results in a higher barrier in the Rh(V)-
complex. Thus, Rh(IV) constitutes an ideal compromise between the two governing forces, namely the
ability of the metal center to oxidize the allyl fragment and the nucleophilicity of the acetate.
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Figure 7. Cyclic voltammogram of VIII recorded at room temperature in DCM (0.001 M in 0.10 M
n-Bu4NPF6). A) Full scan width cyclic voltammagram from 1.7 V to -2.2 V recorded at 500 mV/s.
B) Full scan width cyclic voltammagram from 1.7 to -2.2 V recorded at 1500 mV/s. C)
Voltammograms for proposed Rh(IV/V) couple recorded at 500 mV/s, 800 mv/s, 1000 mV/s, and
1500 mV/s) D) Voltammograms for proposed Rh(III/IV) couple recorded at 100 mV/s, 500 mV/s,
1000 mV/s, 1500 mV/s, and 2000 mV/s. See supplemental figure S13 for additional
electrochemical details.
To test the proposed catalytic mechanism, cyclic voltammetry experiments were carried out to
investigate the redox profile of VIII. Complex VIII showed two irreversible oxidation events, suggesting
that both Rh(IV) and Rh(V) are thermodynamically accessible on an electrochemical time scale (Figure
7A and 7B). As is expected for an electrochemical step that is coupled with a chemical event, the peak
positions of both steps are scan rate dependent (Figures 7C and 7D). The first oxidation occurs at E1 =
~0.42 V versus Fc/Fc+ which we assign to the Rh(III)/(IV) couple, and the second event occurs at E2 =
~0.85 V which we attributed to the Rh(IV)/(V) couple. These data are consistent with an electrochemical
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process coupled to a chemical event, and support our hypothesis that reductive elimination takes place
from the Rh(IV) intermediate. Additionally, we note that the redox potential of Ag+ in DCM is ~0.65 V
(AgTFA),17 rendering it unlikely that the Rh(V) complex (E2 = ~0.85 V) can be accessed using Ag+ as an
oxidant. Taken together, these data support a catalytic cycle that consists of a Rh(III) → Rh(IV) → Rh(II)
→ Rh(III) redox sequence. To further support these conclusions, we sought to investigate stoichiometric
oxidation of VIII using an outer sphere oxidant closely matched to the Rh(III/IV) oxidation potential
determined by cyclic voltammetry (i.e > ~0.42V). To this end, the stoichiometric oxidation of VIII
utilizing 1,1’-diacetylferrocenium hexafluorophosphate (E1/2 = +0.49V vs Fc/Fc+)17b resulted in a 25%
yield of the expected allylic acetate (Figure 8).
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Figure 8. Stoichiometric oxidation of complex VIII with 1,1’-diacetylferrocenium hexafluorophosphate.
Scheme 3 summarizes the proposed mechanism of the Rh catalyzed allylic acetoxylation and
Figure 9 shows the corresponding reaction energy profile. The catalytic cycle begins with the coordination
of the acetate and the olefin substrates 1 to the Cp*Rh fragment to form the initial reactant complex XV,
which undergoes a concerted metalation deprotonation (CMD) traversing the transition XV-TS to activate
the allylic C–H bond. The computed activation energy for this step is 26.7 kcal/mol, which is in good
agreement with the experimental observation that a mildly elevated temperature is required to prepare the
acetate intermediate VIII (vide supra). Ligand exchange affords the Cp*Rh(III)(π-allyl)OAc complex XI
from XVI. As discussed above, the reductive elimination from this intermediate is associated with a very
high barrier (Figure 6a). To push the reaction forward, one electron oxidation of Rh(III) to Rh(IV) is
needed which enables the reductive elimination via XI-TS with a computed barrier of 17.6 kcal/mol.
Intermediate XII can easily undergo a one-electron oxidation to form the Rh(III) intermediate XVII,
which releases product 8 via ligand exchange steps.
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Scheme 3. Proposed catalytic mechanism of the rhodium catalyzed allylic acetoxylation going
through Rh(IV)→Rh(II)
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We also constructed the energy profile of inner-sphere amination initiated from Cp*Rh(IV)(π–
allyl)OAc complex XI, that is also shown in Figure 9. The coordination of the rhodium center by a
carbamate (XIX) is followed by the deprotonation of the amine by the pendant acetate, whose activation
barrier is 20.6 kcal/mol (XIX-TS). Starting from the activated amine (XX), a reductive elimination step
engages an allylic carbon and the pendant amine (XX-TS), that demands a computed activation energy
barrier of 25.0 kcal/mol. The barrier for the amination is 7.4 kcal/mol higher in energy than that of the
reductive elimination step affording the allylic acetate intermediate (XI-TS). The energy profile of the
inner-sphere amination clearly shows that the kinetics of amination is much slower in progression than
that of the acetoxylation. The computational finding is in good agreement with our experimental
observation that the amination initiated from Cp*Rh(III)(π-allyl)TsNH (Figure 5b) yields lower
conversion (10%) than that of the acetoxylation (Figure 5c), even though the temperature of amination
reaction was higher. With the experimental and computational findings, we concluded there is a secondary
catalytic cycle that converts initially formed allylic acetate 8 to the aminated product.
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Figure 9. Energy profile for Rh-catalyzed allylic acetoxylation going through Rh (IV→II)
Formation of Allylic Amines
With the detailed mechanism of the intermediate allylic acetate formation in hand, we turned our
attention to the role of the silver and rhodium salts in the conversion of the allylic acetate to the allylic
amine product. Based on the experimental findings that the amination is viable in the presence of Lewis
acid components (Table 1), we hypothesized both Rh(III) and Ag(I) may serve as Lewis acid–catalysts
promoting the nucleophilic substitution. In the following, we delineate the mechanistic details of the two
possible mechanistic hypotheses for the formation of allylic amine product from the allylic acetate
intermediate, by means of DFT calculations. Inspired by the related AgSbF6 and [Cp*Rh(MeCN)3](SbF6)2
catalyzed amination of allylic acetate,18 we compiled a plausible mechanistic pathway for the amination
reaction which involves an initial Ag+ or Cp* Rh(III)2+ addition to allylic acetate to prepare Lewis acid
coordinated allylic acetate complexes, as illustrated in Scheme 4 (scheme 4 shows the postulated cycle for
Rh(III)). The corresponding energy profiles for the allylic amination of allylic acetate 8 are depicted in
Figure 10. The catalytic cycle is initiated by the addition of the Lewis acid to the allylic acetate 8 yielding
9 or 10. Out of the three possible scenarios of the nucleophilic substitutions (SN1, SN2, and SN2’), our DFT
calculations suggested that the SN1 mechanism is the most plausible route for the nucleophilic substitution.
The dissociation of MOAc (M = Ag or Rh) yield allylic cation intermediates 9a and 10a, associated with
an activation barrier of 14.4 kcal/mol (9-TS) and 14.8 kcal/mol (10-TS). The addition of amine
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nucleophiles (9a-TS)/(10a-TS) requires 16.7 kcal/mol of activation energy for the silver and 15.6 kcal/mol
for the rhodium, which is predicted to be the most difficult step to activate of the amination reaction yet
is viable under the reaction conditions tested. The difference in the activation barriers is in line with the
observation that the amination is faster with Cp*Rh(III) than with Ag(I) (Figure S11-S12). To push the
reaction forward, the aminated intermediates 9b/10b undergo concerted deprotonations via traversing the
transition structure 9b-TS/10b-TS to produce the allylic amine product bound to the silver cation 9c and
to the Cp*Rh(III) 10c. These data as well as our experimental results (Table 1) support that both silver
cation (Ag+) and Cp*Rh(III) acts as Lewis acids mediating the allylic substitution from allylic acetate 8
resulting in allylic amine 11. A full reaction time course study (Figure S14) was conducted and is
consistent with our proposed mechanism. A small, but measurable, steady state concentration of the allylic
acetate (8) is observed over the course of the reaction. The small concentration of acetate 8 reflects the
low calculated barrier for the substitution reaction (14.8 kcal/mol) compared to the turnover limiting C–
H functionalization step (26.7 kcal/mol).
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Scheme 4. Proposed mechanism for Lewis Acid Catalyzed Allylic Amination Reaction from
Allylic Acetate
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Figure 10. Energy profile for AgSbF6 and [Cp*Rh(MeCN)3](SbF6)2 catalyzed allylic amination
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from allylic acetate. The Gibbs free energies were computed at 298.15 K.
CONCLUSIONS
The computational and experimental data provided a detailed picture of the rhodium-catalyzed
C(sp3)–H allylic amination. Overall, the rate-determining step of the entire catalytic cycles examined
computationally was found to be the C–H activation of allylic substrate with a DFT-computed barrier of
26.8 kcal/mol. This is consistent with the experimental kinetic observations that also support C–H
activation as the rate determining step in this transformation. Calculations revealed that the Rh catalyst
facilitates the formation of the allylic acetate using the silver salt as an oxidizing agent via an oxidatively
induced reductive elimination reaction15 where the Rh(III) center of the key intermediate is first oxidized
to Rh(IV). Interestingly, the two-electron oxidation to access the Rh(V) analogue is not found to accelerate
the reaction and we report strong experimental evidence that Rh(IV) is indeed the catalytically competent
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species. Further experimental studies as well as DFT calculations suggested that the amination of the
allylic acetate intermediate proceeds by an SN1 ligand exchange mechanism mediated by Cp*Rh(III)
acting as a Lewis acid catalyst. We note that this study provides insights that are likely applicable to the
related rhodium catalyzed allylic etherification and heteroarylation reactions that were recently
disclosed,8a, 8i but likely do not explain the allylic arylation reaction utilizing aryl boronic acids,8e or the
allylic amidation processes using dioxazolone reagents.8b, 8d, 8f Further studies to provide a unified
mechanistic picture of this emergent field are required. These findings are of particular importance in the
future design of regio– and enantioselective reactions as they clearly demonstrate that the critical C–N
bond forming reaction does not occur via reductive elimination from the Rh-catalyst. Instead, processes
that intercept the allylic acetate intermediate will need to be developed.
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ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
Experimental procedures, computational details, x-ray crystal structure reports, and NMR spectra
Author Information
Corresponding Author
*E-mail: mbaik2805@kaist.ac.kr
*E-mail: sblakey@emory.edu
ORCID
Mu-Hyun Baik: 0000-0002-8832-8187
Simon B. Blakey: 0000-0002-4100-8610
Robert J. Harris: 0000-0003-0640-3487
Jiyong Park: 0000-0002-3225-4510
Taylor A. F. Nelson 0000-0002-4685-1455
Daniel C. Salgueiro 0000-0002-6162-3493
Cora E. MacBeth: 0000-0003-3877-2236
John Bacsa: 0000-0001-5681-4458
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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The research was supported in part by the Institute for Basic Science (IBS-R010-A1) in Korea, the
National Science Foundation (NSF) under the CCI Center for Selective C–H Functionalization (CHE-
1700982), and the American Chemical Society Petroleum Research Fund (ACS-PRF-59563-ND1).
NMR studies for this research were performed on instrumentation funded by the NSF (CHE-1531620).
The X-ray analysis was done by the Emory X-ray Crystallography Facility using the Rigaku Synergy-S
diffractometer, supported by the NSF (CHE-1626172). We gratefully acknowledge Dan Liu
(Department of Chemistry, Emory University) for electrochemical assistance.
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