Rh(III) and Ir(III)Cp? Complexes Provide Complementary Regioselectivity Profiles in Intermolecular Allylic C-H Amidation Reactions

Article abstract of DOI:10.1021/acscatal.9b01338

An efficient regioselective allylic C-H amidation of mono-, di-, and trisubstituted olefins has been developed. Specifically, the combination of dioxazolone reagents with RhCp? and IrCp? catalysts is reported to promote reactions with complementary regios

Full text of DOI:10.1021/acscatal.9b01338

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Letter
Rh(III) and Ir(III)Cp* Complexes Provide Complementary Regioselectivity
Profiles in Intermolecular Allylic C-H Amidation Reactions
Jacob Burman, Robert Harris, Caitlin Farr, John Bacsa, and Simon B. Blakey
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01338 • Publication Date (Web): 08 May 2019
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Rh(III) and Ir(III)Cp* Complexes Provide Complementary
Regioselectivity Profiles in Intermolecular Allylic C-H Amidation
Reactions
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Jacob S. Burman, Robert J. Harris, Caitlin M. B. Farr, John Bacsa, and Simon B. Blakey*
Department of Chemistry, Emory University, Atlanta GA, 30322, United States.
ABSTRACT: An efficient regioselective allylic C-H amidation of mono-, di-, and trisubstituted olefins has been developed.
Specifically, the combination of dioxazolone reagents with RhCp* and IrCp* catalysts is reported to promote reactions with
complimentary regioselectivites to those previously observed in Pd- catalyzed and Ag promoted Rh-catalyzed reactions. We report
that catalyst matching with substrate class is essential for selective reactions. RhCp* complexes are required for high conversion and
selectivities with ß-alkylstyrene substrates, and IrCp* complexes are necessary in the context of unactivated terminal olefins.
KEYWORDS: C-H functionalization, allylic amidation, dioxazolone, π-allyl complex, RhCp*, IrCp*, terminal olefins,
disubstituted olefins
Allylic substitution reactions are established as versatile tools,
strategically employed as key steps in the total synthesis of
many biologically relevant molecules.1 Underpinning their
broad application is the development over many years of a
selection of catalysts based on different transition metals, with
different ligand sets, that allow exquisite mechanism-based
control of regioselectivity and stereoselectivity.2 Critically, in
palladium catalyzed reactions, it has been established that an
outer-sphere attack of a nucleophile on a π-allyl complex favors
formation of linear products, while inner-sphere reductive
elimination mechanisms favor the branched isomers.3
these systems, demonstrating that electron-rich aromatic
compounds,11a and arylboroxines11b can be utilized as
nucleophiles for allylic C-C bond formation. Although the
mechanistic underpinning of these Rh-catalyzed oxidative C-H
functionalization processes using stochiometric silver salts as
oxidants have not yet been experimentally elucidated, Cossy
and co-workers propose a Rh(III/I) catalytic cycle.8
Scheme 1. Intermolecular Allylic C-H Functionalization of
Olefins
C-H functionalization presents an attractive alternative to
allylic substitution, in which the requisite π-allyl complexes can
be accessed directly from their parent olefins, without the need
for preinstallation of an allylic leaving group. However, these
technologies remain in their infancy and limitations in substrate
scope, regioselectivity, and stereocontrol hamper their
widespread adoption.
The work of White and co-workers has shown that palladium
complexes are effective for allylic C-H functionalization and a
variety of C-C,4 C-N,5 and C-O6 bond forming reactions have
been demonstrated (Scheme 1A).7 However, these palladium-
catalyzed reactions are limited to terminal olefins and generally
require activated nucleophiles. Moreover, in intermolecular
reactions they predominantly deliver linear products, with a
single notable exception in which a catalyst system was
developed to provide branched selectivity for allylic
acetoxylation reactions.6c
Recently, building on Cossy’s report of an intramolecular
allylic amination reaction,8 we established that RhCp*
complexes are suitable catalysts for intermolecular C-H
functionalization of di- and trisubstituted olefins, and
demonstrated a significantly expanded nitrogen9 and oxygen10
nucleophile scope (Scheme 1B). Subsequent studies by Glorius
and coworkers have further expanded the synthetic utility of
We hypothesized that dioxazolones, established as oxidative
amidating reagents by Chang and coworkers in directed sp2 C-H
functionalization processes,12 would operate through
a
Rh(III/V) catalytic cycle inducing an inner-sphere reductive
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elimination of a metal-nitrenoid species and potentially provide
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step, thus impacting both the efficiency and regioselectivity of
the reaction. Increasing the loading of AgSbF6 to 30 mol %
resulted in an improved yield and regioselectivity (entry 5, 84%,
16:1) but, further addition of the additive lead to a significant
loss in yield (entry 6, 27%). Control experiments in which either
the RhCp* precatalyst or the CsOAc were left out of the
reaction did not produce amide product supporting the
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complimentary regioselectivity in allylic C-H functionalization
reactions.13 Such an outcome would significantly enhance both
the strategic utility and our understanding of RhCp*-catalyzed
allylic C-H functionalization. During the preparation of this
manuscript, consistent with this hypothesis, Rovis and Glorius
demonstrated that IrCp* complexes promote branch selective
allylic amidation reactions of unactivated terminal olefins.14 In
this manuscript, we report that RhCp* and IrCp* complexes
exhibit different reactivity profiles with different classes of
olefin, and that while IrCp* complexes are required for more
selective reactions of unactivated terminal olefins, RhCp*
complexes are significantly more effective for regioselective
amidation of trans-disubstituted olefins (Scheme 1C).
intermediacy of
a Rh-π-allyl intermediate obtained by
carboxylate assisted CMD (entries 7-8). The relative ratios of
CsOAc to RhCp* complex proved critical for efficient reaction,
with excess carboxylate suppressing the generation of amide
products (7%, entry 9). It is likely that the excess acetate
sequesters the rhodium as catalytically inactive RhCp*(OAc)2.
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Table 2. Effects of Dioxazolone Substitution for Branched
Selective Allylic C-H Amidation
Table 1. Reaction Development for Allylic C-H Amidation
of Disubstituted Olefins
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aYields and product ratios (3:4) were determined by H NMR using 1,4-
Yields are of isolated amide products and the regiomeric ratio of amide
products (branched:linear) was obtained by analysis of the 1H NMR spectra
of the crude reaction mixtures.
dinitrobenzene as an internal standard in the crude reaction mixture. b20 mol
c
% of NaSbF6 was used instead of AgSbF6. Isolated yield in parentheses.
d≤5% quantities of conjugated aryl-diene were observed.
Having developed conditions for an efficient benzylic/branch
selective allylic C-H amidation, we sought to establish the
functional-group tolerance for a range of alkyl-, aryl-, and
heterocyclic-substituted dioxazolones using allylbenzene as a
simple model olefin (Table 2). High yields (75-95%) of allylic
amides are observed for substrates with smaller substituents (5-
6, 13-15, 18-19), with selectivities for the branched isomer
ranging from 3:1 to 7:1. Dioxazolones bearing larger
substituents, like t-Bu-dioxazolone 2, were also efficient (7,
69%, 8:1). However, despite providing the highest
regioselectivities (12:1 – 16:1), aryl substituents on the
dioxazolone resulted in generally lower yields (8-10, 20-36%).
We speculate that resultant aryl-substituted amide products
engage in iterative directed sp2 C-H amidations and prevent
further allylic amidations.15 Amidation with dioxazolones
derived from cyclic ethers, sulfones, and ketones produced
excellent yields (11-12, 14, 86-98%) with good
regioselectivities (5:1 – 14:1). Boc-protected azetidine and
pipiridine were compatible dioxazolones under the reaction
conditions and produced the corresponding amides with high
yields and regioselectivities (15, 78%, 7:1; 16, 79%, 10:1). A
Based on our goal to broadly establish reaction conditions for
the regioselective functionalization of terminal, di- and
trisubstituted olefins, we initiated our study by examining the
amidation of disubstituted olefin 1 (Table 1). t-Bu-Dioxazolone
2
was chosen as the amidating reagent along with
[RhCp*(MeCN)3](SbF6)2 as the precatalyst to allow for
selective introduction of additives. CsOAc was used as a
soluble carboxylate base to promote concerted metalation-
deprotonation (CMD) of the allylic proton. Reacting olefin 1
with 2.0 equivalents of dioxazolone 2 at 40 °C for 24 hours
successfully afforded allylic amides 3/4 with a preference for
benzylic amide 3 (Table 1, entry 1, 29%, 6:1). A short survey
of additives quickly identified that AgSbF6 promoted higher
yields and selectivity for the benzylic amide product (entry 2,
78%, 13:1). Using NaSbF6 instead of the silver-salt resulted in
lower yield and selectivity similar to the additive-free
conditions (entry 3, 25%, 7:1). At this stage the exact role of the
silver salt remains unknown, although it is plausible that it
activates the dioxazolone for oxidative addition to the Rh(III)
species, and remains coordinated during the C-N bond forming
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the straight chain terminal olefin 1-hexene proved to be entirely
dioxazolone bearing an -stereocenter gave the corresponding
amide in good yield and regioselectivity but only limited
diastereoselectivity was observed (17, 68%, 7:1, 1.5:1 d.r.).
Dioxazolones bearing electron rich heterocycles were also
demonstrated to be effective reagents (18, 89%, 7:1 and 19,
43%, 5:1). The general trends we observed are that
dioxazolones with either larger -substituents or substituents
that are inductively withdrawing provide the highest
selectivities and yields of branched amide products.
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unselective, even with the sterically demanding t-Bu
dioxazolone reagent (27, [Rh] = 73%, 1:1). In an attempt to
solve this problem, we investigated alternative group IX metal
complexes as catalysts for this substrate class. We were
delighted to find that the use of [IrCp*Cl2]2 as the pre-catalyst
provided excellent regioselectivity and high yield of the
branched product in the amidation of this simple unactivated
olefin substrate (27, [Ir] = 79%, 12:1). 4-Phenylbutene showed
a similar reactive profile with the Ir-catalyzed reaction
affording higher yield and regioselectivity than the
Rh-catalyzed process (28, [Rh] = 22%, 1.5:1; [Ir] = 73%,
>20:1). Amidation of 4-methoxy-4-phenylbutene further
highlighted the difference in reactivity between the Rh and Ir
catalysts. In this case the RhCp* complex was completely
ineffective, but the IrCp* catalyst delivered the product in good
yield and regioselectivity, and with useful levels of
diastereoselectivity (29, 58%, 8:1 r.r., 5:1 d.r.).
Table 3. Effects of the Olefin Substituent on the Branched
Selective Allylic C-H Amidation of Terminal Olefins.
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Table 4. Comparison of RhCp* vs. IrCp* for the Allylic
Amidation of Disubstituted Olefins.
Yields are of isolated amide products and the regiomeric ratio of amide
products (Branched:Linear) was obtained by analysis of the 1H NMR
spectra of the crude reaction mixtures. aReaction was run at 60 °C. b40 mol
% AgSbF6 was used.
To understand the impact of olefin substitution on the reaction
outcome, we initially investigated a series of allylbenzene
derivatives using t-butyl dioxazolone 2 as the amidation reagent
(Table 3). Both electron-rich and electron deficient substrates
were amidated with excellent regioselectivity (21-23, 10:1 –
>20:1). The reactions with electron-rich substrates tended to
proceed in higher yields. Allylic amidation of the eugenol-
derivative proceeded smoothly with high regioselectivity and
retention of the aryl-triflate moiety (24, 48%, 12:1)
demonstrating compatibility with functional groups that might
engage in competitive oxidative addition reactions during
conventional allylic substitution reactions. Having established
the broad applicability of the reaction conditions in the context
of allylbenzene and its derivatives, we investigated the
extension of this reaction to unactivated terminal olefins. In an
initial reaction, the branched substrate 4-methylpentene, was
amidated with the sterically demanding t-Bu-dioxazolone 2
providing product with respectable yield and regioselectivity
(25, 50%, 7:1). However, when Me-dioxazolone 20 was used,
although the reaction yield increased, the regioselectivity
dropped significantly (26, 89%, 2:1). Furthermore, amidation of
Yields are of isolated amide products and the regiomeric ratio of amide
1
products (Benzylic:Conjugated) was obtained by analysis of the H NMR
spectra of the crude reaction mixtures. aIsolated as 1:1 mixture of
diastereomers.
To complete our initial investigation of this novel allylic
amidation reaction, we addressed the generality of benzylic-
selective amidation of ß-alkyl styrene substrates (Table 4).
Although our initial reaction optimization had identified
[RhCp*(MeCN)3](SbF6)2 as an excellent catalyst for these
compounds, the improved performance of [IrCp*Cl2]2 in the
amidation of unactivated terminal olefins caused us to evaluate
both catalysts. Surprisingly, the two catalysts showed
significantly different reactivity profiles across a broad range of
these disubstituted olefin substrates. For 3, 30-31, and 33-35
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the RhCp*-catalyzed reactions gave uniformly good yields and
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substituent on the π-allyl component (M-C13; Rh = 2.2008(7)
Å, Ir = 2.1813(17) Å). Although each of the M-C bond distances
is slightly longer in the Rh-π-allyl complex 39 than they are in
the analogous Ir-π-allyl complex 40, there are no structural
features that would explain the significant differences in
regioselectivities that are observed under both catalytic and
stochiometric reaction conditions. Detailed computational and
experimental studies are ongoing in our laboratory to elucidate
the origins of the complimentary reactivity observed in this
study.
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excellent selectivities for the benzylic amidation isomer (62-
86%, 16:1 – 20:1 r.r.). The electron-deficient 32 was amidated
in low yield but retained the same sense of regioselectivity
(19%, 9:1). However, the IrCp* complex gave comparatively
low yields (6-48%) and regioselectivities that were strongly
substrate dependent. Electron deficient and neutral ß-alkyl
styrenes (3, 32-34) were amidated with a preference for the
conjugated regioisomer, but ß-alkyl styrenes with electron
donating substituents favored the benzylic regioisomer (30, 31).
We note that functional group compatibility differences also
emerged during this study. In the case of Boc-protected aniline
31, the RhCp* complex is an effective catalyst (62%, >20:1 r.r.)
but the substrate proved unstable under the IrCp* reaction
conditions, and only a 6% yield was observed. In contrast, the
uracil-derivative was incompatible with the Rh-catalyzed
conditions, but the iridium catalyst was able to promote
formation of amide products (35, 41%, 1.2:1).
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Figure 1. Crystal Structures of Disubstituted RhCp*- and
IrCp*(π-allyl) Complexes. Key bond lengths for Rh complex 38:
M-C11 = 2.2235(7) Å, M-C13 = 2.2008(7) Å, and for Ir complex
39: M-C11 = 2.2095(17) Å, M-C13 = 2.1813(17) Å.
In conclusion, we have developed a novel allylic amidation
reaction that provides complimentary regioselectivities to those
observed in previously disclosed allylic C-H functionalization
reactions proceeding through organometallic -allyl
complexes. The synthesis and reactions of stochiometric Rh-
This divergent reactivity was also seen in the amidation of
trisubstituted olefin 36 with the RhCp* complex proving
ineffective, and [IrCp*Cl2]2 promoting highly regioselective
reactions (>20:1 r.r.). Consistent with previous observations,
Me-dioxazolone 20 afforded greater yields of amide product
(37, 53%) compared to the sterically demanding t-Bu-
dioxazolone 2 (38, 15%) (eq 1). The regioselectivity observed
in these reactions mirrors the branched selectivity observed in
terminal olefins, reflecting the similarities in the structures of
the intermediate π-allyl complexes.
and
Ir--allyl
complexes
provide
products
with
regioselectivities that are consistent with the catalytic reactions,
and support a mechanism in which these -allyl complexes are
oxidized to fleeting M(V)-nitrenoid intermediates, that
subsequently undergo inner-sphere reductive elimination. We
observe that it is necessary to match the catalyst to the substrate
class for efficient and selective reactions, with RhCp* catalysts
proving necessary for -alkylstyrene substrates, and IrCp*
complexes required for unactivated terminal olefins. The
origins of these subtle catalyst-substrate matching requirements
remain the focus of ongoing mechanistic studies.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website.
In an attempt to understand the regioselectivity differences
observed for the RhCp* and IrCp* catalyzed reactions of
disubstituted olefins, we prepared the corresponding discreet π-
allyl complexes 39 and 40 from their respective MCp*-
trisacetonitrile monomers via allylic C-H activation and
subsequent isomerization of 4-phenylbutene (eq 2). When each
of these complexes was subjected to t-Bu-dioxazolone 2 in the
presence of AgSbF6 as a halide scavenger, the corresponding
amides were obtained in good yields and regioselectivities that
mirrored the catalytic reactions (eq 3: Rh = 11:1; Ir = 1:2.3).
These stoichiometric reactions are consistent with the
hypotheses that the catalytic reactions proceed via cationic
M(III)Cp*(π-allyl) complexes.
Experimental procedures, crystallography reports and
analytical data (PDF),
Crystallographic data for 39 and 40 (CIF)
AUTHOR INFORMATION
Corresponding Author
* Simon B. Blakey – sblakey@emory.edu
Funding Sources
This research was supported by the National Science
Foundation (NSF) under the CCI Center for Selective C-H
Functionalization (CHE-1700982). 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
The structures of each complex were obtained by x-ray
crystallography. The two structures are isomorphous and
isostructural. In both cases the M-C bond adjacent to the phenyl
group (M-C11; Rh = 2.2235(7) Å, Ir = 2.2095(17) Å) is slightly
elongated compared to the M-C bond adjacent to the methyl
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(8) Cochet, T.; Bellosta, V.; Roche, D.; Ortholand, J. Y.; Greiner,
Synergy-S diffractometer, supported by the NSF
(CHE-1626172).
A.; Cossy, J. Rhodium(III)-Catalyzed Allylic C-H Bond Amination.
Synthesis of Cyclic Amines from ω-Unsaturated N-Sulfonylamines.
Chem. Commun. 2012, 48, 10745-10747.
(9) Burman, J. S.; Blakey, S. B. Regioselective Intermolecular
Allylic C−H Amination of Disubstituted Olefins via Rhodium/π-Allyl
Intermediates. Angew. Chem. Int. Ed. 2017, 56, 13666-13699.
(10) Nelson, T. A. F.; Blakey, S. B. Intermolecular Allylic C−H
Etherification of Internal Olefins. Angew. Chem. Int. Ed. 2018, 57,
14911-14195.
(11) (a) Lerchen, A.; Knecht, T.; Koy, M.; Ernst, J. B.; Bergander,
K.; Daniliuc, C. G.; Glorius, F. Non-Directed Cross-Dehydrogenative
(Hetero)Arylation of Allylic C(sp3)−H Bonds Enabled by C−H
Activation. Angew. Chem. Int. Ed. 2018, 57, 15248-15252. (b) Knecht,
T.; Pinkert, T.; Dalton, T.; Lerchen, A.; Glorius, F. Cp*RhIII-Catalyzed
Allyl–Aryl Coupling of Olefins and Arylboron Reagents Enabled by
C(sp3)–H Activation. ACS Catal. 2019, 9, 1253-1257.
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Notes
The authors declare no competing financial interest
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Y.; Park, Y.; Hwang, Y.; Kim, Y. B.; Baik, M. H.; Chang, S. Selective
Formation of γ-Lactams via C-H Amidation Enabled by Tailored
Iridium Catalysts. Science 2018, 359, 1016-1021.
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Chem. Int. Ed. [Online Early-View]. DOI: 10.1002/anie.201901733.
Published Online: March 20th, 2019.
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