Hydroamination versus Allylic Amination in Iridium-Catalyzed Reactions of Allylic Acetates with Amines: 1,3-Aminoalcohols via Ester-Directed Regioselectivity

Article abstract of DOI:10.1021/jacs.8b05683

In the presence of a neutral dppf-modified iridium catalyst and Cs₂CO₃, linear allylic acetates react with primary amines to form products of hydroamination with complete 1,3-regioselectivity. The collective data, including deuterium labeling studies, corroborate a catalytic mechanism involving rapid, reversible acetate-directed aminoiridation with inner-sphere/outer-sphere crossover followed by turnover-limiting proto-demetalation mediated by amine.

Full text of DOI:10.1021/jacs.8b05683

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Hydroamination versus Allylic Amination in Iridium-Catalyzed
Reactions of Allylic Acetates with Amines: 1,3-Aminoalcohols via
Ester-Directed Regioselectivity
Seung Wook Kim,†,⊥ Thomas Wurm,†,⊥ Gilmar A. Brito,† Woo-Ok Jung,† Jason R. Zbieg,*,§
Craig E. Stivala,*,§ and Michael J. Krische*,†
§Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
†Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: In the presence of a neutral dppf-modified
iridium catalyst and Cs2CO3, linear allylic acetates react
with primary amines to form products of hydroamination
with complete 1,3-regioselectivity. The collective data,
including deuterium labeling studies, corroborate a
catalytic mechanism involving rapid, reversible acetate-
directed aminoiridation with inner-sphere/outer-sphere
crossover followed by turnover-limiting proto-demetala-
tion mediated by amine.
Figure 1. Cationic vs neutral iridium catalysts promote Tsuji−Trost-
he importance of nitrogen-containing compounds in
Tpharmaceutical and agrochemical research continues to
inspire efforts toward the development of metal catalysts for
alkene hydroamination.1,2 Among late transition metal
catalysts,1g those based on rhodium3,4 and iridium5,6 have
shown great promise; however, despite decades of research,
significant challenges remain. Many hydroaminations are
limited to intramolecular processes.4,6 Intermolecular variants
often require highly activated alkenes,3b,5a−d are accompanied
by oxidative amination side-products3c,i,5f or exploit specialized
directing groups to control regioselectivity.3j,k Further, the
mechanisms of these processes are obfuscated by the fact that
simple Brønsted acids, even ammonium salts,7b,f catalyze
hydroamination with levels of efficiency equal to or greater
than the corresponding metal-catalyzed reactions.7,8 Here, we
report the first hydroaminations of allylic acetates. Specifically,
using a neutral dppf-modified iridium catalyst in the presence
of Cs2CO3, linear allylic acetates react with primary amines to
form products of hydroamination with complete 1,3-
regioselectivity. These results are remarkable, as iridium
complexes are well-known to catalyze the substitution of
allylic acetates with amines to form products of allylic
amination (Figure 1).9
type allylic amination and hydroamination, respectively.
roughly equivalent efficiencies. In both cases, chiral ligands did
not induce asymmetry, so the simpler noncyclometalated
complexes were chosen for further optimization. From a survey
of achiral phosphine ligands, the phosphine ligand dppf, 1,1′-
bis(diphenylphosphino)ferrocene, was found to be most
effective. Hydroamination products were not observed in the
absence of metal, phosphine ligand or upon use of mono-
phosphine ligands.
At this point, the effect of base was systematically
investigated (Table 1, entries 1−5). In the presence of
[Ir(cod)Cl]2 (2.5 mol%), dppf (5 mol%) and Cs2CO3 (200
mol%) at 90 °C in THF (1 M), cinnamyl acetate 1a (100 mol
%) and benzyl amine 2a (200 mol%) were converted the
hydroamination products 3a and the deacetylated compound
3a′ in a 2:1 ratio and a combined 66% yield along with trace
amounts of cinnamyl alcohol. In an attempt to minimize
formation of 3a′, lower loadings of Cs2CO3 were explored
(Table 1, entries 1−3); however, although the reaction is
heterogeneous, the combined yield hydroamination products
3a and 3a′ declined.11 Other bases were explored (Table 1,
entries 4 and 5), but Cs2CO3 provided superior results. The
use of cinnamic esters less prone to saponification were
explored (Table 1, entries 6−10), but this also led to a
decrease in the combined yield of hydroamination products 3a
and 3a′. In all experiments, products of acyl transfer to benzyl
amine were not observed.
Recently, in a collaborative endeavor, we reported that
commercially available π-allyliridium C,O-benzoates catalyze
highly enantioselective substitutions of branched allylic
acetates with primary amines.10 In the course of developing
this process, significant quantities (30−40% yield) of hydro-
amination product were formed as single regioisomers in
attempted substitutions of linear allylic acetates. Both iridium
C,O-benzoates and noncyclometalated phosphine-modified
iridium complexes derived in situ from [Ir(cod)Cl]2 displayed
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b05683
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Journal of the American Chemical Society
Communication
obtained in 76% yield accompanied by only trace quantities of
the 3a′ (Table 1, entry 13). To mitigate solvent evaporation, a
number of higher boiling solvents were evaluated and it was
found that 1,2-dimethoxyethane (DME), provided 3a with
equivalent efficiencies (Table 1, entry 14). Finally, although
this effect was not pronounced in reactions of cinnamyl acetate
1a, it was also found that in certain cases milled Cs2CO3 led to
higher and more reproducible yields.11
Table 1. Selected Optimization Experiments in the Reaction
of Cinnamyl Acetate 1a with Benzyl Amine 2a To Form
Hydroamination Product 3a
a
To illustrate scope, optimal conditions for hydroamination
were applied across a diverse set of reactants (Table 2). As
demonstrated by the formation of hydroamination products
3a−3g, primary benzylic amines are effective partners for
hydroamination. Saturated primary amines provide moderate
yields of hydroamination product (3h). A range of aryl-
substituted linear allylic acetates also were evaluated (3i−3p).
These experiments, which were all conducted using benzyl
amine, reveal that both electron rich and electron deficient aryl
groups, as well as heteroaryl groups, are tolerated. The
formation of adduct 3p, derived from AZD-9496 (a non-
steroidal oral estrogen receptor inhibitor),12 which incorpo-
rates an unprotected indole moiety, highlights the functional
group tolerance of the present hydroamination method. As
illustrated by formation of 3q and 3r, alkyl-substituted allylic
acetates provide modest yields of hydroamination product as
single regioisomers. The regioselective formation of 3r is
noteworthy, as it provides strong evidence of the directing
influence of the acetate moiety. Indeed, as cinnamyl methyl
ether, trans-β-methylstyrene and 1-octene do not engage in
hydroamination under these conditions, it would appear that
the acetate moiety not only directs regioselectivity, but is
actually required for hydroamination to occur. Under the
present conditions, secondary amines and anilines only provide
a
All reactions were performed on 0.2 mmol scale. All yields are of
material isolated by silica gel chromatography. See Supporting
Information for further experimental details.
Acute sensitivity to the steric features of the cinnamic ester
(cf. Table 1, entries 1 and 7) along with the regioselectivity of
hydroamination suggested chelation of iridium by the acetate
carbonyl and olefin moieties might play an integral role in the
mechanism. To perhaps favor chelation of iridium and
minimize formation of 3a′ the stoichiometry of cinnamyl
acetate 1a and benzyl amine 2a was altered (Table 1, entries
11−13). Using cinnamyl acetate 1a (300 mol%) and benzyl
amine 2a (100 mol%), the hydroamination product 3a was
a
Table 2. Regioselective Iridium-Catalyzed Hydroamination of Linear Allylic Acetates
a
Yields of material isolated by silica gel chromatography. Standard conditions: [Ir(cod)Cl]2 (2.5 mol%), dppf (5 mol%), Cs2CO3 (200 mol%),
b
amine (100 mol%), DME (1 M), 90 °C. All yields are of material isolated by silica gel chromatography. Cs2CO3 (300 mol%). See Supporting
Information for further experimental details.
B
DOI: 10.1021/jacs.8b05683
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Journal of the American Chemical Society
Communication
Scheme 1. Deuterium Labeling Experiments
Scheme 2. General Catalytic Mechanism for Iridium-
Catalyzed Hydroamination of Linear Allylic Acetates, As
Corroborated by Deuterium Labeling
a
1
2
Reactants and products characterized by H NMR, H NMR and
HRMS. See Supporting Information for further experimental details.
demetalation. The present studies establish a new mechanistic
pathway for alkene hydroamination under basic conditions,
broadening access to 1,3-aminoalcohols and related N-
containing compounds.13 More broadly, this study and prior
collaborative work from the present authors10 demonstrate the
effectiveness of academic-industrial cooperation for the
discovery of useful and robust methods for chemical synthesis.
Future studies will be aimed at developed related metal-
catalyzed C−N bond forming processes.
trace quantities of hydroamination product, and the parent
unsubstituted allyl acetate, H2CCHCH2OAc, provides
mixtures of hydroamination and allylic substitution products.
To gain insight into the reaction mechanism, mono- and di-
deuterated cinnamyl acetates d1-1a and d2-1a were exposed to
standard hydroamination conditions (Scheme 1). To facilitate
assignment of relative stereochemistry, the reaction products
were converted to the cyclic carbamates d1-3a and d2-3a. Axial
disposition of the phenyl moiety was corroborated by NOE
experiments and is presumably due to nonbonded interactions
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b05683.
1
2
■
with the N-benzyl moiety. As determined by H NMR, H
NMR and HRMS, both compounds d1-3a and d2-3a,
completely retain deuterium and were each generated as
1.7:1 mixtures of diastereomers. Guided by the results of
deuterium labeling, a general catalytic mechanism for iridium-
catalyzed hydroamination of linear allylic acetates was
proposed (Scheme 2). Base-induced formation of amidoiri-
dium species I enables entry into the catalytic cycle.11
Association of d1-1a provides the chelated olefin complex II,
which undergoes rapid and reversible inner- or outer-sphere
alkene aminoiridation to form the σ-alkyliridium species cis-III
and trans-III, respectively. Equilibration between cis-III and
trans-III occurs in advance of turnover-limiting proto-
demetalation mediated by benzyl amine to release the product
d1-3a and regenerate amidoiridium species I to close the
catalytic cycle. Consistent with this mechanistic interpretation,
in particular, interconversion between cis-III and trans-III,
diverse chiral iridium complexes did not deliver enantiomeri-
cally enriched hydroamination product. Using cis-cinnamyl
acetate, low conversion to hydroamination product is observed
(15% yield) and recovered cinnamyl acetate is partially
isomerized to the trans-isomer (8:1, cis:trans). These data
suggest the small quantity of hydroamination product observed
in reactions of cis-cinnamyl acetate are likely formed by way of
the trans-isomer and, for cis-cinnamyl acetate, allylic strain may
prevent acetate-mediated chelation of the olefin by iridium. On
the basis of these data, mechanisms involving alkene
isomerization appear less plausible.
S
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*stivala.craig@gene.com
*zbieg.jason@gene.com
*mkrische@mail.utexas.edu
ORCID
Jason R. Zbieg: 0000-0002-2897-8911
Craig E. Stivala: 0000-0002-5024-6346
Michael J. Krische: 0000-0001-8418-9709
Author Contributions
⊥S.W.K. and T.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM069445) and the UT Austin Center for Green
Chemistry and Catalysis are acknowledged for financial
support of this research. The Alexander von Humboldt
Foundation is acknowledged for postdoctoral fellowship
support under the aegis of the Feodor-Lynen program
To summarize, allylic acetates are well-known to undergo
Tsuji−Trost amination upon exposure to amines in the
presence of iridium catalysts with cationic character. Here,
using neutral iridium catalysts under basic conditions, we
report the first examples of allylic acetate hydroamination. The
collective data, including deuterium labeling studies, corrob-
orate a catalytic mechanism involving rapid, reversible acetate-
directed aminoiridation with inner sphere/outer-sphere cross-
over in advance of turnover-limiting amine-mediated proto-
̀
(T.W.). Fundaca̧ o de Amparo a Pesquisa do Estado de Sao
̃ ̃
Paulo (FAPESP) is acknowledged for postdoctoral fellowship
support (G.B., 2017/00734-5). We would also like to thank
Baiwei Lin, Kewei Xu and Yanzhou Liu for analytical data.
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