Regio- and Enantioselective Iridium-Catalyzed Amination of Racemic Branched Alkyl-Substituted Allylic Acetates with Primary and Secondary Aromatic and Heteroaromatic Amines

Article abstract of DOI:10.1021/jacs.8b12152

The air- and water-stable π-allyliridium C,O-benzoate modified by (S)-tol-BINAP, (S)-Ir-II, catalyzes highly regio- and enantioselective Tsuji-Trost-type aminations of racemic branched alkyl-substituted allylic acetates using primary or secondary (hetero)aromatic amines. Specifically, in the presence of (S)-Ir-II (5 mol%) in DME solvent at 60-70 °C, α-methyl allyl acetate 1a (100 mol%) reacts with primary (hetero)aromatic amines 2a-2l (200 mol%) or secondary (hetero)aromatic amines 3a-3l (200 mol%) to form the branched products of allylic amination 4a-4l and 5a-5l, respectively, as single regioisomers in good to excellent yield with uniformly high levels of enantioselectivity. As illustrated by the conversion of heteroaromatic amine 3m to adducts 6a-6g, excellent levels of regio- and enantioselectivity are retained across diverse branched allylic acetates bearing normal alkyl or secondary alkyl substituents. For reactants 3n-3p, which incorporate both primary and secondary aryl amine moieties, regio- and enantioselective amination occurs with complete site-selectivity to furnish adducts 7a-7c. Mechanistic studies involving amination of the enantiomerically enriched, deuterium-labeled acetate 1h corroborate C-N bond formation via outer-sphere addition.

Full text of DOI:10.1021/jacs.8b12152

Article
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
pubs.acs.org/JACS
Regio- and Enantioselective Iridium-Catalyzed Amination of
Racemic Branched Alkyl-Substituted Allylic Acetates with Primary
and Secondary Aromatic and Heteroaromatic Amines
†
†
,§
,§
Seung Wook Kim, Leyah A. Schwartz, 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: The air- and water-stable π-allyliridium C,O-
benzoate modified by (S)-tol-BINAP, (S)-Ir-II, catalyzes highly
regio- and enantioselective Tsuji−Trost-type aminations of
racemic branched alkyl-substituted allylic acetates using primary
or secondary (hetero)aromatic amines. Specifically, in the
presence of (S)-Ir-II (5 mol%) in DME solvent at 60−70 °C,
α-methyl allyl acetate 1a (100 mol%) reacts with primary
(
(
hetero)aromatic amines 2a−2l (200 mol%) or secondary
hetero)aromatic amines 3a−3l (200 mol%) to form the
branched products of allylic amination 4a−4l and 5a−5l,
respectively, as single regioisomers in good to excellent yield
with uniformly high levels of enantioselectivity. As illustrated by
the conversion of heteroaromatic amine 3m to adducts 6a−6g, excellent levels of regio- and enantioselectivity are retained
across diverse branched allylic acetates bearing normal alkyl or secondary alkyl substituents. For reactants 3n-3p, which
incorporate both primary and secondary aryl amine moieties, regio- and enantioselective amination occurs with complete site-
selectivity to furnish adducts 7a−7c. Mechanistic studies involving amination of the enantiomerically enriched, deuterium-
labeled acetate 1h corroborate C−N bond formation via outer-sphere addition.
INTRODUCTION
examples of amphiphilic reactivity in the context of transition
■
1
5
metal catalysis. In the initial communication of these
findings, enantioselective allylic aminations of branched allylic
acetates bearing linear alkyl groups with primary aliphatic
Cyclometalated π-allyliridium C,O-benzoate complexes have
been shown to catalyze diverse alcohol-mediated carbonyl
1
allylations using allyl carboxylates as pronucleophiles. In these
15
2
amines were disclosed. These aminations proceed with
complete branched regioselectivity, overcoming a significant
limitation associated with Type I and II catalysts, which display
incomplete regioselectivity for π-allyl precursors bearing linear
umpoled allylations, the C,O-benzoate moiety assists in
maintaining neutrality and, hence, nucleophilicity of the π-
allyliridium intermediate. Nucleophilic properties are displayed
by other neutral π-allyliridium species. In contrast, as
3
16,17
illustrated by enantioselective Tsuji−Trost-type allylic amina-
alkyl groups.
With regard to the amine nucleophile, the
4
,5
6,7
8,9
tions developed by Takeuchi,
Helmchen,
Hartwig,
cationic π-allyliridium species
Type III SEGPHOS-modified π-allyliridium complexes used in
our initial study enforced high enantioselectivities in reactions
of primary aliphatic amines (Figure 1). Here, we show that the
corresponding tol-BINAP-modified iridium catalyst provides a
significant expansion in scope, enabling highly enantioselective
aminations of branched alkyl-substituted allylic acetates with
electronically diverse primary and secondary aryl amines,
including site-selective reactions of bis(amine) nucleophiles.
Additionally, we report deuterium labeling studies that
corroborate C−N bond formation through an outer-sphere
mechanism.
1
0
11,12
Carreira, and You,
invariably serve as electrophiles. In this latter context, two
distinct classes of iridium catalysts have emerged. Type I
catalysts are used under basic conditions in combination with
linear allyl pro-electrophiles (as branched allyl proelectrophiles
react stereospecifically). Type II catalysts are used under
acidic conditions in combination with branched allyl
proelectrophiles, which react in a non-stereospecific fashion,
perhaps due to displacement of the π-bond of (σ+π)-allyl
13
(
enyl) iridium intermediates by the tethered olefin of the
phosphoramidite ligand (Figure 1).
14
The present authors recently found that neutral π-allyl-
iridium C,O-benzoate complexes, which behave as nucleophilic
allyl donors, can also act as electrophiles, representing the first
Received: November 12, 2018
1
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b12152
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 1. Iridium-Catalyzed Amination of α-Methyl Allyl
Acetate 1a with Primary Aromatic and Heteroaromatic
Amines 2a−2l To Form Enantiomerically Enriched Allylic
a
Amines 4a−4l
Figure 1. Cationic vs neutral chiral iridium complexes for regio- and
enantioselective allylic amination.
RESEARCH DESIGN AND METHODS
■
To develop highly regio- and enantioselective allylic aminations
mediated by aryl amines, a series of π-allyliridium C,O-benzoate
complexes were evaluated in reactions of α-methyl allyl acetate (100
mol%) and aniline (200 mol%) under conditions previously
1
5
optimized for primary aliphatic amines. The iridium catalyst
modified by tol-BINAP, (S)-Ir-II, delivered the product of allylic
amination 4a with significantly higher levels of enantioselectivity than
the corresponding SEGPHOS-modified catalyst, (S)-Ir-I, but a lower
isolated yield of 4a was observed (eq 1). Changing the solvent from
a
Yields of material isolated by silica gel chromatography. Enantio-
selectivities were determined by chiral stationary-phase HPLC
analysis. See Supporting Information for further experimental details.
prepared in enantiomerically enriched form in two separate
8d,18
reports.
In a further exploration of scope, optimized conditions were
applied to the amination of α-methyl allyl acetate using secondary
aromatic and heteroaromatic amine nucleophiles 3a−3l (Table 2).
Indoline 3a, 6- and 7-aza-indolines 3b and 3c, and the 3,3′-spirocyclic
indoline 3d each underwent asymmetric allylation with complete
branched regioselectivity and high levels of enantioselectivity.
Pronounced match-mismatched effects were observed in the
conversion of (S)- and (R)-2-methyl indolines 3e and 3f to adducts
5e and 5f, respectively, suggesting the potential for kinetic resolution.
The amination of 1a using N-methyl aniline 3g and related
compounds 3h and 3i bearing electron withdrawing and donating
groups at the para-position proceeded smoothly to form adducts 5g−
5i, respectively. Among these three N-methyl aniline derivatives (3g−
3i), amination using the more-electron-rich N-methyl-p-anisidine 3i
occurred with notably higher levels of enantioselectivity. As illustrated
by the formation of 5j and 5k, N-methyl anilines containing bromide
(3j) and chloride (3k) functional groups are tolerated. Finally,
amination of 1a using N-methyl-2-(methylamino)benzimidazole 3l is
remarkably efficient, providing adduct 5l in 94% yield with complete
selectivity for allylation of the extranuclear 2-(methylamino) moiety.
To assess how structural variation of the π-allyliridium intermediate
impacts reactivity, regio- and stereoselectivity, a set of branched allylic
acetates 1a−1g were explored in aminations mediated by 2-
(methylamino)benzoxazole 3m (Table 3). In addition to α-methyl
allyl acetate 1a, linear alkyl-substituted allylic acetates 1b and 1c
smoothly underwent amination to form adducts 6a−6c as single
THF to DME improved the isolated yield of 4a, and by decreasing the
reaction temperature from 80 to 70 °C 4a could be formed in 82%
yield and 89% enantiomeric excess (eq 1).
Deviation from these reaction parameters did not result in further
improvement, and given the low cost of tol-BINAP these conditions
were adopted to explore the scope of primary aromatic and
heteroaromatic amine nucleophiles 2a−2l in aminations of α-methyl
allyl acetate (Table 1). Amine nucleophiles containing a diverse array
of functional groups were examined to mirror challenges faced in
medicinal chemistry. In each case, the targeted products of allylic
amination 4a−4l were formed with complete branched regio-
selectivity and uniformly high levels of enantioselectivity. As
illustrated in the formation of 4d, which incorporates a pinacol
boronate moiety, the reaction conditions tolerate rather sensitive
functional groups. The tolerance of ortho-substituted anilines, as
demonstrated by the formation of 4e, is also noteworthy. Perhaps the
most striking feature, however, is the compatibility of the catalyst with
electronically diverse aryl amine partners and the tolerance of Lewis
basic N-heterocycles, as illustrated by the formation 4k and 4l. The
absolute stereochemical assignment of adducts 4b−4l is made in
analogy to that determined for compound 4a, which has been
B
DOI: 10.1021/jacs.8b12152
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 2. Iridium-Catalyzed Amination of α-Methyl Allyl
Acetate 1a with Secondary Aromatic and Heteroaromatic
Amines 3a−3l To Form Enantiomerically Enriched Allylic
Table 3. Iridium-Catalyzed Amination of α-Substituted Allyl
Acetates 1a−1g with Secondary Heteroaromatic Amine 3m
a
To Form Enantiomerically Enriched Allylic Amines 6a−6g
a
Amines 5a−5l
a
Yields of material isolated by silica gel chromatography. Enantio-
selectivities were determined by chiral stationary-phase HPLC
analysis. See Supporting Information for further experimental details.
a
Yields of material isolated by silica gel chromatography. Enantio-
selectivities were determined by chiral stationary-phase HPLC
analysis. See Supporting Information for further experimental details.
regioisomers with high levels of enantiomeric enrichment. Allylic
acetates 1d−1f, which incorporate cycloalkyl substituents, delivered
adducts 6d−6f as single regioisomers, although an erosion in
enantioselectivity is observed using the larger cyclopentyl-substituted
allyl acetate 1f. Finally, using the enantiomeric iridium catalysts (S)-
Ir-II and (R)-Ir-II, the (S)-citronellol-derived allylic acetate 1g reacts
with 3m to form 6g and iso-6g, respectively, with good levels of
catalyst-directed diastereoselectivity. Under these conditions, aryl-
substituted allyl acetates gave low yields (<10%) of allylic amination
product, and linear allylic acetates provided mixtures of allylic
19
amination and hydroamination product in low isolated yield.
Having established the ability to functionalize both primary and
secondary aromatic amines, we attempted the site-selective mod-
ification of reactants 3n−3p, which incorporate both primary and
secondary aromatic amines, using the branched allylic acetate 1a (eqs
2
−4). Upon exposure to standard conditions, 5-aminoindole 3n
undergoes completely chemoselective functionalization at the primary
amine to form adduct 7a as a single constitutional isomer with
excellent levels of enantioselectivity (eq 2). Similarly, in the
conversion of 3o to adduct 7b, complete control of regio- and site-
selectivity is accompanied by high levels of enantioselectivity (eq 3).
The structure of adduct 7b was verified by single crystal X-ray
diffraction analysis, further corroborating the absolute stereochemical
assignment of adducts 4a−4l, 5a−5l and 6a−6g. Finally, N-
cyclohexyl-1,2-diaminobenzene 3p reacts with 1a to deliver adduct
amination enhances step economy by avoiding manipulations devoted
to N-protection−deprotection.
Finally, to better understand the nature of the C−N bond forming
event, asymmetric amination of the enantiomerically enriched (Z)-
deuterated allylic acetate 1h was conducted under standard conditions
20
using (S)-Ir-II (Scheme 1, eq 5). Compound 8a is formed with
1
complete alkene (Z)-stereoselectivity, as determined by H NMR.
Assuming formation of the π-allyliridium occurs with inversion of
stereochemistry, as established in analogous iridium phosphoramidite-
4
−12
7
c, which is modified exclusively at the primary amine (eq 4). The
catalyzed processes,
the stereochemistry of the amination product
ability to engage diamines in site-selective regio- and enantioselective
8a is consistent with outer-sphere addition of the nitrogen
C
DOI: 10.1021/jacs.8b12152
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 1. Iridium-Catalyzed Amination of
have shown that the air and water stable π-allyliridium C,O-
benzoate modified by SEGPHOS, which is well-known for its
Enantiomerically Enriched Deuterated Allylic Acetate 1h
with the Enantiomeric Catalysts (S)-Ir-II (Eq 5) and (R)-Ir-
1
,2
ability to catalyze nucleophilic carbonyl allylation,
also
a
II (Eq 6)
promotes highly regio- and enantioselective electrophilic
allylation of primary aliphatic amines. As demonstrated here,
the corresponding tol-BINAP-modified complex is a signifi-
cantly more effective catalyst for allylic amination, which has
enabled use of primary and secondary aromatic or hetero-
aromatic amine nucleophiles. These π-allyliridium C,O-
benzoate catalyzed processes overcome a longstanding
limitation associated with all known catalytic systems for
asymmetric allylic amination - the ability to promote
enantioselective aminations of racemic branched allylic
acetates bearing n-alkyl groups with complete levels of
4
−12,16
regioselectivitity.
Another notable feature of these
catalysts involves the ability to promote site-selective N-
allylations of reactants that incorporate both primary and
secondary aromatic amines. As demonstrated by mechanistic
studies involving amination of the enantiomerically enriched
deuterated allylic acetate 1h, an outer-sphere mechanism for
C−N bond formation is operative. This work, along with our
a
Yields of material isolated by silica gel chromatography. Enantio-
selectivities were determined by chiral stationary phase HPLC
analysis. See Supporting Information for further experimental details.
15
prior studies, significantly expands the scope of catalytic
asymmetric allylic amination methodology, broadening access
to diverse chiral α-stereogenic amines. Future work under the
aegis of this academic-industrial collaboration will focus on
expanding the range of amine nucleophiles for π-allyliridium
C,O-benzoate-catalyzed allylic amination, in particular, the use
of secondary aliphatic amines and amides, and the develop-
ment of related methods for asymmetric C−N bond formation.
nucleophile. To corroborate the veracity of this experiment, the
amination of allylic acetate 1h was conducted using the enantiomeric
iridium catalyst, (R)-Ir-II (Scheme 1, eq 6). The amination product
8
b is formed with complete alkene (E)-stereoselectivity, as
1
determined by H NMR. The stereochemistry of 8a is again
consistent with outer-sphere C−N bond formation.
Based on the collective data, a general catalytic mechanism and
stereochemical model were proposed (Scheme 2). The π-allyliridium-
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b12152.
■
(
I) complex I is subject to outer-sphere amine addition to form the
*
S
C−N bond and the zwitterionic iridium(I) olefin complex II.
Deprotonation of ammonium moiety of complex II mediated by
cesium carbonate generates the anionic iridium(I) species III. Alkene
exchange with the allylic acetate releases the product of allylic
amination and forms the olefin complex IV. Loss of acetate ion
regenerates the π-allyliridium(I) complex I to close the catalytic cycle.
The indicated stereochemical model accounts for the observed sense
of absolute stereoinduction for outer sphere addition of a nucleophile
to the neutral iridium π-allyl complex I. This model is based upon the
1
Experimental procedures and spectroscopic data ( H
13
NMR, C NMR, IR, HRMS) for all new compounds,
including NMR spectra and HPLC traces for racemic
and enantiomerically enriched compounds, and single-
crystal X-ray diffraction data for compound 7b (PDF)
X-ray crystallographic data for 7b(CIF)
21
coordination mode revealed in closely related crystal structures.
Orientation of the π-allyl is controlled through alleviation of steric
clashes between the naphthyl and tolyl substituents of the phosphine
ligand with the R-group of the resulting π-allyl, as illustrated in the
disfavored mode of addition (Scheme 2).
AUTHOR INFORMATION
Corresponding Authors
zbieg.jason@gene.com
*stivala.craig@gene.com
mkrische@mail.utexas.edu
ORCID
■
*
CONCLUSIONS
Previously reported enantioselective allylic aminations are
largely restricted to chiral iridium−phosphoramidite cata-
■
*
4
−12
15
lysts.
In the initial communication of our work, we
Craig E. Stivala: 0000-0002-5024-6346
Scheme 2. General Catalytic Mechanism and Stereochemical Model for Enantioselective Iridium-Catalyzed Allylic Amination
D
DOI: 10.1021/jacs.8b12152
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Org. Lett. 2005, 7, 1239. (e) Weihofen, R.; Dahnz, A.; Tverskoy, O.;
Helmchen, G. Highly enantioselective iridium-catalysed allylic
aminations with anionic N-nucleophiles. Chem. Commun. 2005,
Michael J. Krische: 0000-0001-8418-9709
Notes
The authors declare no competing financial interest.
3541. (f) Weihofen, R.; Tverskoy, O.; Helmchen, G. Salt-Free
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for partial
support of this research. Genentech is acknowledged for
summer predoctoral internship support (S.W.K. and L.A.S.).
We would like to thank Kewei Xu and Yanzhou Liu for
analytical data and Amber Guillen and Mengling Wong for
assistance with chiral SFC analyses.
M.; SonnenSchein, C.; Tverskoy, O.; Helmchen, G. Enantioselective
Iridium-Catalyzed Allylic Substitutions with Hydroxamic Acid
Derivatives as N-Nucleophiles. Org. Lett. 2011, 13, 2810.
REFERENCES
■
(
1) For selected reviews on alcohol-mediated carbonyl allylation,
(7) Reviews: (a) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies,
̈
see: (a) Han, S. B.; Kim, I. S.; Krische, M. J. Enantioselective iridium-
catalyzed carbonyl allylation from the alcohol oxidation level via
transfer hydrogenation: minimizing pre-activation for synthetic
efficiency. Chem. Commun. 2009, 7278. (b) Ketcham, J. M.; Shin,
I.; Montgomery, T. P.; Krische, M. J. Catalytic Enantioselective C−H
Functionalization of Alcohols by Redox-Triggered Carbonyl Addition:
Borrowing Hydrogen, Returning Carbon. Angew. Chem., Int. Ed. 2014,
M.; Weihofen, R. Iridium-catalysed asymmetricallylic substitutions.
Chem. Commun. 2007, 675. (b) Helmchen, G. In Iridium Complexes in
Organic Synthesis; Oro, L. A., Claver, C., Eds.; Wiley-VCH: Weinheim,
2
009; pp 211−250. (c) Qu, J.; Helmchen, G. Applications of Iridium-
Catalyzed Asymmetric Allylic Substitution Reactions in Target-
Oriented Synthesis. Acc. Chem. Res. 2017, 50, 2539.
(8) (a) Ohmura, T.; Hartwig, J. F. Regio- and Enantioselective
5
3, 9142. (c) Kim, S. W.; Zhang, W.; Krische, M. J. Catalytic
Allylic Amination of Achiral Allylic Esters Catalyzed by an Iridium−
Phosphoramidite Complex. J. Am. Chem. Soc. 2002, 124, 15164.
Enantioselective Carbonyl Allylation and Propargylation via Alcohol-
Mediated Hydrogen Transfer: Merging the Chemistry of Grignard
and Sabatier. Acc. Chem. Res. 2017, 50, 2371.
2) For a recent review on “umpoled allylations”, see: Spielmann, K.;
Niel, G.; de Figueiredo, R. M.; Campagne, J.-M. Catalytic nucleophilic
umpoled’ π-allyl reagents. Chem. Soc. Rev. 2018, 47, 1159.
3) For selected examples of alcohol-mediated carbonyl allylation
involving non-cyclometalated iridium catalysts, see: (a) Bower, J. F.;
Skucas, E.; Patman, R. L.; Krische, M. J. Catalytic C−C Coupling via
Transfer Hydrogenation: Reverse Prenylation, Crotylation, and
Allylation from the Alcohol or Aldehyde Oxidation Level. J. Am.
Chem. Soc. 2007, 129, 15134. (b) Bower, J. F.; Patman, R. L.; Krische,
M. J. Iridium-Catalyzed C−C Coupling via Transfer Hydrogenation:
Carbonyl Addition from the Alcohol or Aldehyde Oxidation Level
Employing 1,3-Cyclohexadiene. Org. Lett. 2008, 10, 1033. (c) Nguyen,
K. D.; Herkommer, D.; Krische, M. J. Enantioselective Formation of
All-Carbon Quaternary Centers via C−H Functionalization of
Methanol: Iridium-Catalyzed Diene Hydrohydroxymethylation. J.
Am. Chem. Soc. 2016, 138, 14210. (d) Holmes, M. T.; Nguyen, K.
D.; Schwartz, L. A.; Luong, T.; Krische, M. J. Enantioselective
(b) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. Identification
of an Activated Catalyst in the Iridium-Catalyzed Allylic Amination
and Etherification. Increased Rates, Scope, and Selectivity. J. Am.
Chem. Soc. 2003, 125, 14272. (c) Leitner, A.; Shu, C.; Hartwig, J. F.
Editing the stereochemical elements in an iridium catalyst for
enantioselective allylic amination. Proc. Natl. Acad. Sci. U. S. A.
(
‘
(
2
004, 101, 5830. (d) Shu, C.; Leitner, A.; Hartwig, J. F.
Enantioselective Allylation of Aromatic Amines after In Situ
Generation of an Activated Cyclometalated Iridium Catalyst. Angew.
Chem., Int. Ed. 2004, 43, 4797. (e) Leitner, A.; Shekhar, S.; Pouy, M.
J.; Hartwig, J. F. A Simple Iridium Catalyst with a Single Resolved
Stereocenter for Enantioselective Allylic Amination. Catalyst Selection
from Mechanistic Analysis. J. Am. Chem. Soc. 2005, 127, 15506.
(f) Leitner, A.; Shu, C.; Hartwig, J. F. Effects of Catalyst Activation
and Ligand Steric Properties on the Enantioselective Allylation of
Amines and Phenoxides. Org. Lett. 2005, 7, 1093. (g) Shekhar, S.;
Trantow, B.; Leitner, A.; Hartwig, J. F. Sequential Catalytic
Isomerization and Allylic Substitution. Conversion of Racemic
Branched Allylic Carbonates to Enantioenriched Allylic Substitution
Products. J. Am. Chem. Soc. 2006, 128, 11770. (h) Yamashita, Y.;
Gopalarathnam, A.; Hartwig, J. F. Iridium-Catalyzed, Asymmetric
Amination of Allylic Alcohols Activated by Lewis Acids. J. Am. Chem.
Soc. 2007, 129, 7508. (i) Markovic, D.; Hartwig, J. F. Resting State
and Kinetic Studies on the Asymmetric Allylic Substitutions Catalyzed
by Iridium−Phosphoramidite Complexes. J. Am. Chem. Soc. 2007,
129, 11680. (j) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.;
Hartwig, J. F. Enantioselective Iridium-Catalyzed Allylic Amination of
Ammonia and Convenient Ammonia Surrogates. Org. Lett. 2007, 9,
3949.
(9) Reviews: (a) Hartwig, J. F.; Stanley, L. M. Mechanistically
Driven Development of Iridium Catalysts for Asymmetric Allylic
Substitution. Acc. Chem. Res. 2010, 43, 1461. (b) Hartwig, J. F.; Pouy,
M. J. Top. Organomet. Chem. 2011, 34, 169.
(10) (a) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M.
Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic
Alcohols: Sulfamic Acid as Ammonia Equivalent. Angew. Chem., Int.
Ed. 2007, 46, 3139. (b) Roggen, M.; Carreira, E. M. Stereospecific
Substitution of Allylic Alcohols To Give Optically Active Primary
Allylic Amines: Unique Reactivity of a (P,alkene)Ir Complex
Modulated by Iodide. J. Am. Chem. Soc. 2010, 132, 11917.
(c) Lafrance, M.; Roggen, M.; Carreira, E. M. Direct, Enantioselective
Iridium-Catalyzed Allylic Amination of Racemic Allylic Alcohols.
Formation of CF -Bearing All-Carbon Quaternary Stereocenters via
3
C−H Functionalization of Methanol: Iridium Catalyzed Allene
Hydrohydroxymethylation. J. Am. Chem. Soc. 2017, 139, 8114.
4) (a) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N.
Iridium Complex-Catalyzed Allylic Amination of Allylic Esters. J. Am.
Chem. Soc. 2001, 123, 9525. (b) Onodera, G.; Watabe, K.; Matsubara,
M.; Oda, K.; Kezuka, S.; Takeuchi, R. Iridium-Catalyzed Enantio-
selective Allylic Alkylation using Chiral Phosphoramidite Ligand
Bearing an Amide Moiety. Adv. Synth. Catal. 2008, 350, 2725.
(
(
5) Reviews: (a) Takeuchi, R. Iridium Complex-Catalyzed Highly
Selective Organic Synthesis. Synlett 2002, 1954. (b) Takeuchi, R.;
Kezuka, S. Iridium-Catalyzed Formation of Carbon-Carbon and
Carbon-Heteroatom Bonds. Synthesis 2006, 2006, 3349.
(
6) (a) Bartels, B.; García-Yebra, C.; Rominger, F.; Helmchen, G.
Iridium-Catalysed Allylic Substitution: Stereochemical Aspects and
III
Isolation of Ir Complexes Related to the Catalytic Cycle. Eur. J.
Inorg. Chem. 2002, 2002, 2569. (b) Lipowsky, G.; Helmchen, G.
Regio- and enantioselective iridium-catalysed allylic aminations and
alkylations of dienyl esters. Chem. Commun. 2004, 116. (c) Welter, C.;
Koch, O.; Lipowsky, G.; Helmchen, G. First intramolecular
enantioselective iridium-catalysed allylic aminations. Chem. Commun.
̈
004, 896. (d) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dubon,
P.; Helmchen, G. Highly Enantioselective Syntheses of Heterocycles
via Intramolecular Ir-Catalyzed Allylic Amination and Etherification.
2
E
DOI: 10.1021/jacs.8b12152
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Angew. Chem., Int. Ed. 2012, 51, 3470. (d) Rossler, S. L.; Krautwald,
S.; Carreira, E. M. Study of Intermediates in Iridium−(Phosphor-
amidite,Olefin)-Catalyzed Enantioselective Allylic Substitution. J. Am.
Chem. Soc. 2017, 139, 3603.
Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic
Amines by Intermolecular Hydroamination of Terminal Allenes.
Angew. Chem., Int. Ed. 2012, 51, 10876. (b) Arnold, J. S.; Nguyen, H.
M. Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transforma-
tions of Racemic Tertiary Allylic Trichloroacetimidates with Anilines.
J. Am. Chem. Soc. 2012, 134, 8380. (c) Chen, Q.-A.; Chen, Z.; Dong,
V. M. Rhodium-Catalyzed Enantioselective Hydroamination of
Alkynes with Indolines. J. Am. Chem. Soc. 2015, 137, 8392. (d) Xu,
K.; Wang, Y.-H.; Khakyzadeh, V.; Breit, B. Asymmetric synthesis of
allylic amines via hydroamination of allenes with benzophenone
imine. Chem. Sci. 2016, 7, 3313. (e) Mwenda, E. T.; Nguyen, H. M.
Enantioselective Synthesis of 1,2-Diamines Containing Tertiary and
Quaternary Centers through Rhodium-Catalyzed DYKAT of Racemic
Allylic Trichloroacetimidates. Org. Lett. 2017, 19, 4814. (f) Guo, W.;
Cai, A.; Xie, J.; Kleij, A. W. Asymmetric Synthesis of α,α-
Disubstituted Allylic Amines through Palladium-Catalyzed Allylic
Substitution. Angew. Chem., Int. Ed. 2017, 56, 11797.
(
11) (a) Ye, K.-Y.; Dai, L.-X.; You, S.-L. Enantioselective synthesis of
2
,5-dihydrobenzo[b]azepine derivatives via iridium-catalyzed asym-
metric allylic amination with 2-allylanilines and ring-closing-meta-
thesis reaction. Org. Biomol. Chem. 2012, 10, 5932. (b) Liu, W.-B.;
Zhang, X.; Dai, L.-X.; You, S.-L. Asymmetric N-Allylation of Indoles
Through the Iridium-Catalyzed Allylic Alkylation/Oxidation of
Indolines. Angew. Chem., Int. Ed. 2012, 51, 5183. (c) Ye, K.-Y.;
Zhao, Z.-A.; Lai, Z.-W.; Dai, L.-X.; You, S.-L. Highly Regioselective
Allylic Substitution Reactions Catalyzed by an Air-Stable (π-
Allyl)iridium Complex Derived from Dinaphthocyclooctatetraene
and a Phosphoramidite Ligand. Synthesis 2013, 45, 2109. (d) Ye,
K.-Y.; Dai, L.-X.; You, S.-L. Regio- and Enantioselective Synthesis of
N-Allylindoles by Iridium-Catalyzed Allylic Amination/Transition-
Metal-Catalyzed Cyclization Reactions. Chem. - Eur. J. 2014, 20, 3040.
(17) For selected reviews on the catalytic enantioselective synthesis
of allylic amines, see: (a) Cannon, J. S.; Overman, L. E. Palladium(II)-
Catalyzed Enantioselective Reactions Using COP Catalysts. Acc.
Chem. Res. 2016, 49, 2220. (b) Grange, R. L.; Clizbe, E. A.; Evans, P.
A. Recent Developments in Asymmetric Allylic Amination Reactions.
Synthesis 2016, 48, 2911. (c) Mailyan, A. K.; Eickhoff, J. A.; Minakova,
A. S.; Gu, Z.; Lu, P.; Zakarian, A. Cutting-Edge and Time-Honored
Strategies for Stereoselective Construction of C−N Bonds in Total
Synthesis. Chem. Rev. 2016, 116, 4441. (d) Fernandes, R. A.;
Kattanguru, P.; Gholap, S. P.; Chaudhari, D. A. Recent advances in
the Overman rearrangement: synthesis of natural products and
valuable compounds. Org. Biomol. Chem. 2017, 15, 2672.
(
e) Yang, Z.-P.; Wu, Q.-F.; You, S.-L. Direct Asymmetric
Dearomatization of Pyridines and Pyrazines by Iridium-Catalyzed
Allylic Amination Reactions. Angew. Chem., Int. Ed. 2014, 53, 6986.
(
f) Zhang, X.; Yang, Z.-P.; Huang, L.; You, S.-L. Highly Regio- and
Enantioselective Synthesis of N-Substituted 2-Pyridones: Iridium-
Catalyzed Intermolecular Asymmetric Allylic Amination. Angew.
Chem., Int. Ed. 2015, 54, 1873. (g) Yang, Z.-P.; Wu, Q.-F.; Shao,
W.; You, S.-L. Iridium-Catalyzed Intramolecular Asymmetric Allylic
Dearomatization Reaction of Pyridines, Pyrazines, Quinolines, and
Isoquinolines. J. Am. Chem. Soc. 2015, 137, 15899. (h) Ye, K.-Y.;
Cheng, Q.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. An Iridium(I) N-
Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular
Allylic Amination Reactions. Angew. Chem., Int. Ed. 2016, 55, 8113.
(18) Madrahimov, S. T.; Markovic, D.; Hartwig, J. F. The Allyl
Intermediate in Regioselective and Enantioselective Iridium-Catalyzed
Asymmetric Allylic Substitution Reactions. J. Am. Chem. Soc. 2009,
(
i) Zhang, X.; Liu, W.-B.; Cheng, Q.; You, S.-L. Iridium-Catalyzed
1
(
31, 7228.
Asymmetric Allylic Amination Reactions with N-Aryl Phosphorami-
dite Ligands. Organometallics 2016, 35, 2467. (j) Yang, Z.-P.; Zheng,
C.; Huang, L.; Qian, C.; You, S.-L. Iridium-Catalyzed Intramolecular
Asymmetric Allylic Dearomatization Reaction of Benzoxazoles,
Benzothiazoles, and Benzimidazoles. Angew. Chem., Int. Ed. 2017,
19) Remarkably, primary aliphatic amines react with linear allylic
acetates under similar conditions to form products of hydroamination
with complete levels of acetate-directed 1,3-regioselectivity: Kim, S.
W.; Wurm, T.; Brito, G. A.; Jung, W.-O.; Zbieg, J. R.; Stivala, C. E.;
Krische, M. J. Hydroamination versus Allylic Amination in Iridium
Catalyzed Reactions of Allylic Acetates with Amines: 1,3-Amino-
alcohols via Ester-Directed Regioselectivity. J. Am. Chem. Soc. 2018,
5
6, 1530.
12) (a) Liu, W.-B.; Xia, J.-B.; You, S.-L. Iridium-Catalyzed
Asymmetric Allylic Substitutions. Top. Organomet. Chem. 2011, 38,
55. (b) Zhuo, C.-X.; Zhang, W.; You, S.-L. Catalytic Asymmetric
Dearomatization Reactions. Angew. Chem., Int. Ed. 2012, 51, 12662.
c) Wu, W.-T.; Zhang, L.; You, S.-L. Catalytic asymmetric
(
1
(
40, 9087.
1
20) For related deuterium labeling experiments, see: (a) Zhang, P.;
Brozek, L. A.; Morken, J. P. Pd-Catalyzed Enantioselective Allyl−Allyl
Cross-Coupling. J. Am. Chem. Soc. 2010, 132, 10686. (b) Chen, J.-P.;
Peng, Q.; Lei, B.-L.; Hou, X.-L.; Wu, Y.-D. Chemo- and Regio-
selectivity-Tunable Pd-Catalyzed Allylic Alkylation of Imines. J. Am.
Chem. Soc. 2011, 133, 14180.
(
dearomatization (CADA) reactions of phenol and aniline derivatives.
Chem. Soc. Rev. 2016, 45, 1570.
(
13) Bartels, B.; Helmchen, G. Ir-catalysed allylic substitution:
mechanistic aspects and asymmetric synthesis with phosphorus
amidites as ligands. Chem. Commun. 1999, 741.
(21) For a comparison of four closely related π-allyliridium C,O-
benzoate complexes via single crystal X-ray diffraction, see: Schmitt,
D. C.; Dechert-Schmitt, A.-M. R.; Krische, M. J. Iridium-Catalyzed
Allylation of Chiral β-Stereogenic Alcohols: Bypassing Discrete
Formation of Epimerizable Aldehydes. Org. Lett. 2012, 14, 6302.
(
14) For spectroscopic and crystallographic evidence of a stable
rhodium enyl complex and its role in enabling regio- and
stereospecific rhodium-catalyzed allylic substitution, respectively,
see: (a) Lawson, D. N.; Osborn, J. A.; Wilkinson, G. Interaction of
tris(triphenylphosphine)chlororhodium(I) with iodomethane, meth-
ylallyl, and allyl chloride. J. Chem. Soc. A 1966, 1733. (b) Tanaka, I.;
Jin-no, N.; Kushida, T.; Tsutsui, N.; Ashida, T.; Suzuki, H.; Sakurai,
H.; Moro-oka, Y.; Ikawa, T. Crystal Structures of (1,5-
3
Cyclooctadiene)di-μ-methoxo-dirhodium(I) and Tetrakis(η -allyl)di-
μ-hydroxo-dirhodium(III). Bull. Chem. Soc. Jpn. 1983, 56, 657.
(
c) Evans, P. A.; Nelson, J. D. Conservation of Absolute
Configuration in the Acyclic Rhodium-Catalyzed Allylic Alkylation
Reaction: Evidence for an Enyl (σ + π) Organorhodium Intermediate.
J. Am. Chem. Soc. 1998, 120, 5581.
(
15) Meza, A. T.; Wurm, T.; Smith, L.; Kim, S. W.; Zbieg, J. R.;
Stivala, C. E.; Krische, M. J. Amphiphilic π-Allyliridium C,O-
Benzoates Enable Regio- and Enantioselective Amination of Branched
Allylic Acetates Bearing Linear Alkyl Groups. J. Am. Chem. Soc. 2018,
1
(
40, 1275.
16) For selected examples of catalytic enantioselective allylic
aminations beyond iridium, see: (a) Cooke, M. L.; Xu, K.; Breit, B.
F
DOI: 10.1021/jacs.8b12152
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX