Development and Mechanistic Investigations of Enantioselective Pd-Catalyzed Intermolecular Hydroaminations of Internal Dienes

Article abstract of DOI:10.1021/acscatal.8b01914

We report the development of highly enantio- and regioselective Pd-catalyzed intermolecular hydroaminations of challenging 1,4-disubstituted acyclic dienes. Several aryl/alkyl-disubstituted dienes and a sterically differentiated alkyl/alkyl-disubstituted diene undergo coupling with a variety of secondary aliphatic amines, indoline, and primary anilines to generate allylic amines with myriad α-alkyl groups in up to 78% yield, >98:2 rr, and 98.5:1.5 er. A number of experiments, including deuterium labeling and transamination studies, shed light on mechanistic details of the reaction, such as the reversibility of individual steps of the proposed catalytic cycle and of the reaction as a whole.

Full text of DOI:10.1021/acscatal.8b01914

Research Article
Cite This: ACS Catal. 2018, 8, 8468−8476
pubs.acs.org/acscatalysis
Development and Mechanistic Investigations of Enantioselective
Pd-Catalyzed Intermolecular Hydroaminations of Internal Dienes
Sangjune Park and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
*
S Supporting Information
ABSTRACT: We report the development of highly enantio- and
regioselective Pd-catalyzed intermolecular hydroaminations of
challenging 1,4-disubstituted acyclic dienes. Several aryl/alkyl-
disubstituted dienes and a sterically differentiated alkyl/alkyl-
disubstituted diene undergo coupling with a variety of secondary
aliphatic amines, indoline, and primary anilines to generate allylic
amines with myriad α-alkyl groups in up to 78% yield, >98:2 rr, and 98.5:1.5 er. A number of experiments, including deuterium
labeling and transamination studies, shed light on mechanistic details of the reaction, such as the reversibility of individual steps
of the proposed catalytic cycle and of the reaction as a whole.
KEYWORDS: palladium, hydroamination, allylic amines, enantioselectivity, mechanism
INTRODUCTION
Scheme 1. Representative Enantioselective Intermolecular
Hydrofunctionalizations of Olefins
■
The enantioselective synthesis of molecules bearing allylic
stereogenic centers is an important undertaking due to the
prevalence of this motif in a large number of natural products
and bioactive compounds and the influence of the stereogenic
center in subsequent diastereoselective transformations of the
1
olefin. The union of two reactants through allylic substitution
is a hallmark method for generating this scaffold but does not
2
−4
often afford compounds with 1,2-disubstituted alkenes.
5
Enantioselective reactions of acyclic 1,3-dienes provide one
route to chiral allyl fragments that bear 1,2-disubstituted
olefins, and hydrofunctionalizations are a significant subset of
these.
A handful of research groups, including our own, have
studied enantioselective intermolecular hydrofunctionaliza-
tions of dienes. Apart from reactions of cyclohexadiene
6
reported by the Hartwig lab, existing methods have utilized
7
−9
terminal acyclic dienes
for C−N and C−C bond-forming
transformations, exclusively affording compounds with methyl-
substituted stereogenic centers (Scheme 1A). For example, we
have demonstrated that Pd−PHOX catalysts are highly
efficient for promoting regio- and enantioselective additions
of both aliphatic amines and carbon pronucleophiles to
10
terminal 1,3-dienes; however, under the optimal conditions
for these transformations, internal dienes fail to react. In
general, enantioselective functionalizations of 1,4-disubstituted
1
1−13
disclosed umpolung strategies with electrophilic, prefunction-
alized amination agents to achieve this aim (Scheme 1C). In
acyclic dienes are rare,
especially via nucleophilic
16
addition. Meek and co-workers recently reported the first
such examples, showing indole additions to this class of dienes
this work, we demonstrate that Pd−PHOX complexes with a
F
noncoordinating BAr counteranion catalyze the hydro-
(
hydroarylation) catalyzed by a Rh−carbodicarbene (CDC)
4
1
7,18
1
4
amination
of internal 1,3-dienes (Scheme 1D). The
complex (Scheme 1B). High levels of enantio- and
regioselectivity were observed. Generally, there is a dearth of
methods available for the hydroamination of disubstituted
olefins via nucleophilic addition with unfunctionalized
Received: May 17, 2018
Revised: July 19, 2018
1
5
amines, although recently a number of laboratories have
©
XXXX American Chemical Society
8468
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
addition of Et N and the choice of solvent proved crucial for
Table 2. Amine Scope in Pd-Catalyzed Hydroamination of
Internal Dienes
3
a,b,c
reaction efficiency and enantioselectivity, delivering products
with allylic stereogenic centers comprised of a number of alkyl
substituents in up to 78% yield, 98.5:1.5 er, and with >98:2
regiomeric ratio (rr).
RESULTS AND DISCUSSION
We initiated our investigations by examining the hydro-
amination of diene 1a (Table 1) with tetrahydroisoquinoline
■
Table 1. Examination of Reaction Conditions for
Enantioselective Hydroamination of Internal Dienes
a
b
c
entry
solvent
Et N
3
yield (%)
er
1
2
3
4
5
6
7
8
CH Cl2
N
Y
Y
Y
Y
Y
Y
N
Y
27
43
5
27
42
62
65
13
63
57.5:42.5
54:46
94:6
89:11
94:6
80:20
93:7
93:7
2
CH Cl2
2
THF
1,4-dioxane
Et O
2
a
hexanes
1:1 hexanes:Et O
1:1 hexanes:Et O
1:1 hexanes:Et O
Reactions run under N with 0.2 mmol amine in 0.2 mL solvent. 1a
2
is a 1:1.8 E,E:E,Z mixture of olefin isomers. > 98:2 rr for 2 in all cases
unless otherwise noted. Isolated yield of purified 2. Enantiomeric
ratio determined by HPLC analysis of purified 2. 15 h reaction. 1 h
reaction.
2
b
c
2
d
e
d
9
96.5:3.5
2
a
Reactions run under N with 0.2 mmol tetrahydroisoquinoline in 0.2
2
mL solvent. 1a is a 1:1.8 E,E:E,Z mixture of olefin isomers. >98:2 rr
b
c
for 2a in all cases. Isolated yield of purified 2a. Enantiomeric ratio
d
determined by HPLC analysis of purified 2a. 7 h reaction.
20
greater nucleophilicity, possibly due to the higher pK ’s of
a
their conjugate acids compared to the more electron deficient
morpholine, piperazines, and THIQ. Acyclic N-methylbenzyl-
amine also efficiently generates allylic amine 2f in 62% yield
and 88.5:11.5 er; however, with the sterically more demanding
diethyl- and dibenzylamine, no hydroamination product could
be observed. Primary alkyl amines are unreactive, presumably
attributable to their lower nucleophilicity in comparison to
(
THIQ). Although the analogous catalyst bearing a BF4
counterion does not effect hydroamination, Pd-1 with its
BArF counteranion generates 1,2-addition product 2a as the
4
sole regioisomer in 27% yield but with low enantioselectivity
(
entry 1). Addition of Et N to the mixture further improved
3
the yield of 2a but without increasing enantioselectivity (entry
1
9
20b
2
). Contrastingly, ethereal solvents lead to dramatically
secondary amines.
higher stereoselectivity (entries 3−5) with Et O delivering 2a
Indoline proved to be an exceptionally good nucleophile for
internal diene hydroamination, but the reaction is prone to
reversibility. In just 1 h, tertiary amine 2g is obtained in 78%
yield and 98.5:1.5 er but the enantiomer ratio declines to 88:12
after 20 h without improving the yield. Despite the lack of
reactivity of primary alkyl amines, some primary anilines
participate in the hydroamination of internal dienes. At room
temperature, secondary amines 2h−j are generated in 52−58%
yield as a single regioisomer. Aniline itself leads to high
enantioselectivity 94:6 er for 2h), but small perturbations in
nucleophile structure greatly affect the reaction outcome as can
be seen in the significantly diminished enantioselectivity in
forming 2i and 2j. For these latter two, enantioselectivity is
constant throughout the course of the reaction. More electron
poor anilines show lower reactivity, epitomized by p-
2
in 42% yield. Somewhat surprisingly, we discovered that
hexanes as solvent further improved the yield (62%, 80:20 er,
entry 6) and that a 1:1 hexanes:Et O mixture gives the best
2
observed balance of yield and enantioselectivity (65% yield,
9
3:7 er, entry 7). As shown in entry 8, the nonpolar reaction
medium is not sufficient for the observed efficiency: Et N is
3
still required. We also found that reducing the reaction time
from 15 to 7 h still leads to 63% yield of 2a but with
significantly higher enantioselectivity (96.5:3.5 er, entry 9),
suggesting that reaction reversibility over time is responsible
for product enantiomerization (vide infra).
Under the optimized reaction conditions, several secondary
aliphatic amines undergo addition to pentadiene 1a in
1
5−20 h (Table 2). N-Substituted piperazines afford allylic
19
amines 2b−d in moderate yield and with excellent regio- and
enantioselectivity (90.5:9.5 to 96:4 er). Morpholine reacts to
give 2e in 71% yield and 96.5:3.5 er. Other secondary amines,
such as piperidine and pyrrolidine, are unreactive despite their
trifluoromethylaniline, which fails to deliver any product.
Thus, while the acidity of the aniline is important, its
nucleophilicity is also a crucial factor for reaction efficiency
(cf., aliphatic amines). No matter which amine was employed
8
469
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
a,b,c,d
Table 3. Internal Diene Variation in Enantioselective Hydroamination
a
b
1
:1 to 1:5 E,E:E,Z mixture of diene 1 unless otherwise noted; see the Supporting Information for details. Isolated yield of purified 3.
c
d
1
Enantiomeric ratio determined by HPLC analysis of purified 3. Regiomeric ratio of 3:4 determined by 400 MHz H NMR spectroscopy of the
e
unpurified mixture. >20:1 E,E:E,Z diene 1k.
1
9
in the hydroamination (Table 2), Et N was found to be
essential for reaction efficiency.
sterically differentiated, high regioselectivity is observed.
3
19
Morpholine addition to diene 1n furnishes allylic amine 3n as a
A range of unsymmetrical internal dienes take part in Pd-
catalyzed hydroamination (Table 3). Substrates with electron
rich aromatic rings (1b−d) lead to the highest yields in
reactions with morpholine, delivering products 3a−c with
good to excellent levels of enantioselectivity. More electron
deficient arenes are tolerated (generation of 3d−e); yields are
somewhat reduced, but enantioselectivity remains high.
Notably and in contrast to electronic variation of the aryl
single isomer in 96:4 er.
In most transformations presented in Tables 1−3, a mixture
of diene stereoisomers was employed. To evaluate the impact
of stereochemistry upon hydroamination, we separately
prepared the two stereoisomers of diene 1a and utilized each
in the hydroamination with morpholine (Scheme 2). Each
diene stereoisomer is capable of furnishing allylic amine (S)-
2e, and in each case, the product is formed with excellent
enantioselectivity; however, (E,Z)-1a generates substantially
more product than the (E,E)-isomer (65 vs 28% yield). The
10b
group of terminal dienes, only 1,2-hydroamination product
is observed in all cases. Other positional substitution of the
3
aromatic ring has minimal effect on the reaction yield and
regioselectivity, again a significant difference to the analogous
terminal dienes (formation of 3f−g); however, enantioselec-
tivity decreases as the substituent is moved closer to the diene’s
point of attachment (compare 3c, 3f, and 3g).
Scheme 2. Reaction Outcome Dependence on Diene
a
Stereochemistry
2
A number of alkyl groups (R ) were explored for the
intermolecular hydroamination. As this substituent becomes
larger than methyl, regioselectivity remains high but is
imperfect (83:17 to 95:5 rr). Reactions proceed in moderate
to good yield (52−80%) and enantioselectivity (80.5:19.5 to
9
9:1 er). Ethereal functionality is tolerated; however, carbonyl
and amino groups inhibit catalysis. It is notable that in some
cases, different amines may lead to drastically different
selectivities in additions to a diene. For example, an n-
propyl-substituted diene undergoes reaction with morpholine
to generate allyl amine 3h with only 83:17 rr and 86.5:13.5 er.
In contrast, the same diene reacts with N-phenylpiperazine to
deliver 3i in 94:6 rr and 99:1 er. In both cases,
enantioselectivity remains roughly unchanged throughout the
course of the reaction. However, such disparate selectivity with
these amines is not a general phenomenon, and few trends in
reaction efficiency or selectivity could be gleaned from our
2
variations in R identity.
Alkyl/alkyl-substituted dienes also participate in Pd-1-
a
Reaction conditions: Pd-1 (0.05 equiv), Et N (3.0 equiv), 1:1
3
catalyzed hydroamination. As long as the two groups are
hexanes:Et O, 22 °C, 20 h.
2
8
470
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
result with the (E,Z)-diene is similar to that obtained with the
Table 4. Deuterium Labeling Studies in Indoline Addition
to Diene 1a
a
1
:1.8 E,E:E,Z stereochemical mixture. Notably, in the
independent reaction of either stereoisomer, diene 1a is
recovered as a stereochemical mixture that slightly favors the
(
E,Z)-isomer. Although the stereochemical preference for
recovering the (E,Z)-diene cannot be explained at this time,
the results also highlight that isomerization of the diene
stereochemistry is occurring with at least a similar if not faster
rate as product formation. Additionally, the data are highly
suggestive that diene coordination is faster than the isomer-
ization process that interconverts (E,E)- and (E,Z)-1a.
yield
C1; C4% D
time
entry (h)
2g
C4% D recovered E,E:E,Z
E,E- and
b
c
,d
b
c
c
Building upon this observation, in an effort to probe aspects
of overall reaction reversibility and the reversibility of
individual steps of the catalytic cycle, we carried out a series
of experiments. As a framework for discussion, a proposed
(%)
in 2g
1a (%)
of 1a
E,Z-1a
e
1
2
13
24
79
1.4:1
1.8:1
E,E: 15; 15
E,Z: 38; 48
E,E: 15; 19
E,Z: 45; 61
f
2
20
28
22
56
2
1
catalytic cycle for the internal diene hydroamination is shown
22
in Scheme 3. After initiation of Pd-1, coordination of diene
a
1
:1.8 E,E:E,Z mixture of diene 1a. >98:2 rr for 2g in both cases.
Isolated purified compound. Determined by 400 MHz H NMR
spectroscopy of purified compound. Deuterium content at C1 in 2g
could not be accurately determined by H NMR due to overlap of the
b
c
1
d
Scheme 3. Proposed Catalytic Cycle for Internal Diene
Hydroamination
1
e
f
C1 proton with indoline aryl protons. 95:5 er. 91:9 er.
Furthermore, in both cases, significantly more of the
deuterium label appears in recovered diene 1a (44% of
available D in entry 1 and 35% in entry 2) than in product 2g,
and at both time points, deuterium is approximately evenly
distributed between C1 and C4 (likely deuterium is roughly
evenly distributed between these two sites in 2g as well).
These data suggest that Pd−H/D insertion to the diene,
followed by β-hydride elimination and diene dissociation are
significantly faster than formation of Pd−π-allyl iv and/or the
amine attack upon it to deliver product. Notably, there is
higher deuterium content in recovered (E,Z)-1a than in the
(
E,E)-isomer.
0
1
a to Pd −PHOX affords intermediate i. Oxidative proto-
Importantly, the overall deuterium content in 2g plus
F
nation by [Et NH]BAr then forms Pd hydride ii. Diene
migratory insertion to Pd−H leads initially to Pd−σ-allyl iii,
which may collapse to π-allyl iv. Subsequent attack by the
amine generates the Pd −allylic ammonium complex v, whose
deprotonation with Et N followed by olefin exchange with
diene 1a then forms product 2 and regenerates i.
We first wished to separate the reversibility of the overall
reaction from the reversibility of Pd−PHOX association with
the diene and Pd−H migratory insertion.
accomplish this, we employed 95% N-deuterated indoline
Table 4). This would enable us (1) to track the position of
the label with respect to the amine within addition product 2g,
2) to assess the degree to which the label was incorporated in
recovered 1a is considerably greater than the yield of the allylic
amine. For entry 1, after 2 h there is 13% yield of 2g yet 48% of
the label appears in the isolated compounds. In entry 2 (20 h
reaction), 51% of the label was transferred from the amine. We
infer that the balance of the label remains at indoline. These
results indicate that a mechanism connected to but beyond the
simple hydroamination catalytic cycle depicted in Scheme 3
exists for exchanging hydrogen from diene 1a for deuterium
from indoline and that this process is faster than hydro-
amination. For example, Pd−H, formed via a β-hydride
elimination that generates deuterated diene 1a, may exchange
H for D by acid/base reaction with indoline, perhaps mediated
3
4
0
3
1
0b,21,23
To
24
(
(
by Et N. This equilibrium isotope effect is likely one factor
3
this product, and (3) to evaluate whether recovered diene 1a
bore any of the label. With the labeled indoline, amine 2g was
isolated in 13% yield after 2 h (entry 1) and 28% yield after 20
h (entry 2), a significantly slower rate than the reaction of
unlabeled indoline. H NMR analysis of 2g showed ca. 23% D
incorporation at C4 in both cases (3.5% of available D in entry
contributing to the slower rate with deuterated indoline, and
the 50% distribution of the label between indoline and 1a/2g
appears to be established early in the reaction course.
25
We next investigated the reversibility of C−N bond
formation and the stereochemical consequences in a series of
experiments. THIQ addition product 2a (95:5 er) was
1
22
1
and 6.5% in entry 2). The D content at C1 could not be
subjected to 5 mol % Pd-1 and 5 mol % additional THIQ
1
accurately determined by H NMR due to overlap of the C1
in the absence of diene under otherwise standard conditions
(Scheme 4). After 20 h, 80% of 2a was recovered, but in lower
enantiopurity (81:19 er), accompanied by 20% yield of diene
1a. The isolation of 1a from the reaction mixture confirms that
the reaction is fully reversible to the free diene, thereby
providing a pathway for product enantiomerization. An
identical experiment involving morpholine and its addition
1
H signal with indoline aromatic resonances. However, high
resolution mass spectrometry revealed the total D content in
the product is greater, illustrating that deuterium is divided
19
between the C1 and C4 carbons. Notably, although the
indicated insertion at either olefin would lead to different
product regioisomers, only one isomer of product is formed in
the reaction.
19
product 2e delivers a similar result.
8
471
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
28
Scheme 4. Demonstration of Reaction Reversibility in
Hydroaminations
catalysts have been utilized. (2) Whereas allylic substitution
conditions are inherently neutral to basic, hydroaminations
conditions are overall acidic, even when buffered with Et N
3
such as in the internal diene hydroaminations developed here.
Added acid may accelerate reaction rate but can lead to
6b,23c
product racemization, likely via diene formation.
The conditions imposed in the reaction in Scheme 4no
excess of amine in the presence of Pd−π-allyl ivmore
resemble the hypothetical situation near the end of a
hydroamination reaction, allowing π-allyl iv to readily collapse
to σ-allyl iii, which is in rapid equilibrium with the free diene
1
a (inferred from deuterated amine studies in Table 4).
Preferential ionization of the major enantiomer of 2a with Pd-
and its equilibration with 1a account for the considerable
1
The similarity in mechanism between allylic amination and
diene hydroamination bears further discussion. Considering
the proposed hydroamination catalytic cycle in Scheme 3 and
our observations of reaction reversibility to the diene, one
might ask if product enantiomerization in Pd-catalyzed allylic
amination can also occur via β-hydride elimination to a diene
29
reduction in 2a enantiopurity. In this process that begins
with 2a (1.0 M), the overall decline in enantiopurity is
significantly greater over 20 h than what is observed in the
hydroamination reaction that converts diene 1a to allylic amine
2a (Table 1).
26,27
from a Pd−allyl species. Indeed, Bunt and co-workers
have
To establish if π-allyl iv could be rapidly intercepted by
excess amine before forming σ-allyl iii, thereby preserving
enantiopurity, we additionally studied a handful of trans-
illustrated that large quantities of diene may be formed during
allylic aminations, including those catalyzed by Pd−PHOX
complexes, although the amount of diene was heavily
dependent on the ligand, the solvent, and the identity or
presence of added base; amine bases tended to lead to more
diene. Two additional points are noteworthy in comparing
these two related transformations. (1) There are relatively few
Pd-catalyzed allylic aminations where there is an opportunity
2f,23
amination reactions (Scheme 5).
THIQ addition product
2a reacts with morpholine under optimized hydroamination
conditions to deliver a nearly equal mixture of THIQ and
morpholine adducts 2a and 2e, respectively (Scheme 5A). The
THIQ allyl amine 2a is recovered with significantly lower
enantiopurity but morpholine-containing 2e is formed in only
a somewhat lower 90.5:9.5 er. The reverse transamination
2
,3
for acyclic diene formation, especially where Pd−PHOX
Scheme 5. Studies Demonstrating Enantiospecificity in Transaminations with Pd-1
8
472
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
process, 2e reaction with THIQ, affords a similar result with
THIQ adduct 2a generated in only somewhat diminished er
but with morpholine adduct 2e recovered in more significantly
transaminations with Pd-1 appears somewhat dependent on
the nature of the amine in contrast to related transaminations
2f,23a
with Pd−BINAP.
19
diminished enantiopurity (Scheme 5B). Diene 1a cannot be
detected with the excess of secondary amine present in either
transamination reaction, although the decreased er of the
transamination products compared to the starting allylic
amines suggests the diene is generated to some degree in
each case. If reactions were occurring exclusively through π-
allyl iv, the enantiomer ratio of the transamination product
should be the same as the starting allylic amine (100%
enantiospecificity). Therefore, the transaminations in parts A
and B of Scheme 5 could be proceeding solely via conversion
of the allylic amine starting material to diene 1a followed by
enantioselective hydroamination of the diene (coupled with
equilibration that lowers enantiopurity over time) or largely
through an enantiospecific transformation with some stereo-
chemical erosion by reaction reversal to diene 1a. Thus, we
examined additional transaminations.
Taken together, our data suggest that the catalyst derived
from Pd-1 is capable of reversing several, if not all,
hydroamination reactions of internal dienes. The equilibrium
position has not been formally established, but the reaction in
Scheme 4, where 80% of THIQ adduct 2a was recovered after
20 h (81:19 er), suggests it favors the products in at least some
instances. Therefore, it is notable that in THIQ hydro-
amination of diene 1a with Pd-1, allylic amine 2a is maximally
obtained in ca. 65% yield even though the enantiomer ratio
continues to decline thereafter (Table 1, entry 9:63% yield,
96.5:3.5 er after 7 h; Table 1, entry 7, 65% yield, 93:7 er after
15 h). This might be attributable to a catalyst decomposition
product, which is capable of ionizing the ammonium salt of 2a
(intermediate v, Scheme 3) but is nonselective and/or poorly
effective in promoting hydroamination, a task which is left to
the remaining intact Pd catalyst. We have not yet identified any
catalyst decomposition species.
When indoline adduct 2g is subjected to morpholine
(
2
Scheme 5C), a mixture of 2e and 2g is generated: incredibly,
g is recovered with only somewhat decreased er over the 20 h
Furthermore, results with isotopically labeled indoline
(Table 4) indicate a rapid equilibrium of diene and σ-allyl iii
prior to product formation (Scheme 3), yet transaminations,
which necessarily proceed via π-allyl iv, occur with high
enantiospecificity (Scheme 5). Therefore, under transamina-
tion conditions where a large concentration of nucleophilic
amine is present, π-allyl iv is trapped by a secondary amine to
give allyl ammonium salt v more quickly than it collapses to σ-
allyl iii, preventing greater erosion of enantiopurity. Con-
versely, in hydroamination reactions, the concentration of
amine available compared to the concentration of Pd−π-allyl iv
decreases over time, another factor that may contribute to
product enantiomerization as the reaction progresses.
reaction (97.5:2.5 to 95:5 er), despite the fact that in the
indoline hydroamination of diene 1a that affords 2g, the er is
lowered from 98.5:1.5 to 88:12 er over the same time period
(
Table 2). Furthermore, morpholine addition product 2e is
furnished in 98:2 er, essentially the same enantiopurity as the
starting allylic amine 2g that was subjected to the trans-
amination and measurably higher than in the morpholine
hydroamination of diene 1a (96.5:3.5 er, Table 2). It should be
noted, however, that in the hydroamination of 1a with
morpholine the enantioselectivity in forming allylic amine 2e is
initially 98:2 er (5 h, 38% yield) but declines over the 20 h
19
The Et N additive likely helps drive the reaction forward by
course of the reaction. The reverse transamination, reaction
of morpholine adduct 2e (95:5 er) with indoline, delivers allyl
indoline 2g in the same enantiopurity as the starting material
3
deprotonation of ammonium v to deliver product, rather than
leading to catalyst exhaustion through extensive unproductive
equilibration, thereby contributing to higher product yields. It
remains unclear why the amine nucleophile cannot fill this role.
2
e (Scheme 5D). Morpholine-containing 2e is recovered in a
diminished 88:12 er. Although this decline appears greater
than the loss of enantiopurity of 2g in Scheme 5C, it should be
remembered that the conversion of morpholine adduct 2e in
Scheme 5D is greater and its starting enantiomer ratio was not
as large. Therefore, in both cases, the lower enantiopurity of
the recovered allylic amine is reflective of the preferential
ionization of the major enantiomer with Pd-1 and the overall
level of conversion. Once more, diene 1a cannot be detected in
the transaminations in parts C and D of Scheme 5. The data
support, but perhaps do not conclusively prove, that
indoline-morpholine transaminations are completely enantio-
specific with Pd-1.
The question therefore still remained to what extent the
transaminations in parts A and B of Schemes 5 were
enantioselective (generation of 2e by an enantioconvergent
reaction via diene 1a, Curtin-Hammett kinetics) versus
enantiospecific (generation of 2e from Pd−π-allyl iv). We
therefore employed racemic Pd-1 catalyst with enantioen-
riched allylic amine 2a and morpholine to distinguish between
these two possibilities (Scheme 5E). We found that subjection
of 2a (95:5 er) to morpholine with racemic catalyst leads to
CONCLUSION
■
We have developed highly regio- and enantioselective Pd-
catalyzed hydroaminations of internal dienes. The success of
the transformation hinges upon a catalyst with a BArF
4
counterion, addition of Et N, and a nonpolar reaction medium.
3
Experiments have shed light on both the reversibility of
individual steps of the catalytic cycle and of the entire reaction,
including the ensuing stereochemical consequences. Future
efforts will be directed toward developing enantioselective
hydrofunctionalizations with other classes of nucleophiles and
unsaturated hydrocarbons and on further understanding the
mechanisms of these transformations.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b01914.
■
*
S
Experimental details, compound characterization, and
NMR spectra (PDF)
30
product 2e in 43% yield and 99:1 er, indicating that the
transaminations involving THIQ and morpholine are largely
enantiospecific with Pd-1. By analogy, we presume that the
transaminations in parts C and D of Scheme 5 are completely
enantiospecific. Thus, the degree of enantiospecificity in
AUTHOR INFORMATION
Corresponding Author
*E-mail: steven.malcolmson@duke.edu.
■
8
473
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
ORCID
Symmetrical Racemic Allylic Carbonates Featuring C−O-Bond
Formation and Dynamic Kinetic Resolution. Tetrahedron Lett. 2005,
Steven J. Malcolmson: 0000-0003-3229-0949
Notes
The authors declare no competing financial interest.
46, 6279−6283. (h) Dong, Y.; Teesdale-Spittle, P.; Hoberg, J. O.
Regioselective Palladium-Catalyzed Allylic Alkylations. Tetrahedron
Lett. 2005, 46, 353−355. (i) Hayashi, T.; Yamamoto, A.; Ito, Y.
Kinetic Resolution of Racemic Allyl Acetates in Asymmetric Allylic
Alkylation Catalysed by a Chiral Ferrocenylphosphine-Palladium
Complex. J. Chem. Soc., Chem. Commun. 1986, 22, 1090−1092.
ACKNOWLEDGMENTS
■
The authors thank Duke University, the American Chemical
Society Petroleum Research Fund (56575-DNI1), and the
National Science Foundation (CHE-1800012) for financial
support. We thank Nathan Adamson, Prof. Ross Widenhoefer
(j) Takahashi, T.; Jinbo, Y.; Kitamura, K.; Tsuji, J. Chirality Transfer
from C−O to C−C in the Palladium Catalyzed S N′ Reaction of (E)-
C
and (Z)-Allylic Carbonates with Carbonucleophile. Tetrahedron Lett.
1
(
984, 25, 5921−5924.
(
Duke), and Prof. Simon Meek (UNC Chapel Hill) for helpful
4) Common exceptions are reactions that proceed through
discussions. We are also grateful to Dr. Peter Silinski for
assistance with mass spectrometry experiments and Dr.
Benjamin Bobay and the Duke NMR center for aid with
NMR spectroscopy experiments.
symmetrical 1,3-disubstituted metal−π-allyl intermediates, which
afford products wherein the olefin and allylic substituents are
identical. See ref 2.
(5) Xiong, Y.; Sun, Y.; Zhang, G. Recent Advances on Catalytic
Asymmetric Difunctionalization of 1,3-Dienes. Tetrahedron Lett. 2018,
59, 347−355.
REFERENCES
■
(6) (a) Leitner, A.; Larsen, J.; Steffens, C.; Hartwig, J. F. Palladium-
(
1) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Substrate-Directable
Chemical Reactions. Chem. Rev. 1993, 93, 1307−1370.
Catalyzed Addition of Mono- and Dicarbonyl Compounds to
Conjugated Dienes. J. Org. Chem. 2004, 69, 7552−7557. (b) Lober,
̈
(
2) For reviews regarding enantioselective allylic substitution, see:
a) Grange, R. L.; Clizbe, E. A.; Evans, P. A. Recent Developments in
Asymmetric Allylic Amination Reactions. Synthesis 2016, 48, 2911−
968. (b) Bausch, C. C.; Pfaltz, A. In Privileged Chiral Ligands and
Catalysts, 1st ed.; Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, Germany,
011; p 221−256. (c) Hartwig, J. F.; Stanley, L. M. Mechanistically
O.; Kawatsura, M.; Hartwig, J. F. Palladium-Catalyzed Hydro-
amination of 1,3-Dienes: A Colorimetric Assay and Enantioselective
Additions. J. Am. Chem. Soc. 2001, 123, 4366−4367.
(
2
(7) For examples where the diene acts as an electrophile, see:
(a) Yang, X.-H.; Dong, V. M. Rhodium-Catalyzed Hydrofunctional-
2
ization: Enantioselective Coupling of Indolines and 1,3-Dienes. J. Am.
Chem. Soc. 2017, 139, 1774−1777. (b) Podhajsky, S. M.; Iwai, Y.;
Cook-Sneathen, A.; Sigman, M. S. Asymmetric Palladium-Catalyzed
Hydroarylation of Styrenes and Dienes. Tetrahedron 2011, 67, 4435−
Driven Development of Iridium Catalysts for Asymmetric Allylic
Substitution. Acc. Chem. Res. 2010, 43, 1461−1475. (d) Trost, B. M.;
Zhang, T.; Sieber, J. D. Catalytic Asymmetric Allylic Alkylation
Employing Heteroatom Nucleophiles: A Powerful Method for C−X
Bond Formation. Chem. Sci. 2010, 1, 427−440. (e) Lu, Z.; Ma, S.
Metal-Catalyzed Enantioselective Allylation in Asymmetric Synthesis.
Angew. Chem., Int. Ed. 2008, 47, 258−297. (f) Harutyunyan, S. R.;
den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Catalytic
Asymmetric Conjugate Addition and Allylic Alkylation with Grignard
Reagents. Chem. Rev. 2008, 108, 2824−2852. (g) Trost, B. M.;
Machacek, M. R.; Aponick, A. Predicting the Stereochemistry of
Diphenylphosphino Benzoic Acid (DPPBA)-Based Palladium-Cata-
lyzed Asymmetric Allylic Alkylation Reactions: A Working Model.
Acc. Chem. Res. 2006, 39, 747−760. (h) Helmchen, G.; Pfaltz, A.
Phosphinooxazolines − A New Class of Versatile, Modular P,N-
Ligands for Asymmetric Catalysis. Acc. Chem. Res. 2000, 33, 336−345.
4441. (c) Shirakura, M.; Suginome, M. Nickel-Catalyzed Asymmetric
Addition of Alkyne C−H Bonds across 1,3-Dienes Using Taddol-
Based Chiral Phosphoramidite Ligands. Angew. Chem., Int. Ed. 2010,
4
(
(
9, 3827−3829.
8) For examples where the diene acts as a nucleophile, see:
a) Holmes, M.; Schwartz, L. A.; Krische, M. J. Intermolecular Metal-
Catalyzed Reductive Coupling of Dienes, Allenes, and Enynes with
Carbonyl Compounds and Imines. Chem. Rev. 2018, 118, 6026−
6052. (b) Gui, Y.-Y.; Hu, N.; Chen, X.-W.; Liao, L.-L.; Ju, T.; Ye, J.-
H.; Zhang, Z.; Li, J.; Yu, D.-G. Highly Regio- and Enantioselective
Copper-Catalyzed Reductive Hydroxymethylation of Styrenes and
1
,3-Dienes with CO . J. Am. Chem. Soc. 2017, 139, 17011−17014.
2
(c) Nguyen, K. D.; Herkommer, D.; Krische, M. J. Enantioselective
(3) (a) Yan, L.; Xu, J.-K.; Huang, C.-F.; He, Z.-Y.; Xu, Y.-N.; Tian,
Formation of All-Carbon Quaternary Centers via C−H Functional-
ization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethy-
lation. J. Am. Chem. Soc. 2016, 138, 14210−14213. (d) Grayson, M.
N.; Krische, M. J.; Houk, K. N. Ruthenium-Catalyzed Asymmetric
Hydrohydroxyalkylation of Butadiene: The Role of the Formyl
Hydrogen Bond in Stereochemical Control. J. Am. Chem. Soc. 2015,
S.-K. Kinetic Resolution of Racemic Allylic Alcohols by Catalytic
Asymmetric Substitution of the OH Group with Monosubstituted
Hydrazines. Chem. - Eur. J. 2016, 22, 13041−13045. (b) Ikeda, K.;
Futamura, T.; Hanakawa, T.; Minakawa, M.; Kawatsura, M.
Palladium-Catalyzed Enantioselective Allylic Alkylation of Trifluor-
omethyl Group Substituted Racemic and Acyclic Unsymmetrical 1,3-
Disubstituted Allylic Esters with Malonate Anions. Org. Biomol. Chem.
137, 8838−8850. (e) Itoh, T.; Montgomery, T. P.; Recio, A., III;
Krische, M. J. Asymmetric Alcohol C−H Allylation and syn-
Crotylation: C9−C20 of Tetrafibricin. Org. Lett. 2014, 16, 820−
823. (f) Zbieg, J. R.; Yamaguchi, E.; McInturff, E. L.; Krische, M. J.
Enantioselective C−H Crotylation of Primary Alcohols via Hydro-
hydroxyalkylation of Butadiene. Science 2012, 336, 324−327.
2
016, 14, 3501−3505. (c) Kawatsura, M.; Terasaki, S.; Minakawa, M.;
Hirakawa, T.; Ikeda, K.; Itoh, T. Enantioselective Allylic Amination of
Trifluoromethyl Group Substituted Racemic and Unsymmetrical 1,3-
Disubstituted Allylic Esters by Palladium Catalysts. Org. Lett. 2014,
1
6, 2442−2445. (d) Du, L.; Cao, P.; Xing, J.; Lou, Y.; Jiang, L.; Li, L.;
Liao, J. Hydrogen-Bond-Promoted Palladium Catalysis: Allylic
Alkylation of Indoles with Unsymmetrical 1,3-Disubstituted Allyl
Acetates Using Chiral Bis(sulfoxide) Phosphine Ligands. Angew.
(9) For select enantioselective difunctionalization reactions of
terminal dienes (not hydrofunctionalizations), see: (a) Jiang, L.;
Cao, P.; Wang, M.; Chen, B.; Wang, B.; Liao, J. Highly Diastereo- and
Enantioselective Cu-Catalyzed Borylative Coupling of 1,3-Dienes and
Aldimines. Angew. Chem., Int. Ed. 2016, 55, 13854−13858. (b) Li, X.;
Meng, F.; Torker, S.; Shi, Y.; Hoveyda, A. H. Catalytic
Enantioselective Conjugate Additions of (pin)B-Substituted Allylcop-
per Compounds Generated in situ from Butadiene or Isoprene.
Angew. Chem., Int. Ed. 2016, 55, 9997−10002. (c) Liu, Y.; Xie, Y.;
Wang, H.; Huang, H. Enantioselective Aminomethylamination of
Conjugated Dienes with Aminals Enabled by Chiral Palladium
Complex-Catalyzed C−N Bond Activation. J. Am. Chem. Soc. 2016,
138, 4314−4317. (d) Wu, X.; Lin, H.-C.; Li, M.-L.; Li, L.-L.; Han, Z.-
Chem., Int. Ed. 2013, 52, 4207−4211. (e) Mao, B.; Ji, Y.; Fananas-
̃
́
Mastral, M.; Caroli, G.; Meetsma, A.; Feringa, B. L. Highly
Enantioselective Synthesis of 3-Substituted Furanones by Palladium-
Catalyzed Kinetic Resolution of Unsymmetrical Allyl Acetates. Angew.
Chem., Int. Ed. 2012, 51, 3168−3173. (f) Hirakawa, T.; Ikeda, K.;
Ogasa, H.; Kawatsura, M.; Itoh, T. Regioselective Synthesis of
Optically Active Trifluoromethyl Group Sybstituted Allylic Amines by
Palladium-Catalyzed Allylic Amination. Synlett 2010, 2010, 2887−
2
890. (g) Gais, H.-J.; Bondarev, O.; Hetzer, R. Palladium-Catalyzed
Asymmetric Synthesis of Allylic Alcohols from Unsymmetrical and
8
474
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
Y.; Gong, L.-Z. Enantioselective 1,2-Difunctionalization of Dienes
Enabled by Chiral Palladium Complex-Catalyzed Cascade Arylation/
Allylic Alkylation Reaction. J. Am. Chem. Soc. 2015, 137, 13476−
Ed. 2015, 54, 1638−1641. (e) Zhu, S.; Niljianskul, N.; Buchwald, S. L.
Enantio- and Regioselective CuH-Catalyzed Hydroamination of
Alkenes. J. Am. Chem. Soc. 2013, 135, 15746−15749. (f) Miki, Y.;
Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed Intermolecular
Regioselective Hydroamination of Styrenes with Polymethylhydrosi-
loxane and Hydroxylamines. Angew. Chem., Int. Ed. 2013, 52, 10830−
13479. (e) Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.;
Sigman, M. S. A Palladium-Catalyzed Three-Component-Coupling
Strategy for the Differential Vicinal Diarylation of Terminal 1,3-
Dienes. Org. Lett. 2014, 16, 4666−4669. (f) Schuster, C. H.; Li, B.;
Morken, J. P. Modular Monodentate Oxaphospholane Ligands:
Utility in Highly Efficient and Enantioselective 1,4-Diboration of
10834.
(17) For hydroamination reviews, see: (a) Huang, L.; Arndt, M.;
Gooßen, K.; Heydt, H.; Gooßen, L. J. Late Transition Metal-
Catalyzed Hydroamination and Hydroamidation. Chem. Rev. 2015,
1,3-Dienes. Angew. Chem., Int. Ed. 2011, 50, 7906−7909. (g) Du, H.;
Zhao, B.; Shi, Y. Catalytic Asymmetric Allylic and Homoallylic
Diamination of Terminal Olefins via Formal C−H Activation. J. Am.
Chem. Soc. 2008, 130, 8590−8591. (h) Du, H.; Yuan, W.; Zhao, B.;
Shi, Y. Catalytic Asymmetric Diamination of Conjugated Dienes and
Triene. J. Am. Chem. Soc. 2007, 129, 11688−11689.
1
15, 2596−2697. (b) Reznichenko, A. L.; Nawara-Hultzsch, A. J.;
Hultzsch, K. C. Asymmetric Hydroamination. Top. Curr. Chem. 2013,
43, 191−260.
18) For other enantioselective intermolecular hydroaminations with
3
(
alkyl and aryl amines, see: (a) Cooke, M. L.; Xu, K.; Breit, B.
Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic
Amines by Intermolecular Hydroamination of Terminal Allenes.
Angew. Chem., Int. Ed. 2012, 51, 10876−10879. (b) Reznichenko, A.
L.; Nguyen, H. N.; Hultzsch, K. C. Asymmetric Intermolecular
Hydroamination of Unactivated Alkenes with Simple Amines. Angew.
Chem., Int. Ed. 2010, 49, 8984−8987. (c) Utsunomiya, M.; Hartwig, J.
F. J. Am. Chem. Soc. 2003, 125, 14286−14287. (d) Kawatsura, M.;
Hartwig, J. F. Palladium-Catalyzed Intermolecular Hydroamination of
Vinylarenes Using Arylamines. J. Am. Chem. Soc. 2000, 122, 9546−
(10) (a) Adamson, N. J.; Wilbur, K. C. E.; Malcolmson, S. J.
Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of
Acyclic 1,3-Dienes with Activated Pronucleophiles. J. Am. Chem.
Soc. 2018, 140, 2761−2764. (b) Adamson, N. J.; Hull, E.;
Malcolmson, S. J. Enantioselective Intermolecular Addition of
Aliphatic Amines to Acyclic Dienes with a Pd−PHOX Catalyst. J.
Am. Chem. Soc. 2017, 139, 7180−7183.
(11) (a) Saito, N.; Kobayashi, A.; Sato, Y. Nickel-Catalyzed Enantio-
and Diastereoselective Three-Component Coupling of 1,3-Dienes,
Aldehydes, and a Silylborane Leading to α-Chiral Allylsilanes. Angew.
Chem., Int. Ed. 2012, 51, 1228−1231. (b) Watkins, A. L.; Landis, C.
R. Regioselective Rhodium-Catalyzed Hydroformylation of 1,3-
Dienes to Highly Enantioenriched β,γ-Unsaturated Aldehydes with
Diazaphospholane Ligands. Org. Lett. 2011, 13, 164−167. (c) Sato,
Y.; Hinata, Y.; Seki, R.; Oonishi, Y.; Saito, N. Nickel-Catalyzed
Enantio- and Diastereoselective Three-Component Coupling of 1,3-
Dienes, Aldehydes, and Silanes Using Chiral N-Heterocyclic Carbenes
as Ligands. Org. Lett. 2007, 9, 5597−5599. (d) Yang, Y.; Zhu, S.-F.;
Duan, H.-F.; Zhou, C.-Y.; Wang, L.-X.; Zhou, Q.-L. Asymmetric
Reductive Coupling of Dienes and Aldehydes Catalyzed by Nickel
Complexes of Spiro Phosphoramidites: Highly Enantioselective
Synthesis of Bishomoallylic Alcohols. J. Am. Chem. Soc. 2007, 129,
9
(
547. For additional C−N bond-forming hydroaminations, see:
e) Koschker, P.; Breit, B. Branching Out: Rhodium-Catalyzed
Allylation with Alkynes and Allenes. Acc. Chem. Res. 2016, 49, 1524−
536. (f) Butler, K. L.; Tragni, M.; Widenhoefer, R. A. Gold(I)-
1
Catalyzed Stereoconvergent, Intermolecular Enantioselective Hydro-
amination of Allenes. Angew. Chem., Int. Ed. 2012, 51, 5175−5178.
(19) See the Supporting Information for further details.
(20) (a) Troshin, K.; Mayer, P.; Mayr, H. How Does Palladium
Coordination Affect the Electrophilicities of Allyl Cations? Develop-
3
ment of a Robust Kinetic Method for Following Reactions of [(η -
+
Diarylallyl)Pd(PPh ) ] with Nucleophiles. Organometallics 2012, 31,
3
2
2416−2424. (b) Kanzian, T.; Nigst, T. A.; Maier, A.; Pichl, S.; Mayr,
H. Nucleophilic Reactivities of Primary and Secondary Amines in
Acetonitrile. Eur. J. Org. Chem. 2009, 2009, 6379−6385.
2
(
248−2249.
12) For an example involving difunctionalization of substituted
cyclohexadienes, see: Sardini, S. R.; Brown, M. K. Catalyst Controlled
Regiodivergent Arylboration of Dienes. J. Am. Chem. Soc. 2017, 139,
(21) (a) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J.
F. A Highly Active Palladium Catalyst for Intermolecular Hydro-
amination. Factors that Control Reactivity and Additions of
Functionalized Anilines to Dienes and Vinylarenes. J. Am. Chem.
Soc. 2006, 128, 1828−1839. (b) Utsunomiya, M.; Hartwig, J. F.
Intermolecular, Markovnikov Hydroamination of Vinylarenes with
Alkylamines. J. Am. Chem. Soc. 2003, 125, 14286−14287.
9
(
823−9826.
13) For examples involving electrophilic addition to internal 2-
azadienes, see: (a) Shao, X.; li, K.; Malcolmson, S. J. Enantioselective
Synthesis of anti-1,2-Diamines by Cu-Catalyzed Reductive Couplings
of Azadienes with Aldimines and Ketimines. J. Am. Chem. Soc. 2018,
140, 7083−7087. (b) Li, K.; Shao, X.; Tseng, L.; Malcolmson, S. J. 2-
(c) Nettekoven, U.; Hartwig, J. F. A New Pathway for Hydro-
Azadienes as Reagents for Preparing Chiral Amines: Synthesis of 1,2-
Amino Tertiary Alcohols by Cu-Catalyzed Enantioselective Reductive
Couplings with Ketones. J. Am. Chem. Soc. 2018, 140, 598−601.
amination. Mechanism of Palladium-Catalyzed Addition of Anilines to
Vinylarenes. J. Am. Chem. Soc. 2002, 124, 1166−1167. (d) Armbruster,
R. W.; Morgan, M. M.; Schmidt, J. L.; Lau, C. M.; Riley, R. M.;
Zabrowsky, D. L.; Dieck, H. A. Palladium-Catalyzed Additions of
Amines to Conjugated Dienes: Alteration of Behavior of
(14) Marcum, J. S.; Roberts, C. C.; Manan, R. S.; Cervarich, T. N.;
Meek, S. J. Chiral Pincer Carbodicarbene Ligands for Enantioselective
Rhodium-Catalyzed Hydroarylation of Terminal and Internal 1,3-
Dienes with Indoles. J. Am. Chem. Soc. 2017, 139, 15580−15583.
(
Triphenyphosphine)palladium Catalysts with Amine Hydroiodide
Salts. Organometallics 1986, 5, 234−237.
22) Addition of amine nucleophile to Pd-1 initiates the precatalyst
and generates an equivalent quantity of Brønsted acid.
23) For relevant Pd-catalyzed transamination studies, see:
a) Wang, Y.; Li, M.; Ma, X.; Liu, C.; Gu, Y.; Tian, S.-K.
(15) Teng, H.-L.; Luo, Y.; Wang, B.; Zhang, L.; Nishiura, M.; Hou,
(
Z. Synthesis of Chiral Aminocyclopropanes by Rare-Earth-Metal-
Catalyzed Cyclopropene Hydroamination. Angew. Chem., Int. Ed.
(
2
(
016, 55, 15406−15410.
(
16) (a) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F.
Deammoniative Condensation of Primary Allylic Amines with
Nonallylic Amines. Chin. J. Chem. 2014, 32, 741−751. (b) Ozawa,
F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji,
M. (π-Allyl)palladium Complexes Bearing Diphosphinidenecyclobu-
tene Ligands (DPCB): Highly Active Catalysts for Direct Conversion
of Allylic Alcohols. J. Am. Chem. Soc. 2002, 124, 10968−10969.
(c) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. General
Nickel-Catalyzed Hydroamination of 1,3-Dienes by Alkylamines:
Catalyst Selection, Scope, and Mechanism. J. Am. Chem. Soc. 2002,
124, 3669−3679.
Regioselective, Asymmetric Formal Hydroamination of Unactivated
Internal Alkenes. Angew. Chem., Int. Ed. 2016, 55, 776−780.
(b) Nishikawa, D.; Hirano, K.; Miura, M. Asymmetric Synthesis of
α-Aminoboronic Acid Derivatives by Copper-Catalyzed Enantiose-
lective Hydroamination. J. Am. Chem. Soc. 2015, 137, 15620−15623.
(c) Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Catalytic
Asymmetric Hydroamination of Unactivated Internal Olefins to
Aliphatic Amines. Science 2015, 349, 62−66. (d) Niljianskul, N.; Zhu,
S.; Buchwald, S. L. Enantioselective Synthesis of α-Aminosilanes by
Copper-Catalyzed Hydroamination of Vinylsilanes. Angew. Chem., Int.
8
475
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476

ACS Catalysis
Research Article
(24) Deuterated indoline was employed as other deuterated amines,
such as THIQ or morpholine, lead to a prohibitively slow reaction
with diene 1a.
(25) For a study regarding the thermodynamics of styrene/aniline
hydroamination, see: Johns, A. M.; Sakai, N.; Ridder, A.; Hartwig, J. F.
Direct Measurement of the Thermodynamics of Vinylarene Hydro-
amination. J. Am. Chem. Soc. 2006, 128, 9306−9307.
(26) (a) Holtzman, B. S.; Roberts, E. T.; Caminiti, N. S.; Fox, J. A.;
Goodstein, M. B.; Hill, S. A.; Jia, Z. B.; Leibler, I. N.-M.; Martini, M.
L.; Mendolia, G. M.; Nodder, S. B.; Costanza-Robinson, M. S.; Bunt,
R. C. Ligand and Base Additive Effects on the Reversibility of
Nucleophilic Addition in Palladium-Catalyzed Allylic Aminations
Monitored by Nucleophile Crossover. Tetrahedron Lett. 2017, 58,
4
32−436. (b) Caminiti, N. S.; Goodstein, M. B.; Leibler, I. N.-M.;
Holtzman, B. S.; Jia, Z. B.; Martini, M. L.; Nelson, N. C.; Bunt, R. C.
Reversible Nucleophilic Addition Can Lower the Observed
Enantioselectivity in Palladium-Catalyzed Allylic Amination Reactions
with a Variety of Chiral Ligands. Tetrahedron Lett. 2015, 56, 5445−
5448.
(27) Takacs, J. M.; Lawson, E. C.; Clement, F. On the Nature of the
Catalytic Palladium-Mediated Elimination of Allylic Carbonates and
Acetates to Form 1,3-Dienes. J. Am. Chem. Soc. 1997, 119, 5956−
5
(
957.
28) von Matt, P.; Loiseleur, O.; Koch, G.; Pfaltz, A.; Lefeber, C.;
Feucht, T.; Helmchen, G. Enantioselective Allylic Amination with
Chiral (Phosphino-oxazoline)Pd Catalysts. Tetrahedron: Asymmetry
1
(
994, 5, 573−584.
29) One pathway for product enantiomerization that may occur
without the conversion of Pd−π-allyl iv to diene 1a and which we
cannot rule out at this time involves facial exchange of Pd−π-allyl iv
0
with another Pd species via outer sphere attack; see: Granberg, K. L.;
Backvall, J.-E. Isomerization of (π-Allyl)palladium Complexes via
̈
Nucleophilic Displacement by Palladium(0). A Common Mechanism
in Palladium(0)-Catalyzed Allylic Substitution. J. Am. Chem. Soc.
1
(
2
992, 114, 6858−6863.
30) Enantioenrichment of product 2e compared to starting material
a reflects the relative rates of ionization of the two starting material
enantiomers, one present in higher concentration, plus the <50%
conversion to product.
8
476
DOI: 10.1021/acscatal.8b01914
ACS Catal. 2018, 8, 8468−8476