Preparation of Chiral Allenes through Pd-Catalyzed Intermolecular Hydroamination of Conjugated Enynes: Enantioselective Synthesis Enabled by Catalyst Design

Article abstract of DOI:10.1021/jacs.9b02637

In this study, we establish that conjugated enynes undergo selective 1,4-hydroamination under Pd catalysis to deliver chiral allenes with pendant allylic amines. Several primary and secondary aliphatic and aryl-substituted amines couple with a wide range of mono- and disubstituted enynes in a nonenantioselective reaction where DPEphos serves as the ligand for Pd. Benzophenone imine acts as an ammonia surrogate to afford primary amines in a two-step/one-pot process. Examination of chiral catalysts revealed a high degree of reversibility in the C-N bond formation that negatively impacted enantioselectivity. Consequently, an electron-poor ferrocenyl-PHOX ligand was developed to enable efficient and enantioselective enyne hydroamination.

Full text of DOI:10.1021/jacs.9b02637

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Article
Preparation of Chiral Allenes through Pd-Catalyzed
Intermolecular Hydroamination of Conjugated Enynes:
Enantioselective Synthesis Enabled by Catalyst Design
Nathan J. Adamson, Haleh Jeddi, and Steven J. Malcolmson
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 May 2019
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Journal of the American Chemical Society
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Preparation of Chiral Allenes through Pd-Catalyzed
Intermolecular Hydroamination of Conjugated Enynes:
Enantioselective Synthesis Enabled by Catalyst Design
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Nathan J. Adamson, Haleh Jeddi, and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
Supporting Information Placeholder
be noted that Cu-catalyzed enyne hydroboration17 delivers chiral
ABSTRACT: In this study, we establish that conjugated enynes
allenes through the direct σ-bond metathesis of the metal for boron
undergo selective 1,4-hydroamination under Pd catalysis to deliver
chiral allenes with pendant allylic amines. Several primary and
secondary aliphatic and aryl-substituted amines couple with a wide
range of mono- and disubstituted enynes in a non-enantioselective
reaction where DPEphos serves as the ligand for Pd. Benzophenone
imine acts as an ammonia surrogate to afford primary amines in a
two-step/one-pot process. Examination of chiral catalysts revealed
a high degree of reversibility in the C–N bond formation that
negatively impacted enantioselectivity. Consequently, an electron-
poor ferrocenyl-PHOX ligand was developed to enable efficient
and enantioselective enyne hydroamination.
in the allenyl metal intermediate.18
Scheme 1. Hydroaminations of Enynes
 Chiral Allenes through Sr-Catalyzed Hydroamination of Enynes
H
5 mol %
Barrett & Hill (2012)
[Sr(HMDS)2]2
Ph
•
+
H
N
N
72% yield
Ph
H
(racemic)
single example
 Internal Alkenes via Pd-Catalyzed Enyne Diamination
5 mol %
[Pd(3-C3H5)Cl]2
12 mol % dppf
Yamamoto (1998)
H
Me
1. INTRODUCTION
H
•
Bn
Bn
H
+
Me
N
H
The development of new transformations for the installation of
amine functionality is critically important for the preparation of
new medicines, agrochemicals, and natural products.
Intermolecular hydroamination1 provides an atom economical way
of generating chiral amines from readily available unsaturated
hydrocarbons via C–N bond formation. Catalytic enantioselective
reactions involving alkynes,2 allenes,3 cyclic4 and acyclic5 1,3-
dienes, vinylarenes,6 cyclopropenes,7 and simple α-olefins8 have
been disclosed.9
1 equiv AcOH
THF, 80 °C
Bn2N
postulated
Bn2N
NBn2
70% yield
H
Me
Proposal: Chiral Allenes via Pd-Catalyzed Hydroamination

R2
H
In contrast to these numerous examples are the paucity of reports
detailing hydroamination of conjugated enynes. Recently, Barrett,
H
[Pd]
R3 R4
[Pd]
I
R1
+
N
H
R1
Hill, and co-workers have demonstrated
a single, non-
R2
enantioselective Sr-catalyzed hydroamination of an enyne that
delivers an aminomethyl-substituted allene (Scheme 1).10 The
Yamamoto laboratory has shown that 3-substituted enynes undergo
Pd–bis(phosphine)-catalyzed double addition of aliphatic amines to
yield 2-butenyl-1,4-diamines.11 These reactions were suggested to
take place by the intermediacy of an aminomethyl-substituted
allene. To our knowledge, there are no reported examples of
enantioselective hydroamination of unactivated enynes.12,13 In
general, intermolecular couplings of unactivated enynes with
nucleophiles are rare, especially in a catalytic enantioselective
fashion.14
H
site-selectivity?
enantioselectivity?
reversibility?
•
•
•
•
H
R1
•
R2
[Pd]
R1
•
R2
R3
N
II
product selectivity?
R4
In part inspired by Yamamoto’s proposal that enyne
diaminations occur by initial formation of an aminomethyl allene,11
we hypothesized that under milder reaction conditions and with the
appropriate catalyst, Pd-catalyzed hydroamination of enynes might
lead to allene products (Scheme 1). Although Pd–H insertion could
occur at the olefin, this cannot lead to a stable π-allyl complex for
amine addition. Instead, alkyne insertion would lead to η1-
butadienyl –Pd I, which could then lead to the η3-butadienyl–Pd II.
Nucleophilic attack at the least hindered electrophilic carbon would
then afford the allene product.19 Such a π-allyl complex has been
In fact, the majority of late transition metal-catalyzed enyne
hydrofunctionalizations have concerned reductive couplings with
aldehydes or ketones as electrophiles.15 Interestingly, reactions that
take place by initial metal–hydride insertion16 (Ru-, Ir-, or Cu-
based catalysts) generally do so at the alkene, forming a propargyl
metal species that is in equilibrium with an allenyl metal. It should
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aReactions under N2 with 0.2 mmol tetrahydroisoquinoline (0.8 M).
invoked as an intermediate in several Pd-catalyzed allylic
substitution and related reactions.20
bIsolated yield of 2a after purification. cNaBF4 instead of NaBArF .
4
1
dReaction with isolated [(DPEPhos)Pd(3-C3H5)]BF4 (Pd-1).
2
3
4
5
6
7
8
9
Yet even if this site-selectivity could be achieved for
hydroamination, several questions remained with regard to enantio-
and chemoselectivity of the Pd-catalyzed process. 1) To achieve
high enantioselectivity, a chiral catalyst would have to control the
direction of the 90° single bond rotation of dienyl I in forming
π-allyl II or alternatively, nucleophilic attack upon II or its
diastereomer would have to be under Curtin–Hammett control.20
Although there was some precedent in allylic substitution with
malonate,20a,b,d amine,20b,c and amide nucleophiles,20c,e would this
be possible in hydroamination? 2) Even if kinetic control of
enantioselectivity could be achieved, would reaction reversibility
via C–N bond ionization and reformation of I erode it over the
course of the reaction? 3) Would the optimal catalyst for
controlling site- and enantioselectivity also selectively lead to
allene formation without further reaction to produce a diamine?11
In this work, we illustrate the successful realization of an enyne
1,4-hydroamination process to prepare myriad racemic
aminomethyl-substituted allenes with DPEphos-ligated Pd as
catalyst. Through the design and development of a new PHOX
ligand, we demonstrate the principles needed for enantioselectivity
control in this transformation.
equivalent results, we opted to continue with the former. NaBF4 in
place of NaBArF gave nearly the same result as well (entry 7)
4
although having a non-coordinating counterion was important for
reaction efficiency.23 The isolated Pd complex (Pd-1) behaved
similarly to that formed in situ (entry 8), and so for exploration of
reaction scope, we employed isolated Pd-1. Under the optimized
conditions, allene 2a was obtained in 88% yield.
Numerous readily accessible enynes couple with a wide range of
commercially available amines for 1,4-hydroamination with Pd-1
(Table 2). A variety of aryl-substituted enynes are effective
partners in transformations with THIQ (2b–k, 63–92% yield).
Substrate electronics have little obvious effect on reaction
efficiency, and several aryl substituents are compatible with the
hydroamination process, including functionality with acidic
protons (2c), aryl bromides (2d), and aldehydes (2e). ortho-
Substituted arenes afford products with only slightly diminished
yields (2j–k). A naphthyl group (2l) and heteroaromatic rings
(2m–n), including a Lewis basic pyridyl substituent, are tolerated.
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Alkyl-substituted enynes and a silyl-substituted enyne undergo
efficient hydroamination with THIQ24 as well (Table 2, 20–u, 52–
91% yield). The functional group tolerance is again impressive, a
testament to the mild reaction conditions for this catalytic process.
A propargylic phthalimido group (2q) and a primary tosylate (2s)
remain intact. A free hydroxyl group (2r) does not interfere in the
process. With extended reaction times, steric hindrance imposed at
the alkyne by a TBS (2t) or cyclohexyl (2u) group can also be
overcome by the Pd-based catalyst.
2. RESULTS AND DISCUSSION
2.1. Development of Non-Enantioselective Enyne
Hydroamination with Alkyl Amines, Aryl-Substituted Amines,
and Benzophenone Imine. We began our study by investigating
the non-enantioselective addition of tetrahydroisoquinoline
(THIQ) to phenyl-substituted enyne 1a (Table 1). Catalyst was
generated in situ from 2.5 mol % [(η3-C3H5)PdCl]2 and 6 mol %
NaBArF with 5 mol % of several achiral bis(phosphine) ligands.
The amine scope is similarly broad (Table 2), both with phenyl-
substituted enyne 1a and phenethyl-containing enyne 1o; the atom
economic reactions generate allenes 2v–am in 51–91% yield.
Several amines, including the more Lewis basic piperidine (2w and
2af) and pyrrolidine (2x and 2ah) that may at times prove
challenging to late transition metal catalysts, couple in good yields.
Additionally, azepane (2y) and a ketal-containing piperidine (2ag),
which may serve as an ammonia surrogate,25 are also effective
partners. Aryl-substituted amines, such as tetrahydroquinoline and
indoline, afford allenes 2z and 2ai in 59% and 70% yields,
respectively. Acyclic secondary amines such as N-
methylbenzylamine (2aa and 2aj) and sterically hindered
diethylamine (2ab and 2ak) add smoothly to enynes. Primary
amines are also capable of participating in the enyne
hydroamination (2ac–ad and 2al–am) although the
transformations require 10 mol % Pd-1 and catalyst turnover is low
(51–61% yield). The 1,4-hydroamination of enyne 1a is readily
scalable (5.0 mmol scale) and can be carried out with as little as 2
4
No matter the phosphine identity, allene 2a was obtained
selectively after 3 h at ambient temperature in CH2Cl2. Other
product regioisomers and diamination of the enyne were not
observed. The efficiency of the reaction was correlated with the
natural bite angle of the phosphine (entries 1–6).21,22 This
phenomenon could perhaps be attributed to an increased rate of
nucleophilic attack upon the Pd--allyl with wider bite angle
ligands.22 As DPEphos and Xantphos gave roughly
Table 1. Role of Ligand Bite Angle on Efficiency of the Non-
Enantioselective Pd-Catalyzed Processa
2.5 mol % [Pd(3-C3H5)Cl]2
H
HN
5 mol % ligand
6 mol % NaBArF
Ph
•
4
+
H
N
CH2Cl2, 22 °C, 3 h
mol % Pd catalyst, prepared in situ with NaBArF (Scheme 2).
Ph
2a
4
1a
(racemic)
Under these conditions, 1.2 g of the THIQ adduct 2a was obtained
in 92% yield.
(1.2 equiv)
b
2a
(%)
entry
ligand
bite angle
yield of
Scheme
2.
Scalability
of
Non-Enantioselective
1
2
dppe
dppp
86°
91°
14
Hydroamination with Tetrahydroisoquinoline
44
62
63
84
83
86
88
3
dppb
94°
4
dppf
99°
1 mol % [Pd(3-C3H5)Cl]2
HN
H
5
DPEphos
Xantphos
DPEphos
DPEphos
104°
108°
104°
104°
2 mol % DPEphos
6
Ph
•
(5.0 mmol)
2.3 mol % NaBArF
4
H
7c
8d
+
N
CH2Cl2, 22 °C, 3 h
(racemic)
2a
Ph
1a
92% yield
(1.2 g prepared)
(1.2 equiv)
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Journal of the American Chemical Society
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Table 2. Scope of Non-Enantioselective Enyne Hydroamination to Prepare Disubstituted Allenesa
3
4
5
6
H
O
R1
Pd-1
R2 R3
5 mol %
•
Ph2P
PPh2
BF4
R2
+
R1
H
N
H
Pd
N
1
CH2Cl2, 22 °C, 3 h
2
R3
7
(1.2 equiv)
(racemic)
Pd-1
8
9
H
G = OMe
82% yield
2b
2c
2d
2e
2f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
G
G = Me 86% yield
G = CN 92% yield
2h
2i
G = NHAc
G = Br
70% yield
84% yield
66% yield
•
G
H
N
G
G = CHO
G
G = CO2Me 86% yield
G = CF3 89% yield
G = Me
76% yield
2j
2g
G = OAc 63% yield
2k
H
H
H
•
•
•
H
H
H
N
O
N
N
N
2l
2m
2nb
88% yield
76% yield
63% yield
HO
2oc
2pc
2qc
2rc
H
86% yield
79% yield
78% yield
58% yield
75% yield
52% yield
Ph
R1
•
H
N
TsO
2sc
2ub,c
77% yield
n-C10H21
2tb,c
PhthN
t-BuMe2Si
NMeBn
NHCy
H
N
NMe
N
N
N
N
2aa
2ace
2ade
2ale
91% yield
61% yield
Ph
•
R2
H
2v
2w
2x
2y
N
NEt2
NHn-Pr
R3
2zd
74% yield
N
74% yield
69% yield
76% yield
N
59% yield
2ab
2aj
76% yield
56% yield
O
O
NMeBn
NHCy
H
O
N
N
N
88% yield
59% yield
Ph
•
R2
H
2ae
2af
2ag
2ah
N
R3
NEt2
NHn-Pr
77% yield
68% yield
92% yield
57% yield
70% yield
2ai
2ak
2ame
77% yield
51% yield
aReactions under N2 with 0.2 mmol amine (0.8 M) and 5 mol % Pd-1 for 3 h unless otherwise noted. Isolated yields of purified products. 15 h reaction.
b
cCatalyst prepared in situ with NaBArF . d20 h reaction. e10 mol % Pd-1.
4
We were also pleased to find that benzophenone imine,3i which
serves as a surrogate for ammonia, undergoes facile addition to
enynes 1 with 5 mol % Pd-1 in the presence of Et3N as a proton
shuttle (Table 3). Selective 1,4-addition occurs to afford 3 after 24
h. The imine may be isolated or hydrolyzed in the workup under
mildly acidic conditions to form the corresponding primary amine
4. For example, reaction with enyne 1a leads to allene 3 in 86%
yield, but addition to naphthyl-substituted enyne 1l and in situ
hydrolysis of the resulting imine delivers primary amine 4a in 65%
yield. Alkyl-substituted enynes also react with benzophenone
imine to form allenes 4b–c after hydrolysis. Thus, through the 1,4-
hydroamination process, myriad chiral allenes that contain tertiary,
secondary, and primary amines may be obtained in racemic form.
addition, catalyzed by Pd-1, enables the isolation of trisubstituted
allenes 6 in 51–82% yield. With a phenyl substituent at C1, several
groups are tolerated at the 3-position, including methyl (6a), linear
alkyl (6b), α-branched cyclohexyl (6c), and a trifluoromethyl group
(6d). An enyne bearing alkyl groups at both the 1- and 3-positions
furnishes trialkyl-containing allene 6e in 82% yield; however, with
aryl substitution at both positions, the enyne proved too unstable to
allow for study.
We additionally examined the addition of THIQ to 1,4-
disubstituted enyne (Z)-7 (Scheme 3). Compared to reactions with
the 1,3-disubstituted congeners, the transformation is markedly less
efficient in the absence of Et3N. After 20
h
with
[Pd(DPEphos)]BArF , aminoethyl allene 8 is isolated in 25% yield
4
Furthermore, we have investigated the addition of THIQ to a
handful of 1,3-disubstituted enynes 5 (Table 4). Selective 1,4-
as
a 2:1 mixture of diastereomers. The stereochemical
configuration of the major isomer was not determined. In the
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presence of Et3N, allene 8 is isolated in 59% yield (1:1 dr).
we next sought to develop an enantioselective variant. With our
1
2
3
4
5
6
7
8
previous successes in 1,3-diene hydrofunctionalization reactions
with Pd(PHOX) catalysts,5b,c,26 we once again turned to ligand L1,
containing an electron-deficient phosphine (Table 5), for enyne
hydroamination.
Table 3. Enyne Hydroamination with Benzophenone Imine
as an Ammonia Surrogatea
Table 5. Initial Examination of Conditions for
H
Enantioselective Enyne Hydroaminationa
Pd-1
5 mol %
Ph
Ph
R1
•
H
+
R1
H
Ph
HN
Ph
2 equiv Et3N
1
Ph
•
N
3
CH2Cl2, 22 °C, 24 h
2.5 mol % [Pd(3-C3H5)Cl]2
L1
H
9
HN
(1.2 equiv)
(racemic)
5 mol %
N
2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6 mol % additive
+
+
H
± workup:
NR1R2
NR1R2
±2 equiv Et3N
R1
10% aq citric acid;
then 2 M aq NaOH
•
Ph
H
solvent, 22 °C, 3 h
1a
Ph
NH2
4
(1.2 equiv)
9
(racemic)
H
H
O
Ar = 3,5-(F3C)2C6H3
L1
Ph
•
Ph
•
N
PAr2
H
H
H
N
Ph
t-Bu
NH2
3
4a
86% yield
Et3N
(Y/N)
yield of
2a (%)b
65% yield
2a 9c
2ad
er of
entry additive
solvent
:
H
H
1
2e
NaBF4
NaBF4
NaBF4
NaBF4
NaBArF
NaBArF
NaBArF
N
N
Y
Y
N
Y
Y
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
<2

4:1

56
53.5:46.5

n-C10H21
•
Ph
•
H
3
<2

NH2
NH2
4e
5e
6
71
19:1
13:1
>20:1
>20:1
63:37
4b
4c
58% yield
57% yield
73
69.5:30.5
<52:48–74:26f
54:46–82:18f
4
4
4
48–73f
65–70f
aReactions under N2 with 1.0 mmol benzophenone imine (0.8 M).
Et2O
7
CH2Cl2
Table 4. 1,3-Disubstituted Enyne Scope for Trisubstituted
Allene Synthesisa
aSee Table 1. bIsolated yield of 2a (single data point unless otherwise
noted). cDetermined by 400 MHz 1H NMR analysis of the unpurified
mixture. dDetermined by HPLC analysis (single data point unless otherwise
R2
Pd-1
H
5 mol %
e
noted). Performed with isolated catalyst; see the Supporting Information.
R1
•
fRange for three experiments.
R2
N
R1
(1.2 equiv)
5
HN
6
However, we quickly discovered numerous differences between
the Pd(DPEphos)- and Pd(PHOX)-catalyzed processes. First, in
situ generation of the catalyst derived from L1 and NaBF4 fails to
generate allene 2a from enyne 1a and THIQ (entries 1 and 3).
Contrastingly, 5 mol % isolated [(η3-C3H5)Pd(L1)]BF4 delivers a
4:1 mixture of allene 2a and diamine 9 in 56% yield (entry 2). The
observation of diamine 9, which likely arises from hydroamination
of allene 2a,11 is another departure from reactions promoted by
DPEphos, which result in complete selectivity for the allene. The
second amine addition can be largely suppressed by the inclusion
of 2.0 equiv Et3N (entry 4, 19:1 2a:9) but enantioselectivity
remains poor. With the catalyst bearing L1 and a BArF4 counterion,
the allene could also be selectively obtained even without Et3N
(entry 5, 13:1 2a:9). The collective data in Table 4 (entries 2 and
4–5) suggest that the identity of the ammonium salt that serves as
the acid source during the reaction is critical to suppressing over-
(racemic)
CH2Cl2, 22 °C, 3 h
product, R1, R2
entry
yield (%)b
6a
6b
6c
6d
6e
1
2
3
4
5
, Ph, Me
60
66
51
60
82
, Ph, n-C6H13
, Ph, Cy
, Ph, CF3
, Cy, Me
aReactions under N2 with 0.2 mmol tetrahydroisoquinoline (0.8 M).
bIsolated yields of purified products.
Scheme 3. THIQ Addition to a 1,4-Disubstituted Enyne
2.5 mol % [Pd(3-C3H5)Cl]2
H
5 mol % DPEphos
amination. Triethylammonium with either BF4 or BArF as
Ph
•
6 mol % NaBArF
4
4
H
counterion selectively leads to proton transfer when Pd is bound to
the alkyne of 1a rather than the allene of product 2a.
Comparatively, the ammonium salt of THIQ shows significantly
different selectivity profiles depending on its counterion. Thus, the
inclusion of Et3N in the reaction mixture seemed likely to be
beneficial for product selectivity in the eventual expansion of the
reaction to other amine nucleophiles beyond THIQ.
N
Ph
Me
Me
7
HN
8
(1.2 equiv)
(racemic)
±2 equiv Et3N
– Et3N: 25% yield, 2:1 dr
+ Et3N: 59% yield, 1:1 dr
CH2Cl2, 22 °C, 20 h
Switching to NaBArF4 as the additive also allows for the in situ
preparation of an active catalyst (entries 6–7) perhaps due to its
2.2.
Development
of
Enantioselective
Enyne
Hydroamination with Pd(PHOX) Catalysts. Having established
the feasibility of transforming conjugated enynes to chiral allenes
by site-selective 1,4-addition of amines with an achiral Pd catalyst,
faster formation of NaCl. With the NaBArF additive and Et3N,
4
only the desired allene was observed; however, the product yield
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and especially the enantioselectivity of the transformation proved
and L3 (Scheme 5B) containing a bis(perfluorophenyl)phosphino
1
2
3
4
5
6
7
8
highly variable under several conditions. In a number of identical
experiments, the enantiopurity of 2a ranged from 82:18 er to nearly
racemic.23
group. We were heartened to find that, consistent with our
hypothesis, the enantiomerization rate was significantly retarded
with L2 (Scheme 5C): the combination of 2a (91:9 er), Pd(L2)
catalyst, and 10 mol % THIQ allows for allene 2a to be recovered
in 72:28 er after 3 h (cf., Scheme 4A).
Scheme 4. Reaction Reversibility and Transamination
Studies
Scheme 5. Design of a Chiral PHOX Ligand to Minimize
Erosion of Allene Enantiopurity
A)
H
2.5 mol % [Pd(3-C3H5)Cl]2
A) Proposed Mechanism for Allene Racemization
L1
5 mol %
Ph
•
9
H
6 mol % NaBArF
Ar2P
4
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar2P
H
H
N
H
THIQ
10 mol %
N
H
Pd
Pd
N
Ph
•
Ph
•
Ph
•
H
2 equiv Et3N
N
III
II
CH2Cl2, 22 °C, 3 h
2a
R3
N
81% recovery
2a
R4
Ar2P
Pd
H
H
H
52:48 er
(92.5:7.5 er)
N
Ph
B)
H
Ph
•
I
Ar2P
Ar2P
H
H
H
N
2.5 mol % [Pd(3-C3H5)Cl]2
N
H
Pd
N
Pd
L1
5 mol %
Ph
•
Ph
•
2a
Ph
•
H
6 mol % NaBArF
4
58% recovery
H
V
R4
N
morpholine
1 equiv
IV
H
56:44 er
R3
N
H
+
2 equiv Et3N
CH2Cl2, 22 °C, 3 h
B) Ligand Design to Slow Enantiomerization Rate
H
O
Ph
•
2a
(91:9 er)
H
O
t-Bu
N
N
O
P(C6F5)2
Fe
N
P(C6F5)2
2an
22% yield
t-Bu
L2
L3
55.5:45.5 er
C) Less Erosion of Enantiopurity with Electron-Deficient PHOX Ligand
We thought that the variability in enantioselectivity might be due
H
to reaction reversibility. Erosion of enantiopurity over time has
been previously observed in Pd-catalyzed 1,3-diene
hydroamination by such a process,27 including Pd(PHOX)
catalysts.5c Indeed, subjection of highly enantioenriched 2a
(92.5:7.5 er) to the Pd(L1) catalyst with 10 mol % THIQ leads to
rapid racemization of the allene (Scheme 4A). Futhermore, the
addition of one equivalent of morpholine to enantioenriched 2a
(91:9 er) and the Pd(L1) catalyst results in 58% recovery of 2a in
only 56:44 er and 22% yield of morpholine adduct 2an in equally
low enantiopurity (Scheme 4B). Although both 2a and 2an were
nearly racemic after 3 h, determination of the equilibrium ratio of
the two allenes by employing the Pd(PHOX) catalyst was thwarted
by formation of diamine products from 2a after extended reaction
times. However, the same process with achiral Pd(DPEphos)
affords a 1.3:1 2a:2an mixture within 3 h.23
Although we cannot rule out other mechanisms28 at this time, the
racemization pathway likely proceeds by ionization of the C–N
bond in Pd(0)–allene complex III (Scheme 5A) to regenerate π-
allyl–Pd II. Isomerization to the diastereomeric complex IV via
alkenyl–Pd I then leads to V after C–N bond formation.
Dissociation of the Pd(PHOX) catalyst from III and V leads to
allene enantiomers.
2.5 mol % [Pd(3-C3H5)Cl]2
L2
5 mol %
Ph
•
H
6 mol % NaBArF
4
H
THIQ
10 mol %
N
Ph
•
H
2 equiv Et3N
CH2Cl2, 22 °C, 3 h
N
2a
69% recovery
2a
72:28 er
(92.5:7.5 er)
Table 6. Improved Enantioselectivity with Electron-
Deficient PHOX Ligandsa
2.5 mol % [Pd(3-C3H5)Cl]2
HN
L2–3
6 mol % NaBArF
5 mol %
H
4
+
Ph
•
H
2 equiv Et3N
N
2a
Ph
solvent, temp, time
1a
(1.2 equiv)
temp
(°C)
time
yield of
Since the ionization of the ammonium group in III or V is at the
heart of the racemization process, we rationalized that redesigning
the catalyst to slow this event by minimizing the trans effect of the
phosphine ligand within complex III/V could lead to more
reproducible results and potentially higher enantioselectivity.
Reasoning that an even more electron-deficient phosphine might
accomplish this goal, perhaps also disfavoring allene coordination
to the catalyst compared to an enyne, led us to prepare ligands L2
2a (%)b
2ac
er of
entry ligand
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(h)
3
L2
1
22
22
22
4
67–73d 82:18–82.5:17.5d
L3
L3
L3
2
3
4
3
66
78
63
86.5:13.5
82.5:17.5
92.5:7.5
19
19
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Page 6 of 10
b
aSee Table 1. Isolated yield of 2a (average of 2–3 experiments unless
otherwise noted). cDetermined by HPLC analysis (average of 2–3
experiments unless otherwise noted). dRange for three experiments.
Whereas addition of THIQ to enynes required 5 mol %
catalyst loading to obtain allenes in good yields,23 other amines
couple efficiently with enyne 1a with only 2 mol % of the
catalyst formed from L3 (Table 7, Condition B: Et2O, 4 °C, 3
h). These optimal conditions enable allene products to be isolated
with greater enantiopurity. As a result, cyclic amines (2v, 2w, 2y,
and 2an) are isolated in 92:8 to 95.5:4.5 er (57–69% yield). Acyclic
alkyl-substituted amines were also tolerated: 2aa was obtained in
53% yield and 93:7 er. Despite displaying similar reaction
efficiency as aliphatic amines, indoline addition to 1a leads to
allene 2ao with only 69.5:30.5 er (59% yield). The lower
enantioselectivity is not due to more rapid product
enantiomerization but rather to lower kinetic selectivity; in fact, the
enantiopurity of 2ao remains constant throughout the course of the
reaction with the L3-derived catalyst.23
1
2
3
4
5
6
7
8
Importantly, addition of THIQ to 1a with the Pd(L2) catalyst
allows for a high degree of reproducibility (Table 6, entry 1) with
2a formed in ca. 70% yield and 82:18 er at room temperature in
CH2Cl2 after 3 h. Ferrocenyl-PHOX L3 gave slightly higher
enantioselectivity (entry 2) and so we chose to optimize further
with this ligand.23 Impressively, even in CH2Cl2 as a polar solvent,
which we have observed in diene hydroamination to increase
enantiomerization rate compared to reactions in Et2O,5c
enantioselectivity only decreases to 82.5:17.5 er after 19 h at room
temperature (entry 3). After cooling the reaction to 4 °C, allene 2a
was obtained in 63% yield and 92.5:7.5 er (entry 4).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The addition of THIQ to several aryl-substituted enynes 1
proceeds with modest reaction efficiency but good levels of
enantioselectivity in the presence of 5 mol % Pd catalyst formed
from L3 (Table 7, Condition A: CH2Cl2, 4 °C, 20 h). Both
electron-rich and electron-poor enynes react with roughly equal
efficiency: anisole 2b is isolated in 64% yield (91:9 er) and
benzoate 2f in 57% yield (94:6 er). An aryl bromide is tolerated in
the coupling, with 2d formed in 52% yield and 94.5:5.5 er. An
ortho-tolyl group leads to lower enantioselectivity (86:14 er) but 2j
is still generated in 57% yield. Although a pyridyl substituent had
little impact on hydroamination with the Pd(DPEphos) catalyst, the
heterocycle significantly impedes the L3-derived catalyst: allene
2m is obtained in 91:9 er but only 32% yield.
The addition of THIQ to alkyl-substituted enynes as promoted
by the Pd(L3) catalyst, however, occurs with low
enantioselectivity,23 perhaps suggesting that ionization of the C–N
bond of the product is competitive with ligand exchange of the
allene for another alkyl-substituted enyne substrate at the Pd(0)
center (displacement of the allene within III, Scheme 5A, for
enyne). The more substituted enynes 5 and 7 (Table 4 and Scheme
3, respectively) are relatively unreactive with the Pd(PHOX)
catalyst; benzophenone imine also does not add to enyne 1a.23
2.3. Reaction Mechanism Investigations. Our proposed
mechanism for the enyne 1,4-hydroamination proceeds through η3-
butadienyl–Pd II (Scheme 6), itself formed from η1-butadienyl–Pd
I, the product of alkyne insertion to a palladium hydride species
VI.29 This pathway mirrors that suggested by Yamamoto11 in a
related process and is also based on prior work in Pd–
bis(phosphine)-catalyzed hydroamination of dienes and styrene,22
which have been shown to proceed through outer-sphere addition
of the amine to a π-allyl–Pd or π-benzyl–Pd complex, respectively.
Alkene insertion to the palladium hydride in complex VII might
also occur to generate propargylic Pd species VIII. Although VIII
cannot collapse to a stable π-allyl–Pd complex, we wondered if
alkene insertion were a competitive process or if alkyne insertion
(VI to I) were the exclusive reaction pathway. We also questioned
whether DPEphos- and L3-derived Pd catalysts might show
different kinetic site-selectivity profiles for migratory insertion.
Table 7. Scope of Enantioselective Enyne Hydroaminationa
H
R1
Condition A or B
•
R2 R3
R1
R2
H
+
N
H
1
N
2
R3
(1.2 equiv)
H
R1
•
MeO
Br
H
2b
2d
N
Condition A
64% yield
91:9 er
52% yield
94.5:5.5 er
Me
Scheme 6. Possible Reaction Pathways in the Course of Pd-
Catalyzed Enyne Hydroamination
MeO2C
N
L
L
P
2f
2j
2l
2m
P
L
P
Pd
Pd
Pd
57% yield
94:6 er
57% yield
86:14 er
61% yield
93:7 er
32% yield
91:9 er
H
H
H
Ph
Ph
VI
Ph
VII
VIII
H
N
NMe
N
Ph
•
VI
I
is the
to insertion the
•
R2
H
exclusive reaction pathway?
2v
2w
N
R3
P
VII VIII
to
is
rapid & reversible?
VII VIII
H
•
•
P
Condition B
H
L
57% yield
94:6 er
69% yield
95.5:4.5 er
L
Pd
is the conversion of
kinetically competitive with
VI
to
Pd
Ph
•
H
Ph
Me
Bn
I
to ?
the productive
II
I
N
N
O
N
N
is there ligand dependence?
•
2aab
2anb
2aob
2y
To investigate these site-selectivity questions, we employed N-
deuterated THIQ (90% labeled) in a reaction with enyne 1a
(Scheme 7). With either bis(phosphine) or PHOX ligand, the
deuterium label is confined to C1 in d-2a (80% labeled) with <5%
incorporation at the allylic C4 position. No deuterium label was
detected in the recovered enyne 1a. Therefore, we can conclude that
59% yield
92:8 er
53% yield
93:7 er
67% yield
95:5 er
59% yield
69.5:30.5 er
aReactions run under N2 with 0.2 mmol amine (0.8 M). Condition A: 2.5
mol % [Pd(3-C3H5)Cl]2, 5 mol % L3, 6 mol % NaBArF , 2 equiv Et3N,
4
CH2Cl2, 4 °C, 20 h. Condition B: 1 mol % [Pd(3-C3H5)Cl]2, 2 mol % L3,
2.5 mol % NaBArF , 2 equiv Et3N, Et2O, 4 °C, 3 h. b5 h reaction.
4
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Journal of the American Chemical Society
H
insertion of the alkyne to the palladium hydride is significantly
faster than olefin insertion.
Ar2P
Pd0(PHOX)
H
N
H
1
2
Pd
Ph
•
Ph
•
H
3
4
5
6
7
8
9
II
AcO
major
enantiomer
Ar2P
H
Scheme 7. Deuterium Labeling Reveals Kinetic Selectivity
for Alkyne Insertion to Pd–H
10
(R)-
Pd
N
Ph
minor
enantiomer
H
ca. 80% D
at C1
2.5 mol %
[Pd(3-C3H5)Cl]2
5 mol % ligand
6 mol % NaBArF
D
Ar2P
I
DN
N
H
H
Pd
Ph
•
(90% D)
Pd0(PHOX)
H
4
Ph
•
OAc
Ph
•
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
+
d-2a
±2 equiv Et3N
IV
H
H
C1
CH2Cl2, temp, time
<5% D
at C4
C4
Ph
10
(S)-
1a
DPEphos
(– Et3N, 22 °C, 3 h): 82% yield
(1.2 equiv)
H
L3
(+ Et3N, 4 °C, 20 h): 73% yield, 91:9 er
Ph
•
H
2 mol %
Having determined that Pd–H migratory insertion occurs
kinetically at the alkyne to furnish η1-butadienyl–Pd I, we next
examined the origin of high enantioselectivity in enyne
hydroamination. Two possibilities seemed likely, the first being
selective collapse of I to η3-butadienyl–Pd II followed by faster
attack of the amine (Scheme 8). The second option is that II might
be in rapid equilibrium with diastereomeric complex IV, with
amine attack upon II being faster than addition to IV (Curtin–
Hammett kinetics). Recognizing that the Trost laboratory20b has
observed a Curtin–Hammett situation in allylic aminations
involving allene substrates that share common intermediates II and
IV, we investigated the allylic amination of racemic allylic acetate
10. Addition of morpholine to rac-10 with the Pd(L3) catalyst
under the conditions for enyne hydroamination affords
aminomethyl-substituted allene 2an in 44% yield and 91:9 er (cf.
95:5 er from enyne hydroamination) with the (R)-enantiomer still
as the major isomer (Scheme 8). Allene 10 is recovered as the
racemate, illustrating enantioconvergence in the reaction (i.e., not
kinetic resolution). The data indicate that allylic amination with
Pd(L3) is under Curtin–Hammett control and strongly suggests that
enyne hydroaminations are as well.
H
2an
3
F
L3
[( )Pd( -C3H5)]BAr
4
Ph
•
44% yield
91:9 er
H
N
O
AcO
O
+
N
H
10
rac-
H
10
(1.2 equiv)
2 equiv Et3N
59% recovery
racemic
Ph
•
Et2O, 4 °C, 3 h
H
OAc
The preferential attack of the amine upon η3-butadienyl II
compared to IV can be rationalized in terms of the transition states
leading to allene–Pd complexes III and V, respectively (Scheme
9). In both π-allyl–Pd complexes II and IV, the phosphine lies trans
to the allyl ligand’s methylene carbon, which undergoes attack by
the amine (trans effect). The C–N bond formation causes
rehybridization at this carbon, which leads to steric clash with the
t-butyl group of the oxazoline en route to V. Comparatively there
is less interaction between these substituents in the amine addition
to II that leads to III.
Scheme 9. Proposed Stereochemical Model for Enyne
Hydroamination
Scheme 8. Allylic Substitution Suggests Curtin–Hammett
Kinetics Operative in Enyne Hydroamination
Fe
Fe
N
HNR2
O
O
(C6F5)2P
H
(C6F5)2P
N
favored
H
Pd
Pd
Ph
•
t-Bu
t-Bu
H
Ph
•
H
II
H
H
III
NHR2
rapid equilibrium
1
I
via  -butadienyl
Fe
Fe
(C6F5)2P
Pd
(C6F5)2P
HNR2
O
O
N
N
H
Pd
H
H
disfavored
t-Bu
t-Bu
Ph
•
H
H
Ph
•
IV
V
NHR2
H
3. CONCLUSION
In this study, we have demonstrated the selective 1,4-addition of
aliphatic amines, aryl-substituted amines, and benzophenone imine
to deliver chiral aminomethyl-substituted allenes. Several tertiary,
secondary, and primary amines can be obtained in racemic form
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2016, 49, 1524–1536. For examples, see: (b) Butler, K. L.; Tragni, M.;
with a Pd(DPEphos) catalyst. The enyne scope is equally broad
with several 1-substituted and 1,3-disubstituted enyne amenable to
the reaction.
Widenhoefer, R. A. Gold(I)-Catalyzed Stereoconvergent, Intermolecular
Enantioselective Hydroamination of Allenes. Angew. Chem., Int. Ed. 2012,
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Rhodium‐Catalyzed Synthesis of Branched Allylic Amines by
Intermolecular Hydroamination of Terminal Allenes. Angew. Chem., Int.
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Synthesis of N-Allylic Indoles via Regio- and Enantioselective Allylation
of Aryl Hydrazines. Nat. Commun. 2015, 6, 7616–7622. (e) Xu, K.;
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Substituted Pyrazoles by Rhodium-Catalyzed Asymmetric Addition to
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Raimondi, W.; Bury, T.; Breit, B. Enantioselective Formation of Tertiary
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1
2
3
4
5
6
7
8
Furthermore, we have demonstrated the first examples of
catalytic enantioselective intermolecular addition of nucleophiles
to 1,3-enynes. Transformations take place in good yield and
enantioselectivity with a Pd(PHOX) catalyst that bears an electron-
poor bis(perfluorophenyl)phosphino group. With the electron-
deficient Pd catalyst, reaction reversibility is slowed significantly,
thereby preserving the stereochemistry set in the initial C–N bond-
forming step. Still, these studies highlight future areas for
improvement, including hydroamination with alkyl-substituted
enynes, disubstituted substrates, and reactions of benzophenone
imine. Likely success in these objectives will require further
catalyst development.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Initial mechanistic investigations indicate that, unlike enyne
reductive couplings with electrophiles that proceed via Rh–H, Ir–
H, or Cu–H insertion at the olefin, Pd–H insertion in enyne
hydroamination takes place exclusively at the alkyne with both
Pd(DPEphos) and Pd(PHOX) catalysts. Additionally, comparison
with known allylic substitutions indicates that enantioselectivity in
the Pd(PHOX)-catalyzed enyne hydroaminations likely takes place
under Curtin–Hammett kinetics involving rapid equilibration of
diastereomeric π-allyl–Pd complexes.
(5) (a) Yang, X.-H.; Dong, V. M. Rhodium-Catalyzed
Hydrofunctionalization: Enantioselective Coupling of Indolines and 1,3-
Dienes. J. Am. Chem. Soc. 2017, 139, 1774–1777. (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. (c) Park, S.; Malcolmson, S. J. Development and
1,4-Addition of nucleophiles to conjugated enynes provides a
new avenue for the synthesis of multisubstituted chiral allenes.
Studies directed towards the catalytic enantioselective addition of
other nucleophiles to 1,3-enynes are underway in this laboratory.
Mechanistic
Investigations
of
Enantioselective
Pd-Catalyzed
Intermolecular Hydroaminations of Internal Dienes. ACS Catal. 2018, 8,
8468–8476.
ASSOCIATED CONTENT
Supporting Information
(6) (a) Kawatsura, M.; Hartwig, J. F. Palladium-Catalyzed
Intermolecular Hydroamination of Vinylarenes Using Arylamines. J. Am.
Chem. Soc. 2000, 122, 9546–9547. (b) Utsunomiya, M.; Hartwig, J. F.
Intermolecular, Markovnikov Hydroamination of Vinylarenes with
Alkylamines. J. Am. Chem. Soc. 2003, 125, 14286–14287.
(7) Teng, H.-L.; Lou, Y.; Wang, B.; Zhang, L.; Nishiura, M.; Hou, Z.
Synthesis of Chiral Aminocyclopropanes by Rare-Earth-Metal-Catalyzed
Cyclopropene Hydroamination. Angew. Chem., Int. Ed. 2016, 55, 15406–
15410.
Experimental procedures, analytical data for new compounds, and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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Intermolecular Hydroamination of Unactivated Alkenes with Simple
Amines. Angew. Chem., Int. Ed. 2010, 49, 8984.
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Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed
Intermolecular Regioselective Hydroamination of Styrenes with
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Catalyzed Hydroamination of Vinylsilanes. Angew. Chem., Int. Ed. 2015,
54, 1638–1641. (d) Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L.
Catalytic Asymmetric Hydroamination of Unactivated Internal Olefins to
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*steven.malcolmson@duke.edu
ORCID
Steven J. Malcolmson: 0000-0003-3229-0949
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Science Foundation (CHE-1800012) and
Duke University for supporting this research. N.J.A. is grateful for
support from NIGMS (T32GM007105) and for a Burroughs-
Welcome fellowship from the Duke Chemistry Department.
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