Palladium(II)-Catalyzed Regioselective syn-Hydroarylation of Disubstituted Alkynes Using a Removable Directing Group

Article abstract of DOI:10.1021/jacs.6b08818

A palladium(II)-catalyzed regioselective syn-hydroarylation reaction of homopropargyl amines has been developed, wherein selectivity is controlled by a cleavable bidentate directing group. Under the optimized reaction conditions, both dialkyl and alkylaryl alkyne substrates were found to undergo hydroarylation with high selectivity. The products of this reaction contain a 4,4-disubstituted homoallylic amine motif that is commonly seen in drug molecules and other bioactive compounds.

Full text of DOI:10.1021/jacs.6b08818

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Article
Palladium(II)-Catalyzed Regioselective syn-Hydroarylation of
Disubstituted Alkynes Using a Removable Directing Group
Zhen Liu, Joseph Derosa, and Keary M. Engle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08818 • Publication Date (Web): 07 Sep 2016
Downloaded from http://pubs.acs.org on September 7, 2016
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Palladium(II)-Catalyzed Regioselective syn-Hydroarylation
of Disubstituted Alkynes Using a Removable Directing
Group
Zhen Liu, Joseph Derosa, Keary M. Engle*
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Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
Supporting Information Placeholder
they require proximal substituents that can be difficult to modify
downstream, which limits overall synthetic flexibility. As a result,
applications of alkyne hydroarylation in organic synthesis remain rare.
ABSTRACT:
A
palladium(II)-catalyzed
regioselective
syn-hydroarylation reaction of homopropargyl amines has been
developed, wherein selectivity is controlled by a cleavable bidentate
directing group. Under the optimized reaction conditions, both dialkyl
and alkylaryl alkyne substrates were found to undergo hydroarylation
with high selectivity. The products of this reaction contain a
4,4-disubstituted homoallylic amine motif that is commonly seen in
drug molecules and other bioactive compounds.
Inspired by earlier precedents of directed carbometalation of
alkynes with organometallic species (e.g., Grignard reagents),10 we
envisioned that by temporarily masking a distal functional group with a
removable Lewis basic auxiliary, high regioselectivity could be achieved
in catalytic hydroarylation with otherwise unbiased alkyne substrates.
In this design, regioselectivity would be controlled principally by the
directing group, which could then be removed after the reaction,
allowing access to biologically important product classes (Scheme 1c).
Though it has been less frequently studied, we elected to focus on
hydroarylation catalyzed by palladium(II).7e,f In doing so, we reasoned
that because palladium(II) is known to promote addition a diverse
range of nucleophiles to unsaturated C–C bonds, we could potentially
extend the insights from this study to other reaction types in the future.
INTRODUCTION
Substituted alkenes are common structural motifs found in
natural products, drug molecules, and organic materials. They are also
important synthetic intermediates that participate in a wide range of
organic transformations. Transition-metal-catalyzed hydroarylation of
alkynes with organometallic reagents is a powerful method to
synthesize substituted alkenes.1 Various classes of organometallic
reagents have been applied in this reaction, including organoboron,
-silane, -stannane, -magnesium, -zinc, -lithium and -copper reagents.2
Among these, organoboron reagents have attracted significant
attention because they are operationally convenient to handle and have
low toxicity.3 In this context, Hayashi and coworkers reported the first
example of rhodium-catalyzed alkyne hydroarylation with arylboronic
acids.4 Later, Oh found that the combination of palladium(0) catalyst,
aryl boronic acid, and HOAc could promote alkyne hydroarylation via
an HOAc oxidative addition/hydropalladation sequence.5 Since then,
transition-metal-catalyzed hydroarylation has emerged as a powerful
technique to synthesize di- and trisubstituted olefins.6–8 Most examples
of metal-catalyzed alkyne hydroarylation give syn-stereoselectivity,
affording a single product when symmetrical alkynes are used as
substrates. When unsymmetrically substituted alkyne substrates are
employed, however, two regioisomeric products are formed, and the
regioselectivity is typically low (Scheme 1a). For example, in Hayashi’s
initial publication, a 3:1 mixture of α and β regioisomers was obtained
in the hydroarylation of 1-phenylpropyne.9
Scheme 1. Background and Project Synopsis
A. Nonselective transition-metal-catalyzed alkyne syn-hydroarylation:
H+
Mn–Ar
Mn
R1
Ar
H
Ar
?
R1
R2
R1
R2
migratory
insertion
proto-
demetalation
R2
B. Steric, electronic, and chelation control strategies with proximal substituents
Mn–Ar
Mn–Ar
Mn–Ar
O
N
R2
R
TMS
R
R1O
δ– δ+
C. This Work: Directed regioselective syn-hydroarylation of unsymmetric alkynes
• Reaction design: Pd(II)-catalyzed hydroarylation with a distal removable directing group
H+
PdII–Ar
PdII
H
Ar
Ar
DG
migratory
insertion
proto-
depalladation
DG
R
R
DG
R
n
n
n
• Inspiration: Product substructure prevalent in drugs and other bioactive compounds
H
R3
H
H
(R1)2N
R
N
N
R2
X
Me
hydro-
arylation
?
CO2H
Ar–B(OH)2
+
Amitriptyline (R = Me, X = CH2)
Nortriptyline (R = H, X = CH2)
(E)-Doxepin (R = Me, X = O)
SK&F 89976-A
(R1)2N
To overcome this issue, several different strategies have been
pursued. One approach has been to introduce a sterically bulky group
(e.g., TMS) to block one of the two possible addition sites.6d,7a A second
strategy, as demonstrated by Hayashi, has been to employ a polarized
alkyne containing an electron-withdrawing group (e.g., an ester) in
conjugation with the π-system to promote selective arylmetalation.4,8b
Lastly, Lautens and others have reported the use of non-removable
functional groups (e.g., a 2-pyridyl moiety) to improve selectivity
through chelation and/or electronic effects (Scheme 1b).2g,6a,6b,6f,7a,7c,7d
R2
(anticonvulsant)
(antidepressants)
RESULTS AND DISCUSSION
To reduce this idea to practice, substituted homopropargyl
amines (e.g., 1a) were selected as the first class of substrates to
investigate. We were attracted to these substrates because the resultant
products would contain a 4,4-diaryl homoallylic amine motif, which is
commonly found in drug molecules and their analogs (Scheme 1c).11
Optimization of the reaction conditions and directing group was
carried out in parallel (Table 1). After initial screening revealed that a
Despite this progress, these strategies possess limitations. Firstly,
these reactions can exhibit variable selectivity as the substitution
patterns on the arylboronate and alkyne substrate change. Secondly,
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c
1
picolinamide (PA) directing group (as in 1a)12 provided the highest
yield and selectivity, reaction conditions were optimized with this
substrate and phenylboronic acid (2a) (Table 1). We were pleased to
find that by using 5 mol % Pd(OAc)2 as the catalyst and PCy3•HBF4 as
the ligand, trisubstituted olefin 3a was observed as the major product,
with minimal formation of the minor isomer 4a (3a/4a = 15:1) (entry
3). The addition of PCy3 as ligand was critical for the success of the
reaction, as only 9% yield was observed without ligand (entry 1). We
believe that the ligand lowers the rate of transmetalation, suppressing
undesired homocoupling of the arylboronic acid, which generates
catalytically unreactive Pd(0). Various inorganic bases were tested
(entries 6–8), and among them KOAc was found to be optimal,
providing up to 64% yield with excellent regioselectivity (3a/4a =
30:1) (entry 8). KF provided slightly higher product yields but poor
selectivity (entry 6). Finally, we found that by decreasing the reaction
temperature and reducing the ligand loading to 1 equiv relative to
palladium, formation of 4a was almost entirely suppressed, and 3a was
generated in 80% yield (78% isolated) (entry 9).
parentheses correspond to isolated yields. Determined by H NMR
analysis. d90 °C.
1
2
3
4
5
6
7
8
The data from our directing group optimization effort shed light on
structure–activity relationships in this reaction (entries 9–18),
revealing that both the electronic properties of the auxiliary and the
geometry of the metal binding sites significantly impact selectivity.
More electron-deficient amides (that have N–H bonds with lower pKa
values) gave better selectivity (entries 11 and 12). Bidentate auxiliaries
(entries 9 and 15–18), which to our knowledge have not been
previously explored in catalysis on alkyne substrates, afforded higher
selectivity than their monodentate counterparts (entries 9 versus 10
and 17 versus 14). Taken together, these data are consistent with a
mechanism in which the auxiliary binds in an LX bidentate mode
during the 1,2-migratory insertion step.
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Table 2. Homopropargyl Picolinamide Scopea
Table 1. Optimization of the Reaction Conditionsa
5 mol% Pd(OAc)2
5 mol% PCy3•HBF4
1 equiv KOAc
R2
N
H
R3
R3
H
N
H
+
NHPA
NHPA
n
n
n
1,4-dioxane, 90 °C
PhB(OH)2
2a
R1
O
cat. Pd(OAc)2
Ligand
Base
R3
(PA)
R1 R2
R1 R2
n = 1–3
DG
H
1a–t
3a–t
4a–t
+
H
1,4-dioxane, 100 °C
DG
DG
H
H
PhB(OH)2
2a
H
NHPA
NHPA
NHPA
1
3
4
DG
Ligand
Base Pd/L (mol%)
Selectivity (3/4)c
3 (%)b
4 (%)b
Entry
1
Me
OMe
3b, 70%
[X-ray]
3a, 78%
3c, 87%
9
——
——
3.7
——
——
15:1
A (NHPA)
A (NHPA)
A (NHPA)
none
K2CO3
——
H
H
trace
55
2
3
(±) BINAP
PCy3•HBF4
K2CO3
K2CO3
5/5
H
H
NHPA
NHPA
NHPA
NHPA
5/10
4
5
6
7
A (NHPA)
XPhos
K2CO3
K2CO3
KF
5/10
5/10
5/10
5/10
34
29
77
3.8
10
12
8.9:1
2.8:1
6.3:1
25:1
NH2
CF3
Cl
F
A (NHPA) N-Acetylglycine
33:1 (3e:4e)
3e, 79%
14:1 (3g:4g)
3g, 67%
3d, 84%
3f, 71%
A (NHPA)
A (NHPA)
PCy3•HBF4
PCy3•HBF4
H
H
K3PO4
10
2.5
2.1
H
H
NHPA
NHPA
NHPA
NHPA
8
A (NHPA)
PCy3•HBF4
KOAc
5/10
64 (60)
30:1
N
S
CO2Me
OMe
9d
A (NHPA)
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
KOAc
KOAc
KOAc
KOAc
5/5
5/5
5/5
5/5
80 (78)
76
——
13
>50:1
5.8:1
8.0:1
18:1
29:1 (3i:4i)
3i, 71%
11:1 (3j:4j)
3j, 55%
4.7:1 (3k:4k)
3k, 25%b
3h, 84%
10d
B
C
D
11d
12d
13d
82
10
H
H
Me
NHPA
H
H
NHPA
89
4.9
NHPA
Me
NHPA
E
F
PCy3•HBF4
PCy3•HBF4
KOAc
KOAc
5/5
5/5
78
80
7.1
14
11:1
40:1 (3n:4n)
3n, 70%
36:1 (3o:4o)
3o, 76%
14d
5.6:1
3l, 80%
3m, 75%
15d
16d
17d
18d
G
H
I
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
KOAc
KOAc
KOAc
KOAc
5/5
5/5
5/5
5/5
14
27
74
72
3.5
3.1
8.1
11
7.4:1
9.6:1
9.1:1
6.7:1
H
H
H
H
NHPA
NHPA
NHPA
NHPA
R
SiMe3
Me
3p (R = Me), 55%
3q (R = Et), 37%c
6:1 3t:4t
3t, 12%
J
3r, 45%c
3s, 27%c
aReaction conditions: 1a–t (0.1 mmol), 2a (0.18 mmol), Pd(OAc)2
(5 mol %), PCy3•HBF3 (5 mol %), KOAc (1 equiv), dioxane (0.4 mL),
90 °C, N2, 4–5 h. Percentages represent isolated yields of the major
regioisomer. The ratio of the two regioisomers was determined by H
NMR analysis of the crude reaction mixture. 10 mol % PCy3•HBF4. 5
mol % PPh3, 1 equiv of K2HPO4, 12–20 h. Yield determined by H
NMR analysis of the curde reaction mixture using CH2Br2 as internal
standard.
O
O
O
O
N
H
N
H
N
H
N
H
N
Ph
N
N
NO2
Ph
1
A (NHPA)
=
B
C
D
E
DG
b
c
O
O
O
O
O
Ph
NBn
O O
S
d
1
S
N
H
N
H
O
N
N
H
H
N
N
N
S
N
Me
F
G
H
I
J
aReaction conditions: 1a (0.1 mmol), 2a (0.18 mmol), Pd(OAc)2
(5–10 mol %), ligand (5–10 mol %), base (1 equiv), dioxane (0.4 mL),
Having optimized the reaction conditions, we next investigated the
substrate scope of this palladium(II)-catalyzed alkyne hydroarylation
reaction. First, various substituted homopropargyl amine derivatives
b
1
100 °C, N2, 4–5 h. Yields were determined by H NMR analysis of the
crude reaction mixture using CH2Br2 as an internal standard. Values in
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were tested with phenylboronic acid (2a) as the coupling partner
Next, the scope of arylboronic acids was studied using
1
2
3
4
5
6
7
8
(Table 2). Aryl substituents with different electronic properties were
examined, providing the corresponding products in moderate to good
yield with excellent selectivity (3b–i).13 In only a few cases was the
minor regioisomer detected (3e, 3g and 3i). Notably, a free amino
group was compatible (3d). Additionally, a chloride group was
tolerated, presenting the opportunity for subsequent diversification via
cross-coupling. Heteroaryl substituted alkynes, namely those
containing 2-thiophenyl (1j) and 2-pyridyl (1k) groups, showed a
competing directing effect with the picolinate auxiliary, as evidenced by
the measurably lower regioselectivity in these cases (3j and 3k)
compared to examples with simple aryl groups. Nevertheless, these
results demonstrate that the picolinate auxiliary has a stronger directing
effect than these monodentate heterocycles, since 3j and 3k were still
the major products. In the case of 3k, this preference is opposite to
what Lautens previously observed with 2-pyridylacetylene substrates.6a
Homopropargyl amines containing alkyl branching (1l and 1m) also
performed well in the reaction, leading to products 3l and 3m as the
only detectable regioisomers. Interestingly, starting materials
containing a more distal directing group could also be hydroarylated in
good yield with only a slight decrease in selectivity (3n and 3o)
demonstrating that products containing different carbogenic skeletons
can be accessed with this method (vide infra). Collectively, these
results establish that alkynes containing one aryl and one alkyl group,
which are typically insufficiently differentiated to give high selectivity
in non-directed hydroarylation, can be regioselectively functionalized
using a removable directing group strategy.
homopropargyl picolinamide 1a as a representative alkyne (Table 3).
An array of substituted arylboronic acids containing substituents on the
para or meta position participated in the reaction, providing the
corresponding hydroarylated products in moderate to high yields
(5a–5h). Arylboronic acids with ortho-substituents were also
competent coupling partners but gave lower yields (5i and 5j). The
selectivity for the desired products 5a–j was consistently high and did
not depend on the electronic properties of the organoboron coupling
partner. In only two cases was the minor regioisomer observed, and in
both instances, the product ratio was >33:1 (5c and 5e). The regio-
and stereoselectivity of this transformation were confirmed by nOe
measurements of 5g (see Supporting Information) and X-ray
crystallographic analysis of 3b.
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10
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An attractive aspect of this method is that the 4,4-diaryl
homoallylic amine products can be obtained with complete control of
alkene stereochemistry. Aryl-substituted homopropargyl picolinamide
starting materials 1a–k are conveniently prepared in one step via
Sonogashira coupling. Thus, the ultimate stereochemistry of the
product can be controlled by choosing which of the two aryl groups is
introduced by Sonogashira coupling and which is introduced by
hydroarylation (e.g., 3b/5a and 3c/5b). As a more general comment,
the majority of the examples in Tables 2 and 3 were prepared in two
steps from a common starting material (homopropargyl picolinamide),
which speaks to the potential utility of this method as tool in divergent
synthesis for medicinal chemistry applications.
Scheme 2. Large-Scale Synthesis of Trisubstituted Olefins 3a,
5b and Removal of the Picolinyl Group
Arguably an even greater challenge is regioselective hydroarylation
of dialkylalkynes. Thus, it was gratifying to observe that homopropargyl
picolinamides containing terminal alkyl groups (1p–s) could also be
converted into hydroarylated products 3p–s with high selectivity (only
one regioisomer detected), albeit in moderate yield. Installation of a
sterically bulky SiMe3 group on the alkyne led to 6:1 selectivity, with
12% isolated yield of the major product 3t.
R
R
5 mol% Pd(OAc)2
5 mol% PCy3•HBF4
1 equiv KOAc
H
H
1a
KOH
NHPA
NH2
+
1,4-dioxane, 90 °C
EtOH, reflux
[1 mmol scale]
Ar B(OH)2
(1.8 equiv)
3a (R = H), 68%
5b (R = OMe), 72%
7 (R = H), 95%
Table 3. Arylboronic Acid Scopea
5 mol% Pd(OAc)2
5 mol% PCy3•HBF4
1 equiv KOAc
N
To demonstrate the practicality and operational simplicity of this
Pd(II)-catalyzed alkyne hydroarylation method, we performed two
representative examples on larger scale (Scheme 2). Electron-neutral
and -rich arylboronic acids were both tested on 1 mmol scale under the
reaction conditions described in Table 4, and the yields in these
experiments were similar to the smaller scale trials. After
hydroarylation, the PA directing group could be conveniently cleaved
to reveal the free amine. As an example, product 3a was hydrolyzed
under aqueous conditions to give primary amine 7 in 95% yield.
H
Ar
H
N
Ar
H
+
NHPA
NHPA
1,4-dioxane, 90 °C
ArB(OH)2
2b–k
(PA)
Ph
O
H
Ph
Ph
1a
5a–h
6a–h
Me
MeO
NC
H
H
NHPA
NHPA
NHPA
35:1 (5c:6c)
5c, 40%
5a, 80%
5b, 78%
F3C
To better understand the influence of directing group
distance/geometry on reaction outcome, we compared substrates with
different tether lengths between the alkyne and the picolinamide
directing group (Scheme 3). In all four cases that were examined, the
reaction proceeds in >70% yield under the standard conditions.
Interestingly, with propargyl substrate 1u, containing the smallest
tether length, the reaction gave only a 3:1 ratio of the two regioisomers
3u and 4u, compared to >50:1 with substrate 1a. Systematically
introducing additional methylene units (1n and 1o), led to only a
moderate erosion of selectivity from 40:1 to 36:1. The finding that 1a
gave the highest selectivity is likely due to the formation of a stable
5-membered palladacycle upon syn-carbopalladation with this
substrate. For substrates 1n and 1o, with more distal PA directing
groups, the attenuation of selectivity could be due to the formation of
less stable 6- and 7-membered palladacycles following
syn-carbopalladation. The origin of the more dramatic loss of selectivity
with propargyl substrate 1u is likely due to the fact that putative
4-membered palladacycle formed via syn-carbopalladation is
H
H
H
O
NHPA
NHPA
NHPA
Me
33:1 (5e:6e)
5e, 78%
5d, 70%
5f, 65%
O
O
H
H
H
NHPA
NHPA
NHPA
R
5i (R = Me), 22%
5j (R = Ph), 18%
5h, 54%
5g, 84%
aReaction conditions: 1a (0.1 mmol), 2b–k (0.18 mmol), Pd(OAc)2
(5 mol %), PCy3•HBF3 (5 mol %), KOAc (1 equiv), dioxane (0.4 mL),
90 °C, N2, 4–5 h. Percentatges represent isolated yields of the major
1
regioisomer. The ratio of the two regioisomers was determined by H
NMR analysis of the crude reaction mixture.
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Journal of the American Chemical Society
Page 4 of 6
prohibitively unstable, causing the system to default to more inherent
non-directed selectivity. While transition state inductive effects14 could
also explain the trend from 1a (n = 2) to 1n (n =3) to 1o (n =4), the
selectivity with 1u (n = 1) would not be consistent with this model.
1
2
3
In the second type, palladium(II) is the active catalyst, and the
reaction is run under basic conditions (generally with inorganic base)
and typically in the presence of phosphine ligand (Scheme 4b).7d,e The
proposed sequence begins with transmetalation between palladium(II)
and the aryl boronate. 1,2-Migratory insertion (carbopalladation)
followed by protodepalladation then generates the product and closes
the catalytic cycle.
4
5
6
7
8
9
Scheme 3. Comparison of Alkynyl Picolinamides with
Different Tether Lengths
5 mol% Pd(OAc)2
5 mol% PCy3•HBF4
1 equiv KOAc
H
Ph
NHPA
n
Ph
NHPA
H
NHPA
+
Ph
1,4-dioxane, 90 °C
The reaction conditions in the present alkyne hydroarylation
reaction appear to fall into the latter category (Pd(II)-catalyzed
nucleopalladation). Nevertheless, we were interested in more precisely
elucidating the reaction mechanism and examining potential
n
n
Ph
Ph
PhB(OH)2
2a
1u (n = 1)
1a (n = 2)
1n (n = 3)
1o (n = 4)
3u (n = 1)
3a (n = 2)
3n (n = 3)
3o (n = 4)
4u (n = 1)
4a (n = 2)
4n (n = 3)
4o (n = 4)
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3 (%) 4 (%)
ratio
differences
in
reactivity/selectivity
between
these
two
n = 1
n = 2
n = 3
n = 4
68
78
70
76
23
<1
<2
~2
3:1
>50:1
40:1
palladium-catalyzed pathways with homopropargyl amine substrates.
To begin, we first took note of relevant literature precedents. Using a
Pd(0)/PCy3/HOAc system,
36:1
Marinelli and coworkers, have
previously demonstrated hydroarylation of 3-arylpropargyl amines in
43–85% yields and >20:1 selectivity favoring Ar group transfer to the
alkynyl carbon atom distal from the amine (Scheme 5).7c The authors
report 9 examples, all of which contain electron-withdrawing
substituents on the arene. Based on analysis of reactivity trends and
computed charge distribution in putative intermediates, the authors
conclude that the regioselectivity is due to electronic bias in the alkyne,
with the hydride of the [Pd(II)–H] species reliably attacking the
alkynyl carbon atom with the highest partial positive charge in the
π-alkene complex.16
MECHANISTIC ANALYSIS
With palladium as the catalyst, two main mechanistic paradigms
have been proposed for alkyne hydroarylation with arylboronic acids,
each operating under different reaction conditions (Scheme 4). The
first type, as invented by Oh,5 involves palladium(0) as the catalyst,
generally in combination with a phosphine ligand and in an acidic
solvent medium (e.g., HOAc) (Scheme 4a).7a–c,7f To generate the
catalytically active species in these systems, a palladium(0) precatalyst,
such as Pd2(dba)3, can be employed directly or a palladium(II)
precatalyst, such as Pd(OAc)2, can be reduced in situ. In the proposed
sequence of events, the [Pd(0)Ln] species oxidatively adds to HOAc,15
to generate a [Pd(II)–H] intermediate, which adds across the alkyne in
Scheme 5. Relevant Literature Precedent Involving
Pd(0)/PCy3/HOAc Catalysis to Effect Hydroarylation of
3-Arylpropargyl Amines and Attempted Application of this
Catalytic System to 4-Arylhomopropargyl Amine Substrates
a
1,2-migratory insertion (hydropalladation) event to give a
vinylpalladium(II) species. This intermediate then undergoes
transmetalation with the aryl boronate, followed by C–C reductive
elimination to form the product and regenerate Pd(0), thereby closing
the catalytic cycle.
A. Hydroarylation under Pd(0)/PR3/HOAc conditions (Ref. 7c) and authors' proposal for electronic control.
H
O
O
5 mol% Pd(OAc)2
10 mol% PCy3
3 equiv Ph–B(OH)2
BnHN
Ph
PdIILn
Me
Me
Me Me
H
Scheme 4. Comparison of Two Commonly Invoked
Mechanistic Paradigms
via:
H
BnHN
Me
1.3 equiv HOAc
EtOH, 80 °C
N
Bn
δ+
Me
77%
Me
Me
(>20:1)
O
Me
B. Reactive 3-arylpropargyl amine substrates in Ref. 7c (9 total examples bearing the 6 aryl groups below).
A. Pd(0)/Pd(II) hydropalladation pathway
O
O
O
CN
H
Ar
S
Me
Me
EWG
(Ar)
[Pd0Ln]
HOAc
R1
R2
H
N
Ar =
R
CF3
C–C reductive
elimination
oxidative
addition
R' R'
N
CF3
H
PdII Ar
R2
PdII
H
C. N-Protected 4-phenylhomopropargyl amine substrates under Pd(0)/PR3/HOAc conditions from Ref. 7c.
Ph
OAc
H
R1
5 mol% Pd(OAc)2
10 mol% PCy3
Ph
H
+
NHR
NHR
NHR
3 equiv Ph–B(OH)2
B
Ph
Ph
A
R =
Bn
H
PdII
R2
1.3 equiv HOAc
EtOH, 80 °C
R1
R2
result
trace
Ar–B(OH)2
Ph
R1
R = PA (1a)
R = Bn (1v)
1,2-migratory insertion
(hydropalladation)
transmetalation
2-picolinoly (PA) ~15% (A:B = 4.5:1)
Given that Marinelli’s Pd(0)/PCy3/HOAc conditions gave a
product with similar connectivity to that obtained under our
conditions, we questioned whether this catalytic system would be
effective in a reaction with a 4-phenylhomopropargyl amine derivative,
our standard substrate. To probe this, we exposed our standard
PA-protected 4-phenylhomopropargyl amine substrate 1a and
Bn-protected analog 1v to Marinelli’s reactions conditions (Scheme
5c). In the case of 1a, hydroarylation took place in only 15% yield, with
a 4.5:1 of regioisomers. Though Marinelli had previously demonstrated
reaction compatibility with N-Bn-protected 3-arylproparyl amines,
with homopropargyl amine 1v, only trace product was formed. The
poor reactivity in both cases could be due to the fact that the arene is
not sufficiently electron-poor to allow for facile hydropalladation, while
the poor selectivity in the case of 1a could be due to competing
B. Pd(II) nucleopalldation pathway
Ar
R1
H
[PdIILn]
Ar–B(OH)2
+ base
R2
H+
proto-
depalladation
trans-
metalation
Ar
R1
PdII
R2
PdII–Ar
R1
R2
1,2-migratory insertion
(carbopalladation)
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Journal of the American Chemical Society
electronic and chelation effects on the putative [Pd(II)–H] species.
These data show that the mechanism of our system is likely distinct
from the Marinelli system and related Pd(0) cycles.
scale), and clean removal of the PA directing group via hydrolysis was
1
2
3
4
5
6
7
8
demonstrated. Future investigation will focus on elucidating the
reaction mechanism and developing other regioselective
hydrofunctionalization reactions of alkenes and alkynes using a
removable directing group strategy. These results will be reported in
due course.
Next, to confirm the source of the hydrogen atom in our reaction, a
deuterium labeling study was performed under reaction conditions that
were slightly modified to minimize the amount of H+ in solution
(Scheme 6). Upon addition of 1 equiv D2O, 40% deuterium was
observed exclusively at the vinylic position, with the remaining
non-deuterated product presumably arising from the NHPA group.
This result is consistent with the vinylic hydrogen in the product
arising from the boronic acid or the NHPA group under the standard
reaction conditions. This experiment also rules out the possibility of
[1,4]-palladium migration from vinylic position to an ortho-aryl
position prior to protodepalladation, since no deuterium incorporation
was detected on the aromatic ring.
ASSOCIATED CONTENT
Supporting Information
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Experiment details, spectra data, copies of H and 13C NMR spectra,
and X-ray crystallographic data. These materials are available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
A
plausible mechanism for this Pd(II)-catalyzed alkyne
hydroarylation reaction is proposed in Scheme 7. Initially, the
palladium catalyst, Pd(OAc)2, coordinates with the PCy3 ligand and
picolinate directing group to generate Pd(II) species A. With the
assistance of base, intermediate A undergoes transmetalation with the
arylboronic acid to generate aryl palladium complex B, which can
undergo syn-1,2-migratory insertion (carbopalladation) to form
Corresponding Author
* E-mail: keary@scripps.edu
Notes
The authors declare no competing financial interest.
bicyclic palladacycle intermediate C. Complex
C reacts via
ACKNOWLEDGMENT
This work was financially supported by TSRI and Pfizer, Inc. We thank
Prof. Arnold L. Rheingold (UCSD) for X-ray crystallographic analysis.
protodepalladation17 to afford palladium complex D, which can
undergo ligand exchange with a new substrate molecule to release the
product and regenerate Pd(II) species A. It is also possible that the
active Pd(II) species first participates in transmetalation to generate an
arylpalladium(II) complex prior to coordination of the picolinamide
directing group of the substrate.
REFERENCES
(1) For reviews, see: (a) Negishi, E. Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley-Interscience: New York, 2002. (b)
Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899. (c) Fagnou, K.;
Lautens, M. Chem. Rev. 2003, 103, 169.
Scheme 6. Deuterium Labeling Study
5 mol% Pd(OAc)2
5 mol% PCy3
D/H
Ph
O
Ph
1 equiv KOAc
1 equiv D2
B
B
NHPA
NHPA
(2) For organosilane reagents, see: (a) Fujii, T.; Koike, T.; Mori, A.;
Osakada, K. Synlett 2002, 295. (b) Lin, B.; Liu, M.; Ye, Z.; Zhang, Q.;
Cheng, J. Tetrahedron Lett. 2009, 50, 1714. For organostannane reagents,
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Lett. 1996, 811. (d) Fugami, K.; Hagiwara, S.; Oda, H.; Kosugi, M. Synlett.
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organozinc reagents, see: (f) Murakami, K.; Yorimitsu, H.; Oshima, K. Org.
Lett. 2009, 11, 2373. For organolithium reagents, see: (g) Hojo, M.;
Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi, A. Angew. Chem.
Int. Ed. 2001, 40, 621. For organocopper reagents, see: (h)
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(5) Oh, C. H.; Jung, H. H.; Kim, K. S.; Kim, N. Angew. Chem. Int. Ed. 2003,
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(6) For rhodium-catalyzed hydroarylation of alkynes with boronic acids,
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Yoshida, M. J. Org. Chem. 2003, 68, 762. (c) Genin, E.; Michelet, V.;
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see: (a) Kim, N.; Kim, K. S.; Gupta, A. K.; Oh, C. H. Chem. Commun. 2004,
618. (b) Gupta, A. K.; Kim, K. S.; Oh, C. H. Synlett 2005, 457. (c) Arcadi,
A.; Aschi, M.; Chiarini, M.; Ferrara, G.; Marinelli, F. Adv. Synth. Catal.
2010, 352, 493. (d) Rodriguez, A.; Moran, W. J. Lett. Org. Chem. 2010, 7, 7.
(e) Xu, X.; Chen, J.; Gao, W.; Wu, H.; Ding, J.; Su, W. Tetrahedron 2010,
66, 2433. (f) Yang, Y.; Wang, L.; Zhang, J.; Jin, Y.; Zhu, G. Chem. Commun.
2014, 50, 2347.
O
+
O
O
B
Ph
1,4-dioxane, 90 °C
Ph
1a
(0.4 equiv)
3a
53% yield
(40% D)
Scheme 7. Proposed Reaction Mechanism
Ar B(OH)2 , OAc
N
N
PdII
Ph
X
L
3a
A
1a
ligand
exchange
trans-
metalation
1a, L
Pd(OAc)2
(L = PCy3
Ph
N
N
N
N
)
Ar
PdII
L
PdII
L
Ph
H
Ar
X
D
B
Ar
B
1,2-migratory
insertion
proto-
depalladation
E:
O
B
O
B
Ar
O
Ar
N
N
PdII
–E
L
Ar B(OH)2
H2O
+E
Ar
Ph
C
CONCLUSION
In conclusion, we have reported a regioselective syn-hydroarylation
of non-symmetrical disubstituted alkyne substrates using a removable
picolinamide (PA) directing group. This reaction was found to be
highly regio- and stereoselective, allowing for nearly exclusive
formation of a single product isomer in most cases. Moreover, the
reaction proceeded effectively with both dialkyl and alkylaryl
disubstituted alkyne substrates, including those containing more distal
directing groups. The reaction was amenable to scale up (1.0 mmol
(8) For other transition-metal-catalyzed hydroarylation reaction of alkynes
with boronic acids, see: (a) Shirakawa, E.; Takahashi, G.; Tsuchimoto, T.;
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Page 6 of 6
Kawakami, Y. Chem. Commun. 2001, 2688. (b) Yamamoto, Y.; Kirai, N.;
(13) In some cases, trace amounts of the anti-hydroarylation regioisomers
were formed. However, in all cases these were observed in less than 3%
yield.
Harada, Y. Chem. Commun. 2008, 2010. (c) Lin, P.-S.; Jeganmohan, M.;
Cheng, C.-H. Chem. Eur. J. 2008, 14, 11296. (d) Robbins, D. W.; Hartwig,
J. F. Science 2011, 333, 1423.
(9) Under certain hydroarylation conditions, selective aryl addition at the b
position of 1-phenylpropyne has also been observed. See: Refs. 7c, 7d and
7e.
(10) For a review, see: (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem.
Rev. 1993, 93, 1307. For selected examples of directed carbometalation,
see: (b) Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125,
14670. (c) Ryan, J.; Micalizio, G. C. J. Am. Chem. Soc. 2006, 128, 2764.
(11) For selected examples of drug molecules containing a 4,4-diaryl
homoallylic amine motif, see: (a) Borden, L. A.; Dhar, T. G. M.; Smith, K.
E.; Weinshank, R. L.; Branchek, T. A.; Gluchowski, C. Eur. J. Pharmacol.
1994, 269, 219. (b) Barbui, C.; Hotopf, M. Br. J. Psychiatry 2001, 178, 129.
(c) Prochazka, A. V.; Weaver, M. J.; Keller, R. T.; Fryer, G.; Licari, P. A.;
Lofaso, D. Arch. Intern. Med. 1998, 158, 2035. (d) Fulton-Kehoe, D.;
Rossing, M. A.; Rutter, C.; Mandelson, M. T.; Weiss, N. S. Br. J. Cancer
2006, 94, 1071.
1
2
3
4
5
6
7
8
(14) (a) Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu, Y.-D.; Sigman,
M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960. (b) Xi, Y.; Hartwig, J. F.
J. Am. Chem. Soc. 2016, 138, 6703.
(15) For selected examples of [Pd(0)Ln] oxidative addition to carboxylic
acids to form [Pd(II)–H] species, see: (a) Trost, B. M.; Romero, D. L.;
Rise, F. J. Am. Chem. Soc. 1994, 116, 4268. (b) Kadota, I.; Shibuya, A.;
Gyoung, Y. S.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120, 10262. (c)
Konnick, M. M.; Gandhi, B. A.; Guzei, I. A.; Stahl, S. S. Angew. Chem. Int.
Ed. 2006, 45, 2904.
(16) The authors in Ref. 7c also demonstrate that the opposite regioisomer
is preferentially formed under alternate reaction conditions using a Rh(I)
catalyst. In this case the regioselectivity is also proposed to be rooted in
electronic effects, with the Rh(I)–Ar, attacking the more electropositive
alkynyl carbon atom.
(17) For selected examples on protonolysis of the alkenyl C–Pd bond, see:
(a) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1991,
56, 5816. (b) Wakabayashi, T.; Ishii, Y.; Ishikawa, K.; Hidai, M. Angew.
Chem. Int. Ed. 1996, 35, 2123. (c) Sashida, H.; Kawamukai, A. Synthesis,
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G.; Chen, Y.; Wang, Y.; Zheng, R. Chem. Commun. 2012, 48, 5796.
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(12) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 13154.
TOC Image
N
H
H
N
cat. Pd(II)
R2
NHPA
ArB(OH)2
R1
O
(PA)
R1
• 30 examples
• high regioselectivity
• removable PA directing group
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