1-Aminopyridinium Ylides as Monodentate Directing Groups for sp3 C-H Bond Functionalization

Article abstract of DOI:10.1021/jacs.9b06643

1-Aminopyridinium ylides are efficient directing groups for palladium-catalyzed β-arylation and alkylation of sp³ C-H bonds in carboxylic acid derivatives. The efficiency of these directing groups depends on the substitution at the pyridine moiety. The unsubstituted pyridine-derived ylides allow functionalization of primary C-H bonds, while methylene groups are unreactive in the absence of external ligands. 4-Pyrrolidinopyridine-containing ylides are capable of C-H functionalization in acyclic methylene groups in the absence of external ligands, thus rivaling the efficiency of the aminoquinoline directing group. Preliminary mechanistic studies have been performed. A cyclopalladated intermediate has been isolated and characterized by X-ray crystallography, and its reactivity was studied.

Full text of DOI:10.1021/jacs.9b06643

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
1‑Aminopyridinium Ylides as Monodentate Directing Groups for sp3
C−H Bond Functionalization
Ky Khac Anh Le, Hanh Nguyen, and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
ABSTRACT: 1-Aminopyridinium ylides are efficient direct-
ing groups for palladium-catalyzed β-arylation and alkylation
of sp3 C−H bonds in carboxylic acid derivatives. The
efficiency of these directing groups depends on the
substitution at the pyridine moiety. The unsubstituted
pyridine-derived ylides allow functionalization of primary
C−H bonds, while methylene groups are unreactive in the absence of external ligands. 4-Pyrrolidinopyridine-containing ylides
are capable of C−H functionalization in acyclic methylene groups in the absence of external ligands, thus rivaling the efficiency
of the aminoquinoline directing group. Preliminary mechanistic studies have been performed. A cyclopalladated intermediate
has been isolated and characterized by X-ray crystallography, and its reactivity was studied.
1. INTRODUCTION
Carbon−hydrogen bond activation and functionalization
methodology has evolved from organometallic curiosity to
applications in the synthesis of complex natural products.1
However, selective functionalization of unactivated (not
benzylic or α to a heteroatom) sp3 C−H bonds still presents
a challenge. Positional selectivity is usually achieved by
employing a directing group that coordinates metal and
positions it for cleavage of the desired C−H bond. Both mono-
and bidentate directing groups have been extensively used for
this purpose. Monodentate directing groups can be broadly
categorized as X or L type (Figure 1). Examples of X-type
directing groups, sometimes categorized as weak, include
carboxylates 1, polyfluoroanilides 2, and hydroxamic acids 3.2
L-Type monodentate auxiliaries (or strong directing groups)
include pyridines, oxazolines, oxime derivatives, and tertiary
amines.3 With few exceptions,3a,4 monodentate groups allow
functionalization of only primary unactivated sp3 C−H bonds.
Secondary C−H bonds in acyclic structures typically react only
in the presence of added ligands, and transformations often
require high loadings of palladium catalyst as well as forcing
conditions. Reactivity in the presence of added external ligands
has important practical consequences with respect to
asymmetric C−H functionalization, since background reaction
leading to erosion of enantioselectivity is suppressed.5
Bidentate, usually monoanionic, auxiliaries have been
categorized as strong directing groups.1e,6 They allow for an
efficient functionalization of both primary and secondary
Figure 1. Directing groups for sp3 C−H functionalization.
alkane C−H bonds. In some cases, even tertiary C−H bonds
are reactive.7 The aminoquinoline, picolinamide, and 2-
performed in situ.10 The electron-rich, bidentate, monoanionic
thiomethyaniline auxiliaries were introduced in 2005 and
2010.8 Many similar directing groups have been found
subsequently.9 Recently, C−H functionalizations have been
rendered catalytic with respect to bidentate auxiliaries, and
sometimes the formation of the directing groups can be
auxiliaries facilitate both the C−H activation and functional-
Received: June 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b06643
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Article
ization steps, especially if high-valent transition metal
intermediates are involved. There are cases, however, where
weaker or monodentate coordination may be preferable. For
example, development of catalytic, asymmetric transformations
requires binding of external ligands to metal. Strong, bidentate
auxiliaries may outcompete the chiral ligand, resulting in
significant racemic background reaction. After the C−H
activation step, the substrate coordinates to metal as a
tridentate ligand, saturating its coordination sites (14). The
decreased number of open sites at the metal and the stability of
the intermediate palladacycles may interfere with the
subsequent C−H functionalization step. Consequently, mono-
dentate auxiliaries possessing efficiency of bidentate directing
groups would have advantages in C−H bond functionalization,
perhaps allowing for mild C−H functionalization and strong
influence of added ligands.
In 1974, McWhinnie and co-workers showed that
benzoylated 1-aminopyridine ylides can be cyclometalated by
palladium, rhodium, and platinum complexes.11 In the next 40
years, these ylides were used as substitutes for pyridine oxides,
mostly for functionalization of the pyridine ring.12 We
speculated that sp3 C−H functionalization could be achieved
if aliphatic carboxylic acid amides of 1-aminopyridine were
employed. We report here that 1-aminopyridine ylides are the
first monodentate directing groups that allow for general
functionalization of primary and secondary unactivated sp3 C−
H bonds in the absence of external ligands. Properties of these
auxiliaries can be easily tuned by substitution at the 4-position
of the pyridine moiety. These new directing groups rival
aminoquinoline in efficiency and may supplement it in the
synthesis of complex natural products and multiple bond
functionalization.13
sodium tetrafluoroborate increased the yield (entries 3 and 4).
Further improvement was observed when sodium triflate
additive was used (entry 5). An increased amount of NaOTf
did not result in higher reaction yield (entry 6). Highest yield
was obtained at 90 °C (entry 8), while other temperatures gave
lower yields (entries 7 and 9). Aryl bromides and aryl triflates
are unreactive under these conditions.
2.2. Arylation of Primary C−H Bonds. The arylation of
1-(propionylamino)pyridinium ylide was conducted with a
broad range of electron-rich (entries 1−5 and 15), electron-
poor (entries 6−14), and heterocyclic (entries 15−18) aryl
iodides. The products were obtained in good yields (Table 2).
This reaction tolerates substituents at either para- or meta-
positions of the aryl iodides. No arylation products were
observed if ortho-substituted aryl iodides were employed,
consistent with results obtained with aminoquinoline amides.
The reaction can accommodate a range of functional groups,
such as methoxy (entry 2), alkyl (entries 1 and 3), bromo
(entry 7), ether (entries 2, 5, and 15), ester (entry 6),
trifluoromethyl (entries 9, 10, and 13), fluoro (entries 11 and
14), chloro (entry 14), and enolizable ketone (entry 17).
Interestingly, even an aldehyde moiety is tolerated (entries 12
and 16). Some heterocycles, such as dihydrobenzofuran (entry
15), furan (entry 16), thiophene (entry 17), and protected
indole (entry 18), are also compatible with reaction conditions.
Introduction of strongly electron-withdrawing substituents
decreases reaction yields (entries 8 and 9).
Next, we investigated the possibility of room-temperature
reaction and low catalyst loadings (Scheme 1). Arylation of
ylide 16 was successful by using 1 mol % Pd(OAc)2 catalyst if
an acetyl-protected aminoethyl phenyl thioether was added.2e
Room-temperature arylation was also successful in the
presence of this ligand.
Reaction scope with respect to amide coupling component
was investigated subsequently (Table 3). The arylation
proceeded exclusively at the methyl group for the 2-
methylbutyric acid derivative (entry 1). The phenyl-substituted
compound afforded product in 91% yield (entry 2). Arylation
of isobutyric acid amide gave a mixture of diarylation and
monoarylation products in 58% and 37% yields, respectively
(entry 3). The reaction is compatible with trifluoromethyl and
methoxy substitution on the amide (entries 4 and 6). More
hindered substrates, such as cyclohexyl-substituted amide, are
reactive as well, giving product in 83% yield (entry 5).
Interestingly, the phthaloyl-protected alanine derivative affords
arylation product in a reasonable yield, and no loss of
enantiomeric excess was observed (entry 7). No arylation of
secondary C(sp3)−H bonds was observed when the reaction
was carried out under the standard conditions.
2. RESULTS AND DISCUSSION
2.1. Reaction Optimization. The initial reaction opti-
mization was based on previous results using monodentate
directing groups for C−H functionalization (Table 1).14
However, conditions employing acetic acid solvent resulted
in low yield of 17 (entry 1). Performing the reaction in
hexafluoroisopropanol resulted in an improved 63% yield
(entry 2). Addition of disodium hydrogen phosphate or
a
Table 1. Optimization of Reaction Conditions
entry
T, °C
solvent
additive
yield, %
2.3. Arylation of Secondary C−H Bonds. Yu has shown
that addition of mono-N-protected amino acid ligands allows
palladium-catalyzed arylation of secondary, unactivated sp3 C−
H bonds even when weak directing groups are used.5a Inspired
by this precedent, we investigated the effect of mono-N-
protected amino acid ligands on secondary C(sp3)−H
arylation. After considerable optimization, it was discovered
that addition of N-acetyl-L-phenyalanine ligand afforded
optimal reactivity. The results of secondary C(sp3)−H
arylation are presented in Table 4. A higher loading of
palladium acetate and use of silver trifluoroacetate additive is
required to obtain good yields of products. The butanoic acid
derivative afforded product in 67% isolated yield (entry 1).
Cyclic substrates can be arylated as well. Cyclohexanecarbox-
1
2
3
4
5
100
110
110
110
110
110
100
90
AcOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
40
63
74
80
87
87
87
91
74
Na2HPO4
NaBF4
NaOTf
NaOTf
NaOTf
NaOTf
NaOTf
b
6
7
8
9
80
a
Amide 0.15 mmol, 4-iodotoluene 2.5 equiv, AgOAc 1.5 equiv,
additive 1.0 equiv. Yields of 17 were determined by 1H NMR analysis
b
using 1,1,2-trichloroethane internal standard. NaOTf 1.2 equiv.
AcOH = acetic acid, HFIP = hexafluoroisopropanol, OTf = triflate.
B
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a
Table 2. Arylation Scope with Respect to Aryl Iodides
a
Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated yields. Py = 1-pyridyl. Please see Supporting Information for details.
ylic acid amide gave two monoarylation diastereoisomers in
92% yield with a crude diastereomer ratio of 4:1 (entry 2). The
cyclopentanecarboxylic acid derivative is monoarylated in 85%
yield (entry 3), while cyclobutanecarboxylic acid amide reacts
to produce diarylated product in 82% yield (entry 4).
Interestingly, β-methylene C(sp3)−H bond arylation of a
protected amino acid occurs in reasonable yield (entry 5), and
single product diastereomer was obtained, consistent with
results obtained with an aminoquinoline directing group.15
As shown above, unsubstituted iminopyridinium ylide
auxiliary is about as efficient in directing C−H bond
functionalization as Yu’s perfluoroarylamides,5a requiring
added ligands to effect arylation of methylene groups.
Assuming a catalytic cycle similar to that proposed for
aminoquinoline amides,8b,15 it is likely that a more electron-
C
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a
Scheme 1. Reactions with Low Catalyst Loading and at
Room Temperature
Table 3. Arylation Scope with Respect to Amides
rich substrate/ligand will facilitate oxidation, forming Pd(III)
(or Pd(IV)) species, irrespective of whether the reaction
proceeds via Pd(IV) or dimeric Pd(III) complexes.16,17
Furthermore, while the electronic effect of coordinated
ligand/substrate on the C−H activation step is unclear, in
some cases strong σ-donor ligands allow for efficient
cyclometalation.18 Consequently, a strongly donating auxiliary
may increase the efficiency of C−H arylation. Functionaliza-
tion of 1-aminopyridine ylide butyramides possessing an
electron-donor substituent was investigated (Scheme 2). As
predicted, strongly donating pyrrolidinopyridine-substituted
ylide 50 gave the highest product yield, while methoxy- and
dimethylamino-substituted 48 and 49 afforded lower con-
versions. Pyridine derivative 47 did not react under these
conditions. The reactivities track the corresponding pyridine
catalytic efficiencies in alcohol acylation reactions.19
After a short optimization, the scope of acylated 4-
pyrrolidinopyridine ylide arylation was investigated (Table
5). The butyryl derivative was arylated in a 68% yield (entry
1). Alkyl groups possessing a phenyl (entry 2), cyclohexyl
(entry 3), or branched chains (entry 4) were arylated in good
yields. For some substrates, increasing the palladium acetate
loading to 10 mol % gives higher yields (entries 2 and 4).
Cyclic structures, such as ylides derived from cyclohexane- and
cyclobutanecarboxylic acids, are arylated in good yields
(entries 5 and 6). In those cases, cis-products are obtained
either predominately (entries 5 and 7) or exclusively (entry 6).
Amide-containing substrates also react, albeit at higher
palladium loading (entry 7). Fluoro- and trifluoromethyl
functionalities are compatible with reaction conditions, and
products were isolated in acceptable yields (entries 8 and 9).
2.4. Alkylation of C−H Bonds. Alkylation of C−H bonds
was also successful (Scheme 3). Reactions require use of
dibenzyl phosphate silver salt additive.20a Ethyl iodoacetate
reacts with a propionic acid derivative to give an 82% yield of
62. Similarly, reactions with trifluoromethyl- and alkyl-
substituted ylides afford products in acceptable to good yields
(63 to 65). Benzyl ester gives alkylation product 66 in a
reduced 14% yield. Methyl iodide is a competent alkylation
agent, and 67 was obtained in 51% yield.
a
Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated
b
yields. Please see Supporting Information for details. Ar = 3,5-
Me2C6H3. Monoarylation product also isolated (37% yield).
c
Arylation of starting material (92% ee) gave 41 (92% ee).
methanolysis with no erosion of enantiomeric excess (41 to
70).20b
2.6. Mechanistic Considerations. A presumed C−H
functionalization intermediate 72 was formed by reaction of
amide 71 with palladium acetate in acetonitrile, isolated, and
fully characterized (Scheme 5). It exists as a green-yellow solid
that is soluble in hydroxylic solvents, is insoluble in
acetonitrile, and decomposes in dichloromethane, forming a
chloro-bridged complex. The structure of 72 was verified by
single-crystal X-ray diffraction analysis. The ORTEP diagram
2.5. Directing Group Removal. The pyridinium moiety
can be easily removed through zinc-mediated N−N bond
cleavage. In the case of a 4-pyrrolidinopyridinium auxiliary,
magnesium was used instead of zinc (Scheme 4). Additionally,
the directing group can be cleaved by Lewis acid promoted
D
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Table 4. N-Acetyl-L-phenyalanine-Enabled Secondary
Table 5. Secondary C(sp3)−H Arylation without Added
a
a
C(sp3)−H Arylation
External Ligands
a
Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated
yields. Please see Supporting Information for details. Ar = 4-FC6H4.
b
c
d
Enantiomeric excess: 25%. Cis/trans 4.6/1. Enantiomeric excess:
e
33% for the cis isomer. Enantiomeric excess: 23%.
Scheme 2. Arylation of Substituted Ylides
of 72 is shown in Figure 2. Complex 72 crystallizes in
monoclinic space group C2/c and exists as a dimer in the solid
state with a Pd−Pd distance of 2.8821(3) Å, which is shorter
than the van der Waals radii sum of 3.26 Å, signifying a Pd−Pd
bonding interaction.21 The palladium−C(alkyl) bond length is
2.007(2) Å, while the palladium−N(amide) distance is
1.984(2) Å. The N(1)−Pd(1)−C(1) angle is 80.17(21)°,
showing distortion from an idealized square-planar geometry at
the palladium center. It appears that no transition metal
complexes of acylated 1-aminopyridine ylides have been
crystallographically characterized.22
Our attempts to oxidize 72 to a Pd(III) or Pd(IV) complex
with a range of oxidants such as halogens and peroxides were
not successful, and ligand loss from palladium was observed.
Reactions with 4-fluorophenyl iodide were more informative.
Complex 72 did not react with aryl iodide in methanol at 25
°C on a time scale of days. However, reactions in
hexafluoroisopropanol were successful (Table 6).
a
Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated
yields. Please see Supporting Information for details. Ar = 4-FC6H4.
b
c
d
Ten mol % Pd(OAc)2. Cis/trans 5/1. Diastereomer ratio: 1.6/1;
e
f
36 h, 110 °C. 36 h, 110 °C. Diastereomer ratio: 1.5/1; 36 h, 110 °C.
PPY = 4-pyrrolidino-1-pyridyl.
Reaction in hexafluoroisopropanol solvent for one hour gave
a mixture of mono- and diarylation products (entry 1). After
24 h, some triarylation product was observed (entry 7).
Addition of silver trifluoroacetate increased the rate of
arylation (entry 2), while sodium trifluoroacetate and triflate
had little effect on the reaction (entries 3 and 4). No arylation
was observed in methanol solvent even in the presence of silver
trifluoroacetate (entry 5). Addition of acetonitrile shut down
E
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a
Scheme 3. Alkylation of C−H Bonds
Table 6. Reactivity of 72 with Aryl Iodide
Entry
solvent
additive
73 (%) 74 (%) 75 (%)
1
2
3
4
5
6
HFIP
HFIP
HFIP
HFIP
MeOH
HFIP
HFIP
HFIP
none
44
16
36
39
0
0
44
11
21
38
25
24
0
0
28
41
0
11
2
2
0
0
5
26
AgOCOCF3
NaOCOCF3
NaOTf
AgOCOCF3
CH3CN AgOCOCF3
none
b
Scheme 4. Directing Group Removal
7
b
8
AgOCOCF3
a
Time: 1 h, trifluoroacetate or triflate additive: 1.2 equiv, acetonitrile
additive: 7.5 equiv. Yield determined by NMR with 1,1,2,2-
b
tetrachloroethane internal standard. Time: 24 h.
Scheme 6. H/D Exchange Experiments
Scheme 5. Cyclometalated Intermediate
recovered starting material. This is distinct from the
corresponding reactivity of aminoquinoline amides, where
H/D exchange is observed.8b,15 Furthermore, C−H function-
alizations directed by bidentate, monoanionic auxiliaries
proceed in coordinating solvents such as acetonitrile.8b While
extensive mechanistic speculations are premature at this point,
pyridine ylide-directed C−H functionalizations may proceed
via dimeric species, as evidenced by the shutting down of the
reaction when coordinating solvents are added.23
3. SUMMARY
We report here that 1-aminopyridinium ylides are efficient
directing groups for palladium-catalyzed β-arylation and
alkylation of sp3 C−H bonds in carboxylic acid derivatives.
The unsubstituted pyridine-derived ylides can direct function-
alization of primary C−H bonds. Addition of external ligands
allows for functionalization of methylene groups. Directing
group efficiency is improved if electron-donor substituents are
introduced at the 4-position of the pyridine ring. Thus, 4-
pyrrolidinopyridine-containing ylides are capable of C−H
functionalization of acyclic methylene groups in the absence of
external ligands. Preliminary mechanistic studies have been
performed. A cyclopalladated intermediate was isolated,
characterized by X-ray crystallography, and its reactions were
studied. Aminopyridine ylide directing groups may find
extensive use in new methodology development as well as in
synthesis of natural products, supplementing current applica-
tions of bidentate, monoanionic auxiliaries.
Figure 2. ORTEP view of 72. Selected interatomic distances (Å) and
angles (deg): Pd1−N1 1.984(2); Pd1−C1 2.007(2); Pd1−Pd1
2.8821(3); N1−N2 1.415(3); N1−Pd1−C1 80.17(10); C1−Pd1−
O2 94.77(10).
the reaction completely (entry 6). Acetonitrile presumably
breaks up the dimeric structure of 72. After 24 h, reaction with
added silver salt gave a mixture of arylation products (entry 8).
Furthermore, it appears that cyclometalation is irreversible
(Scheme 6). No H/D exchange in the methyl group was
observed if amide 76 was heated under the catalytic conditions
with added acetic acid-d4. If amide 76 was arylated in HFIP-d2,
deuterium was not incorporated in the methylene group of the
F
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4. EXPERIMENTAL SECTION
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4.1. General Procedure for the Arylation Directed by a 1-
Amino-4-pyrrolidinopyridine Auxiliary. A 8-dram vial equipped
with a magnetic stir-bar was charged with amide (0.5 mmol), 1-fluoro-
4-iodobenzene (278 mg, 1.25 mmol), Pd(OAc)2 (5.7 mg, 5 mol %),
AgOCOCF3 (133 mg, 1.2 equiv), NaOTf (86 mg, 1.0 equiv), and
hexafluoroisopropanol (3.5 mL). The mixture was stirred at room
temperature for 5 min, covered with aluminum foil, and then heated
at 90 °C for 24 h. After completion, the reaction was cooled to room
temperature and diluted with a CH2Cl2/MeOH mixture (5 mL, 9:1).
The suspension was filtered through a pad of Celite, and the solid
phase was washed with dichloromethane (2 × 20 mL). The filtrate
was concentrated under reduced pressure. The residue was subjected
to column chromatography on silica gel using an appropriate eluent.
After purification, the product was dried under reduced pressure.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b06643.
■
S
Crystallographic data for 72 (CIF)
Detailed experimental procedures and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*olafs@uh.edu
■
ORCID
Olafs Daugulis: 0000-0003-2642-2992
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Welch Foundation (Chair No. E-0044) and
NIGMS (Grant No. R01GM077635) for supporting this
research. We are grateful to Dr. Xiqu Wang for collecting and
solving the X-ray structure of 72 and to Dr. Rana M. Kashif
Khan for initial experiments with a 1-aminopyridine auxiliary.
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