Mechanistic Insight Leads to a Ligand Which Facilitates the Palladium-Catalyzed Formation of 2-(Hetero)Arylaminooxazoles and 4-(Hetero)Arylaminothiazoles

Article abstract of DOI:10.1002/anie.201705525

By using mechanistic insight, a new ligand (EPhos) for the palladium-catalyzed C?N cross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of the ligand-supported palladium(II) complexes and leads to significantly improved reactivity. The use of a catalyst system based on EPhos with NaOPh as a mild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized 2-arylaminooxazoles. Previously, these were not readily accessible using palladium catalysis.

Full text of DOI:10.1002/anie.201705525

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Accepted Article
Title: Mechanistic Insight Leads to a Ligand That Facilitates the Pd-
Catalyzed Formation of 2-(Hetero)Arylaminooxazoles and 4-
(Hetero)Arylaminothiazoles
Authors: Esben P. K. Olsen, Pedro L. Arrechea, and Stephen L.
Buchwald
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705525
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10.1002/anie.201705525
Angewandte Chemie International Edition
COMMUNICATION
Mechanistic Insight Leads to a Ligand That Facilitates the Pd-
Catalyzed Formation of 2-(Hetero)Arylaminooxazoles and 4-
(Hetero)Arylaminothiazoles.
Esben P. K. Olsen, Pedro L. Arrechea, and Stephen L. Buchwald*
an effective supporting ligand for selective monoarylation of
primary amines catalyzed by palladium.4b,12 The methoxy
substituent at the C3-position (Figure 1b) has been found to play
an important role in the selectivity and reactivity of catalysts
supported by this ligand.11a, 13 Reductive elimination studies have
demonstrated that BrettPhos-supported palladium(II) complexes
will reside as the O- and C-bound isomers (Figure 1b), and the
O-bound isomer is less competent for reductive elimination. We
thus hypothesized that the O-bound complexes may be “off-
cycle” palladium intermediates that must be eventually
converted to the product-producing C-bound complex (IV). We
felt that the development of a ligand that favored C-bound
isomers might enable a catalyst system with improved reaction
rates and efficiencies for challenging substrate classes.
Abstract: Using mechanistic insight, a new ligand (EPhos) for the
Pd-catalyzed C–N cross-coupling between primary amines and aryl
halides has been developed. Employing an isopropoxy group at the
C3-position favors the C-bound isomer of ligand-supported Pd(II)
complexes and leads to significantly improved reactivity. The use of
a
catalyst system based on EPhos with NaOPh as a mild
homogeneous base proved to be very effective in the formation of 4-
arylaminothiazoles and highly functionalized 2-arylaminooxazoles.
Previously, these were not readily accessible using Pd-catalyzed
methodology.
Palladium catalyzed C–N bond-forming reactions have
impacted the synthesis of nitrogen-containing molecules in a
range of scientific disciplines1, including materials science2,
chemical biology3 and medicinal/process chemistry4. Insights
into the mechanism of the reaction have informed the
development of better ligands and reaction conditions, resulting
in C–N cross-coupling protocols of substantial utility and
generality.5 Nevertheless, important limitations to the scope of
the reaction remain, especially with respect to the coupling of
highly functionalized or heterocyclic substrates, which are of
particular relevance to the synthesis of biologically active
compounds.6 Indeed, medicinal chemists at Merck recently
disclosed that 55% of the metal-catalyzed C–N cross-coupling
reactions performed at their facilities failed to deliver any desired
product in late stage synthesis of drug leads, highlighting some
of the persistent barriers to overcome in the development of this
transformation.7
The cross-coupling of five-membered heteroarylamines
with aryl halides remains challenging in many cases despite
their frequent occurrence as substructures of natural products8,
pharmaceuticals and other biologically active molecules.9 For
example, researchers at AstraZeneca recently reported their
difficulties in developing conditions for the palladium-catalyzed
cross-coupling of 2-aminooxazoles.10 The authors reported that
only trace amounts of coupling product could be obtained in the
case of the parent 2-aminooxazole (4), although a handful of 4-
and 5-substituted derivatives could be coupled in low to
moderate yield. To prepare the coupling product of 4, a multistep
procedure involving the saponification and decarboxylation of
the 4-ethylester derivative was required. In general,
improvements in the cross-coupling of five-membered
heteroarylamines, such as 2-aminooxazole 4, would be a useful
advance for the field of transition metal-catalyzed cross coupling.
We previously reported BrettPhos11 (Figure 1b/2a, L1) as
Figure 1. a) Simplified catalytic cycle for a palladium catalyzed C–N cross-
coupling reaction. b) Bulky substituents for R1 favor the C-bound isomer (see
supporting information). Analogous C-bound/O-bound isomers have been
observed for III and IV.
With this hypothesis in mind, we synthesized an array of
L1 analogues that we believed could decrease the percentage
of the O-bound isomer. This study (detailed in the supporting
information) led to the identification of EPhos (L3) as an
effective ligand for the cross-coupling of 4 with an array of
hindered and/or functionalized aryl chlorides and bromides, as
well as commercial pharmaceuticals. In addition, the catalytic
system was used to prepare several functionalized 4-
(hetero)arylaminothiazoles. Studies that employed reaction
calorimetry and NMR implied that reactions with palladium
catalysts based on L3 show improved reaction rates and the
resting state of the catalyst is solely as the C-bound isomer.
[*]
Dr. E. P. K. Olsen, Dr. P. L. Arrechea, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA, 02139 (USA)
E-mail: sbuchwal@mit.edu
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10.1002/anie.201705525
Angewandte Chemie International Edition
COMMUNICATION
bearing a methyl ester group in the ortho position, condensation
took place, resulting in the formation of the tricyclic heterocycle
7j. An appreciable yield could be obtained with P3 in the
presence of NaOPh (Conditions A). The unsubstituted 5H-
oxazolo[2,3-b]quinazolin-5-one is previously unknown, although
the thio-analog has been prepared using a copper catalyzed
reaction.15
H
N
a)
Cl
H2N
3.0 mol% P1 - P4
N
N
A: NaOPh, THF, 80 oC, 3 h
B: K2CO3, THF, 80 oC, 3 h
O
O
N
5b
N
4
6b
100
90
80
70
60
50
40
30
20
10
0
78
54
50
Figure 2. Ligands for palladium catalyzed C–N cross-couplings.
36
25
The results in Figure 3 show the improved reactivity
observed with L3-based palladium catalysts. The cross coupling
0
0
of 2-aminooxazole
4 with 3-chloropyridine (5b) and 2,6-
P1 (A) P1 (B) P2 (A) P2 (B) P3 (A) P4 (A) P4 (B)
Me
dimethylchlorobenzene (5c) was examined with a range of
ligands and reaction conditions. A series of precatalysts14 based
on BrettPhos (P1), tBuBrettPhos (P2), EPhos (P3), and XPhos
(P4) as the supporting ligands were evaluated in the presence of
either NaOPh (Conditions A) or K2CO3 (Conditions B), and it was
determined that the use of P3 provided the highest yields for
either pair of starting materials (see the supporting information
for the full set of details for this study). P1-P3 each afforded
product with 3-chloropyridine (5b), while no product was
obtained using P4, highlighting the importance of the 3-alkoxy
substituent in the ligand structure. In the case of 2,6-
dimethylchlorobenzene (5c), P2 was found to be ineffective,
presumably due to the combined steric hindrance from the
ligand and the aryl chloride.
Me
b)
H
H2N
2.0 mol% P1 - P4
N
Cl
N
N
A: NaOPh, 2-MeTHF, 100 oC, 3 h
B: K2CO3, tBuOH, 100 oC, 3 h
O
O
Me
Me
6c
5c
4
92
85
100
90
80
70
60
50
40
30
20
10
0
38
With two sets of conditions (Conditions
A and B)
0
0
0
0
employing P3 as the precatalyst, the scope of the cross coupling
of aminooxazole 4 was explored with a wide variety of aryl
chlorides and bromides. When relatively simple and unhindered
aryl halides were employed, precatalysts based on BrettPhos
(P1) and EPhos (P3) performed comparably. However, when the
cross coupling of more complex or sterically hindered substrates
was attempted, significantly better yields were obtained with the
EPhos-supported Pd catalyst P3 (7h-7m). A variety of functional
groups could be tolerated, including a ketone (7a), a nitro group
(7d), an unprotected alcohol (7i), an acetal (7l), and secondary
and tertiary amines (7m, 7o, 7r, 7q). A collection of heterocycles
also proved to be efficiently transformed under these conditions.
Importantly, ortho-substituted substrates (7k-7n) reacted
efficiently when P3 was employed and several densely
functionalized pharmaceuticals also underwent coupling in high
yields (7o-7q).
P1 (B) P2 (A) P2 (B) P3 (A) P3 (B) P4 (A) P4 (B)
Figure 3. a) Precatalysts tested for the formation of 6b. b) Precatalysts tested
for the formation of 6c.
As 4-bromothiazole is also sensitive to strong base, a mild
homogeneous base was similarly expected to improve reaction
outcomes with this coupling partner. P3 (A) afforded 8a and 8d
in significantly higher yields with lower catalyst loadings than
what has previously been reported (Scheme 1).10b Furthermore,
products 8b and 8c could be obtained in excellent yields with 2.0
mol% catalyst loading at 80 °C. Although the aryl bromide was
used in excess for the case of 8c, no diarylation product was
observed, highlighting the high selectivity for the monoarylation
product using this catalyst system. Notably, excellent yields
were also obtained when aminopyrazine (8e) and
aminopyrimidine (8f) were employed.
3-Chlorobenzonitrile did not undergo cross coupling with 4
when either BrettPhos (P1) or EPhos (P3) was employed,
although
a nitrile group was tolerated when a different
heteroarylamine was used (7d). When using an aryl chloride
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10.1002/anie.201705525
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COMMUNICATION
Scheme 1. Palladium catalyzed cross-couplings of 2-aminooxazoles with aryl chlorides and bromides. [a] Reaction conditions A: 2-aminooxazole (1.2 mmol), aryl
halide (1.0 mmol), precat (0.02-0.075 mmol), NaOtBu (1.2 mmol) PhOH (1.3 mmol), 2-MeTHF (4.0 mL), 100 °C, 3 h. Reaction conditions B: 2-aminooxazole (1.2
mmol), aryl halide (1.0 mmol), precat (0.02-0.075 mmol), K2CO3 (1.4 mmol), tBuOH (4.0 mL), 100 °C, 3 h. [b] THF (4.0 mL), 80 °C, 3 h. [c] 0.5 mmol scale. [d]
0.125 M.
Although NaOPh is a relatively uncommon base for
palladium catalyzed C–N cross-coupling reactions, several
previous reports have documented its use.16 Hartwig reported
that KOPh was optimal for the palladium-catalyzed arylation of
fluoroalkylamines, and the resting state of the catalytic reaction
was determined to be a LPd(Ar)OPh complex.16a We queried
whether analogous phenoxo complexes based on L1 or L3
might be observable under catalytic conditions. Subjecting a
solution of L1Pd(Ar)Cl (Ar=2-MeC6H4) (OA1b) or L3Pd(Ar)Cl
(Ar=2-MeC6H4) (OA3c) in THF to NaOPh at room temperature
gave rise to new signals in the 31P NMR spectrum 4-5 ppm
downfield of the signals for OA1b and OA3c (see the Supporting
information). The cross-coupling of aniline and 2-chlorotoluene
using NaOPh as the base, and OA1b (5.0 mol%) as the catalyst
were predominant and were identified as the isomers of the
phenoxo complex in which palladium is bound to either the 1’-
aryl carbon (C-bound) or the 3-alkoxy group (O-bound) (Figure
1b).11a Interestingly, the O-bound isomer seemed to accumulate
over the duration of the reaction. When the same experiment
was conducted with OA3c, only the peak corresponding to the
C-bound isomer was observed, suggesting that the bulky
isopropoxy group disfavors the O-bound isomers.
While studying palladium-catalyzed amination reactions at
room temperature, we observed a complex but reproducible
kinetic profile for the cross-coupling of 3-bromoanisole (1) and n-
propylamine (2) when using the L1-based complex LPd(II)ArBr
(OA1, 0.7 mol%) as the palladium source and NaOtBu as base
(Figure 4).17 In contrast, when the L3-based complex OA3 was
used, a rapid reaction with a simple kinetic profile was observed.
Although the complex kinetics observed with OA1 precluded a
o
was monitored by 31P NMR at 60 C in THF-d8. During the
course of the reaction, these two phosphorus-containing species
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COMMUNICATION
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Figure 4. Reaction progress kinetic profiles for the Pd-catalyzed reaction of 3-
bromoanisole with n-propylamine. NaOtBu was used as the base, and OA1
and OA3 were used as the catalysts. Reactions were run at 20 °C in dioxane.
[8]
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In conclusion, a new ligand (L3, EPhos) for the palladium
catalyzed C–N cross-couplings has been developed, which was
applied to the formation of 2-(hetero)arylaminooxazoles and 4-
(hetero)arylaminothiazoles. Furthermore, experiments have
demonstrated that the respective palladium(II) phenoxo complex
is the resting state for this reaction when NaOPh is applied as
the base. The O-bound isomer was not observed if L3 was
used as the supporting ligand (Figure 3). Although this
phenomenon does represent a significant difference in behavior
between L1 and L3, ongoing studies will elucidate whether this
equilibrium accounts for the difference in efficiency observed
between these ligands.
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Acknowledgements
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Martínez-Ilarduya, P. Espinet, Angew. Chem. 2016, 128, 13470-13474.:
Angew. Chem. Int. Ed. 2016, 55, 13276-13280.
Research reported in this publication was supported by the
National Institutes of Health under award number GM58160
whom we gratefully acknowledge. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health. E. O. thanks
the Villum Foundation for a postdoctoral fellowship. We thank Dr.
Yiming Wang, Dr. Michael Pirnot, and Dr. Mycah Uehling for
their help in the preparation of this manuscript.
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2336.
Keywords: EPhos • 2-aminooxazole • C–N cross-coupling •
palladium catalysis • sodium phenoxide
[17] D. G. Blackmond, Angew. Chem. 2005, 117, 4374-4393: Angew. Chem.
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10.1002/anie.201705525
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COMMUNICATION
COMMUNICATION
Esben P. K. Olsen, Pedro L. Arrechea,
Stephen L. Buchwald*
Page No. – Page No.
Mechanistic Insight Leads to a New
Ligand That Facilitates the Pd-
Catalyzed Formation of 2-
(Hetero)Arylaminooxazoles and 4-
(Hetero)Arylaminothiazoles.
A new ligand, EPhos, for Pd-catalyzed C–N cross-couplings has been developed
based on a structure activity relationship of BrettPhos related ligands. The ligand
was succesfully applied in the Pd-catalyzed formation of 2-
(hetero)arylaminooxazoles and 4-(hetero)arylaminothiazoles, structures that have
previously proven problematic to form by transition metal catalysis.
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