Catalytic Direct C2-Alkenylation of Oxazoles at Parts per Million Levels of Palladium/PhMezole-Phos Complex

Article abstract of DOI:10.1021/acs.orglett.6b02619

General direct C2-alkenylation of oxazoles is reported using alkenyl tosylates at parts per million levels of palladium catalyst. From a series of ligands screened, PhMezole-Phos emerged as the promising ligand candidate to facilitate this reaction. Signi

Full text of DOI:10.1021/acs.orglett.6b02619

Letter
pubs.acs.org/OrgLett
Catalytic Direct C2-Alkenylation of Oxazoles at Parts per Million
Levels of Palladium/PhMezole-Phos Complex
Wai Chung Fu,†,§ Yong Wu,‡,§ Chau Ming So,† Shun Man Wong,† Aiwen Lei,*,‡ and Fuk Yee Kwong*,†
†State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon 852, Hong Kong
‡College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei, P.R. China
S
* Supporting Information
ABSTRACT: General direct C2-alkenylation of oxazoles is
reported using alkenyl tosylates at parts per million levels of
palladium catalyst. From a series of ligands screened,
PhMezole-Phos emerged as the promising ligand candidate
to facilitate this reaction. Significantly, the method is scalable
and exhibits excellent substrate tolerance. Highly sterically
hindered substrates and small vinyl tosylate can be coupled
successfully. Moreover, our method enables a rapid diversification of oxazole-based C^N ligands which can be readily derived
into new group 9 organometallic compounds.
a
Scheme 1. Direct C2-Alkenylation of (Benz)oxazoles
2-Alkenylated oxazole and benzoxazole derivatives are
Cessential motifs in pharmaceuticals and medicinal
chemistry, while alkenylazoles play important roles in the
construction of organic materials.1 However, traditional organic
syntheses leading to these compounds often require harsh
reaction conditions and prefunctionalization of reagents.2 On
the other hand, emerging transition-metal-catalyzed reactions
allow the rapid and concise functionalization of heterocyclic
C−H bonds and synthesis of heteroarenes.3 The research for
metal-catalyzed direct functionalization of azoles has been
intensive, and notably, direct C2-alkenylations with alkenyl
electrophiles have received significant attention.4 Other
catalytic approaches include cross-dehydrogenative coupling5
(C−H/C−H coupling) and addition of alkynes to transition-
metal complexes to form heteroarenes.6
In view of the C−X/C−H direct alkenylation of benzox-
azoles, the first method employing alkenyl bromides was
pioneered by Doucet and co-workers using a PdCl(C3H5)-
(dppb) catalyst (Scheme 1A).4a Later, the group of Piguel
reported copper4b and palladium catalysts,4c respectively, for
the alkenylation of oxazoles, and a few isolated examples of Pd
catalysts also showed fair efficacy in these reactions.4d,e In
addition to alkenyl halides, ketone derivatives were demon-
strated as applicable electrophilic coupling partners by
Ackermann (Scheme 1B).4f Very recently, the work of
Yamaguchi and Itami detailed a nickel catalyst for the
alkenylation of oxazoles with enols and esters (Scheme
1C).4g The aforementioned methods often employed high
catalyst loadings (5−10 mol %), and the scope might be
impaired by the unavailability of particular substrates. Although
nickel sources are economically attractive, the cost of ancillary
ligands and efforts in removal of high loading of nickel salt after
the reaction may offset this factor. As part of our laboratory’s
interest in developing cross-coupling of alkenyl electrophiles7
a
dppb = 1,4-bis(diphenylphosphino)butane, dppe = 1,2-bis-
(diphenylphosphino)ethane, dcype = 1,2-bis(dicyclohexylphosphino)-
ethane.
and direct functionalization of C−H bonds,8 we decided to
address these difficulties. Herein we report the first general,
direct C2-alkenylation of (benz)oxazoles using alkenyl tosylates
with ample reaction scope and substrate compatibility.
Remarkably, the catalyst loading can reach up to 250 ppm
(0.025 mol %). We also demonstrated the scalability and
Received: September 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
further practicality of our method by utilizing the newly
synthesized alkenyloxazoles in the preparation of new group 9
organometallic compounds.
promoted the reaction but gave a lower product yield (Table
1, entry 13).
Encouraged by the initial ligand screening results, we next
studied other reaction parameters (Table 2). We found that
Alkenyl halides are not generally available. However, the
pseudohalide complements, alkenyl tosylates, can be readily
prepared from easily available ketones with diverse substitution
patterns that are not accessible within their halide counterparts.
In addition to the advantages of substitution pattern and
availability, their cost-effectiveness and higher stability are
desirable from a synthetic perspective.9 Nonetheless, the
oxidative addition of alkenyl tosylates to Pd(0) is more
demanding than those of alkenyl halides. We anticipated that
the main challenge was the identification of a suitable ancillary
ligand for overcoming this energy barrier. To address this, we
investigated the catalytic efficacy of a library of electronically
and sterically diverse ligands using a model reaction between
benzoxazole and 1 (Table 1). Commercially available ligands as
a
Table 2. Reaction Condition Optimization
b
entry
base
Pd source
ppm
solvent
% yield
1
LiO-t-Bu
NaO-t-Bu
KO-t-Bu
Li2CO3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2(ACN)2
Pd2(dba)3
Pd(dba)2
500
500
500
500
500
500
500
500
500
100
100
100
100
100
100
100
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
toluene
dioxane
THF
94
17
2
3
trace
0
4
5
LiOH
0
6
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
74
a
7
75
Table 1. Screening of Ancillary Ligands
8
71
9
DMA
trace
66
10
11
12
13
14
15
16
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
41
57
30
54
c
Pd(OAc)2
Pd(OAc)2
55
d
60
a
Reaction conditions: 1 (0.3 mmol), base (0.6 mmol), benzoxazole
(0.45 mmol), solvent (0.3 M), Pd source (500 ppm), Pd/PhMezole-
Phos = 1:4, under nitrogen at 110 °C for 18 h under N2, calibrated
b
GC−FID yields were reported. Loading of the Pd monomer with
c
d
respect to 1. Pd/PhMezole-Phos = 1:3. Pd/PhMezole-Phos = 1:2.
only LiO-t-Bu was able to promote the reaction, while lithium
hydroxide and lithium carbonate were inapplicable (Table 2,
entries 1 vs 2−5). Toluene and ethereal solvents reduced the
yield to 71−75%, and DMA gave no product yields (Table 2,
entries 1 vs 6−9). The less expensive Pd(OAc)2 was shown to
be the optimal palladium catalyst among the other Pd(II) and
Pd(0) sources surveyed (Table 2, entries 10 vs 11−14).
Another crucial reaction parameter was the metal-to-ligand
ratio, and 1:4 was found to be the best, as a lower ligand ratio
led to a drop in product yields (Table 2, entries 10 vs 15−16).
Having confirmed the optimal reaction conditions, we next
examined the substrate scope of our catalyst system (Scheme
2). We first evaluated a series of fundamentally different alkenyl
tosylates in terms of conjugation, electron-richness, and steric
profile. Tetralone- (Scheme 2, 1a−g) and cycloalkanone-
derived enol tosylates (Scheme 2, 1h−o) were successfully
converted to the corresponding products in good-to-excellent
yields, whereas alkyl rings as large as 12 carbons (Scheme 2, 1l)
were also applicable. The reaction with highly congested o-aryl-
substituted enol tosylates gave the desired product in 73 and
74% yields (Scheme 2, 1p,q). Substrates featuring an
unprotected N−H site were tolerated and afforded up to
98% yield (Scheme 2, 1r−t). Arylacetone-derived substrates
also reacted under these reaction conditions and gave 1u and
1v in 89% and 80% product yield, respectively. It is particularly
noteworthy that the coupling product 1x with unprecedented
vinyl tosylate was successfully obtained, while other catalytic
approaches such as CDC (cross-dehydrogenative coupling)
sometimes required the use of ethylene gas. For the scope of
a
Reaction conditions: 1 (0.3 mmol), LiO-t-Bu (0.6 mmol),
benzoxazole (0.45 mmol), t-BuOH (0.3 M), Pd(OAc)2/ligand
under nitrogen at 110 °C for 18 h under N2; calibrated GC−FID
yields are reported. Pd(OAc)2 loading = 500 ppm.
b
well as customized ligands10 used in our previous works were
screened. In general, we found that monodentate phosphines
were superior to bidentate phosphines (Table 1, entries 1−8,
11 vs 9−10), while PhMezole-Phos11 (L2) was outstanding in
this survey. Triarylphosphine L12 was inferior to the
aforementioned electron-rich and bulky ligands (Table 1,
entry 12). N-Heterocyclic carbenes ligand such as L13
B
DOI: 10.1021/acs.orglett.6b02619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Pd/PhMezole-Phos-Catalyzed Direct C2-
Alkenylation of (Benz)oxazoles
Scheme 4. Application to the Synthesis of Cyclometalated
Ir(III) Complexes Using 1a
a
motifs would provide a more flexible fit to certain protein
binding pockets in comparison with the existing planar
aromatic C^N ligands used.
In conclusion, we have demonstrated the first example of
high-yielding and scalable direct C2-alkenylation of oxazoles
using alkenyl tosylates with only parts per million levels of
palladium catalyst. Our method enables a facile access to a wide
range of substitution patterns via alkenyl tosylates that can be
easily derived from readily available ketones. Highly sterically
hindered ortho-substituted alkenyl tosylates and small vinyl
tosylate were successfully coupled. We envisioned that the use
of Pd catalyst at parts per million levels minimizes the residual
Pd in products, which is highly important for pharmaceutical
syntheses. New cyclometalated Ir(III) complexes were
synthesized employing the C2-alkenyloxazoles to demonstrate
the applicability of our method. We believe our method could
allow the rapid diversification of group 9 organometallic
compounds for high-throughput screening techniques. Future
efforts will be focused on the extension of reaction scope to
other azole compounds.
a
Reaction conditions: Alkenyl tosylate (0.3 mmol), LiOt-Bu (0.6
mmol), oxazoles (0.45 mmol), t-BuOH (0.3 M), Pd(OAc)2/
PhMezole-Phos = 1:4 under nitrogen at 110 °C for 18 h under N2,
isolated yields were reported. Catalyst loading is reported in
parentheses as ppm of Pd with respect to alkenyl tosylate. Reaction
times were not optimized for each substrate.
oxazoles, 4-, 5-, or 6-substituted benzoxazoles as well as oxazole
derivative (Scheme 2, 1w) were found to be suitable in this
catalysis. To realize the synthetic utility of our method, we
carried out the gram-scale synthesis of 1a without any
alternation of reaction conditions, and 2.1 g of product was
successfully afforded (85% yield, Scheme 3).
Scheme 3. Gram-Scale Synthesis of 1a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02619.
In light of the remarkable catalytic efficiency of our system,
we envisioned our method could be employed for the rapid and
efficient assembly of potential C^N donor ligands for
cyclometalated group 9 organometallic complexes. Group 9
organometallic compounds such as Ir(III) and Rh(III)
complexes have been well-documented to be utilized as
molecular therapeutics, cell-imaging agents, optoelectronics,
and luminescent molecular probes for biomolecules or metal
ions due to their highly environmentally sensitive emissive
behavior.12 Here, we prepared a new class of Ir(III) complexes
using 1a (Scheme 4). On the basis of reported synthetic
procedures,13 1a was successfully coupled with iridium(III)
chloride and afforded the dichlorobridged iridium dimer
complex. The dimer was subsequently treated with a series of
N^N donor ligands to afford the corresponding mononuclear
Ir(III) complexes in good yields (Scheme 4, Ir1−Ir3). We
anticipated that the adjustable alkyl extension of the alkenyl
Detailed experimental procedures for catalytic studies
and metal complexes syntheses; 1H, 13C spectra;
characterization data of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: aiwenlei@whu.edu.cn.
*E-mail: fuk-yee.kwong@polyu.edu.hk.
Author Contributions
§W.C.F. and Y.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We thank the Research Grants Council of Hong Kong (CRF:
C5023-14G), General Research Fund (PolyU 153034/15P),
and State Key Laboratory of Chirosciences for financial
support.
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