Palladium-Catalyzed Heteroarylation and Concomitant ortho-Alkylation of Aryl Iodides

Article abstract of DOI:10.1002/anie.201507128

Three-component couplings were achieved from common aryl halides, alkyl halides, and heteroarenes under palladium and norbornene co-catalysis. The reaction forges hindered aryl-heteroaryl bonds and introduces ortho-alkyl groups to aryl rings. Various heterocycles such as oxazoles, thiazoles and thiophenes underwent efficient coupling. The heteroarenes were deprotonated in situ by bases without the assistance of palladium catalysts. Three-in-one: The heteroarylation of aryl iodides and ortho-alkylation of the aryl rings occur in a single operation. The palladium and norbornene cocatalyst system effectively promoted the cleavage of two C-H bonds and the formation of two new C-C bonds, including a very hindered aryl-heteroaryl bond.

Full text of DOI:10.1002/anie.201507128

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507128
German Edition: DOI: 10.1002/ange.201507128
Heterocycles
Palladium-Catalyzed Heteroarylation and Concomitant
ortho-Alkylation of Aryl Iodides
Chuanhu Lei, Xiaojia Jin, and Jianrong (Steve) Zhou*
Abstract: Three-component couplings were achieved from
common aryl halides, alkyl halides, and heteroarenes under
palladium and norbornene co-catalysis. The reaction forges
hindered aryl–heteroaryl bonds and introduces ortho-alkyl
groups to aryl rings. Various heterocycles such as oxazoles,
thiazoles and thiophenes underwent efficient coupling. The
heteroarenes were deprotonated in situ by bases without the
assistance of palladium catalysts.
2-Arylated oxazoles and related 1,3-azoles are present in
many drug candidates, and have interesting activities against
a diverse set of targets including cancers, Alzheimerꢀs disease,
anemia, and type-II diabetes.[1] We report herein a new
reaction manifold that allows quick construction of hindered
aryl–heteroaryl bonds from three common reagents. The
products are difficult to access from other synthetic methods.
For instance, both cross-couplings[2] and direct heteroaryla-
tion[3] of hindered aryl halides require tedious preparation of
the aryl halides, especially when two different o,o’-substitu-
ents are present on aryl rings.
In recent years, direct couplings of (hetero)arenes have
emerged as an efficient and step-economic way to form aryl–
heteroaryl bonds.[4] These reactions avoid prior synthesis of
(hetero)aryl halides and (hetero)arylmetal reagents. To con-
Scheme 1. Representative types of heteroarylation.
trol regioselectivity in (hetero)arenes, directing groups were
installed,[5] or the innate electrophilicity and acidity of certain
extra rings in the products. Without tethers, very little product
was obtained.
Herein, we report a three-component coupling of aryl
halides, alkyl halides and oxazoles (Scheme 1e). Some other
heteroarenes such as thiophenes can also react efficiently. The
reaction enables arylation of heteroarenes and simultaneous
À
C H bonds on the heteroarenes were exploited (Sche-
me 1a,b).[6] Elegant regioselective couplings of two different
heteroarenes have been disclosed by the groups of Hirano
and Miura, You, and Yamaguchi and Itami, as well as others
(Scheme 1c).[7] Catalyst control of regioselectivity is more
challenging and examples of this kind emerged recently,
wherein couplings at unconventional sites were allowed.[8] It
should be pointed out that in the examples above, the sites of
ortho-alkylation. In
a
typical Catellani-type pathway
(Scheme 2), insertion of 2-norbornene into A and ortho-
palladation results in the key palladacycle C. Subsequent
C H activation are the sites of aryl–heteroaryl bond forma-
oxidative addition of an alkyl halide[10] and C C reductive
À
À
tion. As a distinct variant, Lautens et al. reported intra-
molecular heteroarylation of aryl halides with heterocycles
carrying tethered alkyl halides by using palladium/norbor-
nene cocatalysis (Scheme 1d).[9] The covalent linkage was
elimination allows ortho-alkylation in E. After deinsertion of
norbornene, an arylpalladium species (F) is generated and it
can be trapped by various nucleophiles and olefins[11] as
reported by the groups of Catellani,[12] Lautens,[13] and
others.[14] We hypothesized that trapping F intermolecularly
with heteroarenes, for example, oxazoles, would lead to the
coupling product P with very hindered aryl rings. In this
pathway, many side-reactions are foreseeable from premature
coupling of the upstream species A, B, or E with heteroarenes.
We first attempted a model coupling of o-tolyl iodide, 1-
bromohexane and 1,3-benzoxazole (Scheme 3).[15] A small,
weakly electron-donating tri-2-furylphosphine[16] was essen-
tial to achieve the desired reaction and gave good yield of the
desired product (76%). Under optimized reaction conditions,
no direct alkylation of benzoxazole was detected. If PPh3 was
À
essential for fast cleavage of heteroaryl C H bonds by
electrophilic palladation, but the tethers were retained as
[*] Dr. C. Lei, X. Jin, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201507128.
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Communications
Scheme 2. A proposed pathway and possible byproducts.
used as a ligand, the product yield fell to 21% and premature
heteroarylation of B became predominant to give 42% yield
of BP-B (see Scheme2). When dppp, dppf, and other
bis(phosphine)s were used, coordinative saturation by the
bis(phosphine)s prevented insertion of norbornene and led to
significant premature coupling of A with benzoxazole. With-
out any added phosphine, no product P was formed. When
the palladium loading was reduced to 5 mol%, the product
yield fell slightly to 60%.
The choice of bases proved to be critical. Among many
inorganic bases, only NaOH gave a good yield of the desired
À
product. Thus, NaOH efficiently removed two types of C H
À
hydrogen atoms: the ortho-C H bond of B and the relatively
acidic hydrogen atom on C2 of benzoxazole, in a later stage of
the catalytic cycle (Scheme 2). Other inorganic bases and
trialkylamines led to very poor yields. NaI in situ converted
alkyl bromides into more reactive alkyl iodides. In reactions
of alkyl iodides, NaI was not added. We also tried reaction
conditions prescribed by Lautens et al. in which Cs2CO3 and
tri(2-furyl)phosphine were used as the base and supporting
ligand, respectively. Only less than 20% of P was detected
(see the Supporting Information).
The heterocycles were not restricted to benzoxazoles,
oxazoles, and thiazoles (Scheme 3a). For example, selective
heteroarylation also took place selectively at the C8-position
of caffeine. Interestingly, oxadiazoles and electron-poor
thiophenes also coupled in reasonable yields. Thiophenes
have relatively acidic hydrogen atoms at the C2-position with
pKa values of below 30 in DMSO.[17] In some cases, Cs2CO3
and CuBr were used as a base and additive to improve yields.
We believe the copper salt assisted in both deprotonation of
Scheme 3. Examples of heterocycles and alkyl halides. The yields are
those for products isolated from reactions using aryl iodide
(0.3 mmol), alkyl halide (4 equiv), heterocycle (1.2 equiv), norbornene
(2 equiv), NaOH (2 equiv), NaI (2 equiv), and 10 mol% Pd catalyst in
dry acetonitrile (3 mL). 908C, 24 h.
Thus, oxidative addition of alkyl halides was most likely of the
SN2-type and did not engage a cyclopropylmethyl radical.
Both primary alkyl chlorides and isopropyl iodide gave low
yields.
With regard to the scope of the aryl iodides, both electron-
withdrawing trifluoromethyl and electron-donating methoxy
groups were tolerated at the ortho position (Scheme 4a). 3-
iodopyridine also coupled smoothly. From phenyl iodide and
para-substituted aryl iodides, the main products were 2,6-
dilakylated ones (Scheme 4b). The yields of the products
isolated from the dialkylation were reasonable, considering
À
that three new C C bonds were formed in one operation in
À
the C H bonds and subsequent transmetalation to arylpalla-
a congested environment. Curiously, meta-substituted aryl
iodides led to BP-E as major products, which retained the
norbornene fragment.
dium species. Pyridine N-oxides did not couple, unfortunately.
Both primary alkyl bromides and iodides coupled effi-
ciently (Scheme 3b). Polar groups of esters and nitriles
survived well under the basic conditions. Notably, from
cyclopropylmethyl bromide, ring opening was not detected.
We prepared a putative palladacycle A[18] of the catalytic
cycle (Scheme 2) and then subjected it to the coupling
conditions with benzoxazole (Scheme 5a). In the presence
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Angewandte
Chemie
of tri-2-furylphosphine, the coupling product P was formed in
31% yield, along with 17% of BP-B, 11% of BP-C, and some
unidentified products. Notably, extensive exchange of furyl
and phenyl groups between two phosphines was detected by
GC and GCMS. This exchange may have caused the moderate
yield of P in this study and illustrated the importance of tri-2-
furylphosphine in promoting the desired coupling process on
palladium. The small, weakly donating monophosphine
probably slowed down reductive elimination of upstream
organopalladium species (Scheme 2). Without added trifur-
ylphosphine, very little P was formed.
When 1,3-benzoxazole was vigorously stirred in a suspen-
sion of NaOH powder in [D3]acetonitrile, almost complete H/
D exchange was detected at the C2-position after 0.5 hours at
1
2
room temperature, as monitored by both H and H NMR
spectroscopy (Scheme 5b).[19] Importantly, no decomposition
of benzoxazole by ring opening occurred in [D3]acetonitrile,
even at 908C. In comparison, 80% of the benzoxazole
underwent ring opening in [D4]methanol.[20] We also observed
fast H/D exchange at the C5-position of 2-cyanothiophenes at
room temperature under similar reaction conditions, as shown
in Scheme 5c. When [D1]benzoxazole was subjected to the
coupling condition in MeCN for 2 hours at 908C, the
recovered benzoxazole lost almost all deuterium
(Scheme 5d).[21] This loss is consistent with fast and reversible
deprotonation of benzoxazole by NaOH to form an anionic
benzoxazole in a low concentration.
In summary, we report an intermolecular heteroarylation
reaction of aryl iodides with concomitant o-alkylation of aryl
rings from three common reagents. Hindered aryl–heteroaryl
bonds were constructed in a single operation and such bond
constructions usually require tedious multistep synthesis. As
À
a key reaction design, norbornene was used to assist ortho-C
H activation of the aryl rings, by following a Catellani-type
pathway. Importantly, this reaction is distinct from previous
procedures by Lautens et al. with respect to the activation of
Scheme 4. Examples of ortho- and para-substituted aryl iodides in
couplings. The yields are for products isolated from reactions using
the aryl iodide (0.3 mmol).
À
the heteroaryl C H bonds (Scheme 1d). Herein, NaOH
caused direct deprotonation of the heterocycles without the
assistance of palladium catalysts.
Acknowledgements
We thank the Singapore Ministry of Education Academic
Research Fund (MOE2013-T2-2-057 and MOE2014-T1-
001-021) and Nanyang Technological University for
financial support.
À
Keywords: C H activation · cross-coupling · heterocycles ·
palladium · synthetic method
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13397–13400
Angew. Chem. 2015, 127, 13595–13598
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Received: July 31, 2015
Published online: September 11, 2015
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