Palladium(II)-catalyzed dehydrogenative cross-coupling between two C sp3-H bonds: Unexpected C=C bond formation

Article abstract of DOI:10.1002/anie.201303099

C=C bond construction: A palladium-catalyzed oxidative C sp 3-H/C sp 3-H cross-coupling is shown to forge C=C bonds rather than C sp 3-C sp 3 bonds through reactions of indolin-2-ones or benzofuran-2-ones with O-benzoyl hydroxylamines in the absence of an added oxidant. Copyright

Full text of DOI:10.1002/anie.201303099

Angewandte
Chemie
Communications
Oxidative Cross-Coupling
G. Li, S. Qian, C. Wang,
J. You*
&&&& — &&&&
Palladium(II)-Catalyzed Dehydrogenative
À
Cross-Coupling between Two Csp3
H
=
Bonds: Unexpected C C Bond Formation
=
C C bond construction: A palladium-
reactions of indolin-2-ones or benzo-
À
À
catalyzed oxidative Csp3 H/Csp3 H cross-
furan-2-ones with O-benzoyl hydroxyla-
mines in the absence of an added
oxidant.
=
coupling is shown to forge C C bonds
À
rather than Csp3 Csp3 bonds through
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DOI: 10.1002/anie.201303099
Oxidative Cross-Coupling
Palladium(II)-Catalyzed Dehydrogenative Cross-Coupling between
À
=
Two Csp3 H Bonds: Unexpected C C Bond Formation**
Gaocan Li, Shengyou Qian, Chunxia Wang, and Jingsong You*
Developing efficient synthetic methods for the formation of
carbon–carbon bonds is crucial for organic synthesis. In recent
Oxindoles (indolin-2-ones)[3–5] and benzofuran-2-ones[6]
are prevalent in many natural products and pharmaceutical
targets, and are also versatile building blocks for the synthesis
of structurally complex and biologically active compounds. In
particular, the 3-methyleneindolin-2-one derivative is an
important subclass found in numerous pharmacologically
important natural and synthetic compounds.[7] 3-(Amino-
methylene)-2-oxoindolines exhibit GABAeric neurotrans-
mitter inhibitor properties (Pfizer).[7a] In recent years, the
development of methods for the C3-functionalization of
indolin-2-ones has been an active area of intensive
research.[3,8] On the other hand, six-membered-ring nitro-
gen-containing heterocyclic alkaloids are also widely present
in natural products and important biologically active mole-
cules. In an effort to explore the palladium(II)-catalyzed
À
years, transition-metal-catalyzed Csp3 H functionalization to
À
À
À
forge Csp3 Csp1, Csp3 Csp2, and Csp3 Csp3 bonds has attracted
much attention.[1] From the step-economic and academic
perspective, the dehydrogenative cross-coupling of sp3-hy-
À
À
bridized C H bonds with other C H bonds is one of the most
attractive, yet most challenging, methods of carbon–carbon
bond construction without the need for time-consuming
prefunctionalization of both substrates. Lately, the dehydro-
À
genative cross-coupling of a-Csp3 H bonds of amines, ethers,
À
allylic and benzylic groups, and alkane Csp3 H bonds with
À
a wide range of Csp3 H bonds has evolved into a powerful
strategy for forming new Csp3 Csp3 bonds (Scheme 1a). These
À
direct amination of the C3 H bond of indolin-2-ones[5f,g] with
À
cyclic O-benzoyl hydroxylamines, which have been widely
used as aminating reagents,[9] an unexpected dehydrogenative
À
cross-coupling reaction between two Csp3 H bonds occurred
to afford 3-(aminomethylene)-2-oxoindoline 3a instead of
3-amino-2-oxoindoline 3a’ [Eq. (1); Bz = benzoyl]; a result
Scheme 1. Transition-metal-catalyzed dehydrogenative cross-coupling
À
between two Csp3 H bonds.
oxidative cross-coupling reactions usually involve ionic or
radical intermediates (single electron transfer (SET) process)
in the presence of transition-metal catalysts (mainly copper
and iron salts) and oxidants such as tert-butyl hydroperoxide,
hydrogen peroxide, dioxygen, benzoquinone (BQ), and 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ).[1d–f,2] Despite the
great advantage of this method, to date no studies have
that was confirmed by single crystal X-ray diffraction
(Supporting Information, Figure S2).[10] To the best of our
=
knowledge, this is the first example of C C bond formation
À
À
through a palladium(II)-catalyzed oxidative Csp3 H/Csp3
cross-coupling reaction.
H
=
À
addressed the formation of C C bonds, Csp2 Csp2, through
After the surprise observation that 1-methylindolin-2-one
À
À
a dehydrogenative cross-coupling between two Csp3 H bonds
with the loss of four hydrogen atoms (Scheme 1b).
1a and piperidin-1-yl benzoate 2a underwent oxidative Csp3
À
H/Csp3 H cross-coupling to give the olefin 3-(aminomethy-
lene)-2-oxoindoline (3a) in the presence of Pd(OAc)2, we set
out to optimize the reaction conditions. Several parameters
(including, metal catalyst, base, solvent, and temperature)
were investigated, as shown in Table S1. The catalytic system
comprised of [Pd(cod)Cl2] (5 mol%; cod = 1,5-cycloocta-
diene) as the catalyst, and K3PO4 (3.0 equiv) as the base in
1,4-dioxane at 1108C for 18 h afforded a 94% yield of 3a
(Table S1, entry 16). Notably, iron and copper salts, which
have been extensively used as catalysts in the dehydrogen-
[*] G. Li, S. Qian, C. Wang, Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (PR China)
E-mail: jsyou@scu.edu.cn
[**] This work was supported by grants from the National Basic
Research Program of China (973 Program, 2011CB808600), and the
National NSF of China (Nos 21025205, 21272160, and 21021001).
À
ative cross-coupling between two Csp3 H bonds, did not
promote any coupling reactions between 1a and 2a (Table S1,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303099.
entries 17–20).
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À
À
The transition-metal-catalyzed oxidative Csp3 H/Csp3
H
cross-coupling reactions of indolin-2-ones have been surpris-
ingly underdeveloped thus far, although the C3-functional-
ized indolin-2-ones are ubiquitous units in many natural
products, biologically active molecules, and pharmaceuticals.
We rationalized that the bottleneck in these types of oxidative
reactions could be attributed to the C3-position of indolin-2-
ones being particularly susceptible to oxidation. Thus, the
discovery of an efficient and mild oxidant would be a key to
overcoming this substantial hurdle. In the current catalytic
system, O-benzoyl hydroxylamine itself serves as both the
oxidant and the coupling substrate, and piperidine, as the
reductive product of piperidin-1-yl benzoate, was clearly
observed by GC-MS (for details, see the Supporting Infor-
mation).[11] In fact, the addition of 2,2,6,6-tetramethylpiper-
idin-1-yl benzoate (TEMPOBz) resulted in improved yield
(Table S1, entry 12 vs. entry 13), whereas the addition of extra
oxidants such as copper or silver salts greatly decreased the
yield of the heterocoupling products. Furthermore, the
reaction of 1-methylindolin-2-one (1a) with piperidine,
1-methylpiperidine, or 1-benzylpiperidine instead of piper-
idin-1-yl benzoate (2a) did not occur, even in the presence of
extra oxidant, which implies the key role of the N-benzoate
group.
With the optimized conditions in hand, the range of
indolin-2-ones was tested, as summarized in Scheme 2. We
were delighted to find that a broad range of N-substituted
indolin-2-ones gave the desired products in good to excellent
yields. The catalytic system was compatible with a variety of
functional groups on both the aromatic moiety and the N1-
substitutent of indolin-2-ones. Although indolin-2-ones are
Scheme 2. Cross-coupling of piperidin-1-yl benzoate 2a with a variety
of indole-2-ones 1. Reactions were performed in the presence of
indole-2-one (0.3 mmol), piperidin-1-yl benzoate 2a (0.9 mmol), [Pd-
(cod)Cl2] (5 mol%), and K3PO4 (3.0 equiv) in 1,4-dioxane (2.0 mL) at
1108C for 18 h. Yields of isolated products are shown in parentheses.
[a] 6 h. [b] Z/E isomer ratios were determined by 1H NMR spectrosco-
py, and are shown in parentheses.
À
known to go through palladium-catalyzed direct C H aryla-
tion with aryl halides in the presence of base,[8a,b] it is
important to stress that the halogen atoms (F, Cl, Br), which
may be subjected to further synthetic transformations, were
well tolerated in the current catalytic system (3i–3l,
Scheme 2). Moreover, the reaction of 5-acetyl-indole-2-one
also proceeded well (3o, Scheme 2).
sized according to a literature procedure.[14a] In the presence
of Pd(OAc)2 (1.0 equiv), the treatment of 1-methylindolin-2-
one 1a with 5 delivered the desired product 3a in 23% yield
with the recovery of 1a in 58% yield [Eq. (2)]. In spite of the
To further expand the scope of the method, the cross-
coupling of various O-benzoyl hydroxylamines was inves-
tigated (Scheme 3). It was gratifying to observe that a variety
of piperidin-1-yl benzoates worked well in our catalytic
system (4a–4d, Scheme 3). Morpholino benzoate was also
capable of undergoing the coupling reaction (4e,
Scheme 3).[12] Benzofuran-2-ones also smoothly furnished
the desired products with satisfactory yields (4 f–4j,
Scheme 3).
À
The oxidative coupling mechanism of a-Csp3 H bonds of
low yield of the desired product (probably owing to the
instability of 2,3,4,5-tetrahydropyridine in the current cata-
lytic system), these observations suggest that 2,3,4,5-tetrahy-
dropyridine might be the real coupling partner.
On the basis of these observations, a tentative catalytic
cycle was proposed (Scheme 5). First, a palladation occurrs at
the 3 position of 1-methylindolin-2-one 1a, because of its
amines by a SET process is usually proposed to involve an
iminium ion intermediate, which is attacked by a nucleophile
to afford the desired product (Scheme 4).[1,13] Although the
reaction mechanism is not very clear at present, a radical
pathway can be ruled out through investigation of the effect
of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) on the coupling reaction of 1a with 2a (for details,
see the Supporting Information). GC-MS and 1H NMR
analysis further revealed the formation of 2,3,4,5-tetrahydro-
pyridine (5) in the catalytic system (for details, see the
Supporting Information).[9e,14] Subsequently, 5 was synthe-
À
acidic C3 H bond (pKa = 18.5), to generate the intermediate
IM1 in the present of base.[1a,8a] Next, IM1 reacts with 2,3,4,5-
tetrahydropyridine (5), which is generated in situ from
piperidin-1-yl benzoate (2a), to form the key palladium
intermediate IM2. Alternatively, the formation of a palladated
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the desired product could not be excluded. Finally, Pd0 could
be reoxidized to PdII to realize the catalytic cycle with
piperidin-1-yl benzoate 2a, which could also serve as a hydro-
gen acceptor.
In summary, we have discovered for the first time
=
a method for constructing new C C bonds through palla-
À
dium-catalyzed oxidative cross-coupling between two Csp3
H
bonds. The palladium(II)-catalyzed dehydrogenative cross-
coupling reactions of indolin-2-ones with O-benzoyl hydrox-
ylamines afford versatile 3-(aminomethylene)-2-oxoindolines
in the absence of an extra oxidant. The reaction conditions are
very simple, and tolerate an array of functional groups,
including ester, acetyl, methoxy, fluoro, chloro, and bromo
groups. Aside from acting as an aminating reagent, O-benzoyl
hydroxylamines have herein been endowed with a novel
=
function as the nucleophilic reagent for C C bond formation.
We anticipate that this unexpected finding may have a broader
=
impact on the construction of other types of C C bonds.
Received: April 13, 2013
Revised: May 20, 2013
Published online: && &&, &&&&
Scheme 3. Cross-coupling of indole-2-one or bezofuran-2-ones with
a variety of O-benzoyl hydroxylamines. Reactions were performed in
the presence of indole-2-one or bezofuran-2-one (0.3 mmol), O-benzoyl
hydroxylamine (0.9 mmol), [Pd(cod)Cl2] (5 mol%), and K3PO4
(3.0 equiv) in 1,4-dioxane (2.0 mL) at 1108C for 18 h. Yields of isolated
products are shown in parentheses. [a] Pd(cod)Cl2 (10 mol%).
[b] Regioselectivity determined by 1H NMR spectroscopy, and shown in
parentheses. [c] PPh3 (10 mol%).
Keywords: O-benzoyl hydroxylamines · cross-coupling ·
indolin-2-ones · palladium
.
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