Pd-Catalyzed Alkyne Insertion/C-H Activation/[4 + 2] Carboannulation of Alkenes to the Synthesis of Polycyclics

Article abstract of DOI:10.1021/acs.orglett.8b03884

An unprecedented Pd-catalyzed alkyne insertion/C-H activation/intramolecular [4 + 2] carboannulation of alkenes has been reported. In this transformation, the C-H activation was triggered by an in situ generated alkenylpalladium species via the Pd-catalyzed cross-coupling reaction of aryl iodides and alkynes. Subsequently, the resulting five-membered C, C-palladacycle intermediates were added across the alkenes, providing a unique approach to access diversified polycyclics in good efficiency. Two new rings and three C-C bonds were formed in one pot.

Full text of DOI:10.1021/acs.orglett.8b03884

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Alkyne Insertion/C−H Activation/[4 + 2]
Carboannulation of Alkenes to the Synthesis of Polycyclics
Songjin Guo, Panpan Li, Zhe Guan, Libo Cai, Siwei Chen, Aijun Lin,* and Hequan Yao*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: An unprecedented Pd-catalyzed alkyne inser-
tion/C−H activation/intramolecular [4 + 2] carboannulation
of alkenes has been reported. In this transformation, the C−H
activation was triggered by an in situ generated alkenylpalla-
dium species via the Pd-catalyzed cross-coupling reaction of
aryl iodides and alkynes. Subsequently, the resulting five-
membered C, C−palladacycle intermediates were added
across the alkenes, providing a unique approach to access
diversified polycyclics in good efficiency. Two new rings and three C−C bonds were formed in one pot.
ransition-metal-catalyzed C−H activation/[4 + 2]
heteroannulation of alkenes has emerged as an efficient
fused oligocycle lactam skeletons has been reported by Rovis9
and Glorius,10 independently (Figure 1b). However, all of
these elegant works relied on heteroatom-directed groups (N
or O) to assist the C−H activation, forming stable five-
membered C, X-metallacycle complexes (X = heteroatom) to
enable the annulation process. Herein, we disclosed a Pd-
catalyzed alkyne insertion/C−H activation/intramolecular [4
+ 2] carboannulation of alkenes. In this reaction, the C−H
activation was triggered by an in situ generated alkenylpalla-
dium species via the Pd-catalyzed cross-coupling reaction of
aryl iodides and alkynes. Subsequently, the resulting five-
membered C, C-palladacycle species11 were added across the
alkenes, providing a unique approach to access diversified
polycyclics in good efficiency (Figure 1c). Setting the
potentially competitive benzannulation between the five-
membered C, C-palladacycles and alkynes12 or aryl halides13
is a key to the success of this tandem reaction.
T
synthetic tool for the rapid construction of functional six-
membered heterocycles.1 By using amides as the directing
groups, Glorius,2 Guimond,3 Rovis,4 Cramer,5 and Wang6 have
disclosed the intermolecular C−H activation/alkene insertion
to the synthesis of dihydroisoquinolones via rhodium or
ruthenium catalysis (Figure 1a). Besides, with imines as the
Initially, 1-iodo-3-((2-methylallyl)oxy)benzene 1a and 1,2-
diphenylethyne 2a were chosen as the benchmark substrates to
identify the systems capable of mediating this challenging
transformation. Several palladium catalysts were first screened
in the presence of NaOPiv·H2O (2.0 equiv) in DMF (2.0 mL)
at 90 °C (Table 1, entries 1−5), and Pd(OAc)2 could offer the
desired product 3aa in 53% yield. Subsequent investigation of
bases revealed that the use of CsOAc could increase the yield
to 73%, whereas other bases such as NaOAc, K2CO3, Cs2CO3,
and KHCO3 led to a diminished yield (Table 1, entries 6−10).
Screening of solvents indicated that the dipolar aprotic solvent
DMF was optimal (Table 1, entries 7 and 11−14). Moreover,
the addition of ligands was useless to improve the reaction
effiency (Table 1, entries 15−19). In the absence of palladium
catalyst, no desired product could be detected (Table 1, entry
Figure 1. Transition-metal-catalyzed C−H activation/[4 + 2]
annulation of alkenes.
directing groups, Rovis described a rhodium-catalyzed C−H
activation/alkene insertion to construct 2,3-dihydropyridines
(Figure 1a).7 Very recently, Daugulis reported a cobalt-
catalyzed oxidative annulation of benzoic acids with alkenes to
synthesize 1-isochromanons (Figure 1a).8 Intramolecular
rhodium-catalyzed C−H activation/[4 + 2] annulation of
benzamides with a tethered alkene for the construction of
Received: December 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03884
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
Pd(PPh)4
ligand
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
-
-
-
-
-
-
-
-
-
-
-
-
-
-
NaOPiv·H2O
NaOPiv·H2O
NaOPiv·H2O
NaOPiv·H2O
NaOPiv·H2O
NaOAc
CsOAc
K2CO3
Cs2CO3
KHCO3
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
MeOH
DCE
toluene
DMF
DMF
DMF
DMF
DMF
DMF
20
41
27
34
53
22
Pd2(dba)3
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
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(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
c
73 (70)
24
ND
45
49
ND
ND
ND
52
62
52
d
BINAP
PPh3
DavePhos
bpy
1,10-phen
-
43
46
NR
e
CsOAc
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10.0 mol %), ligand (20.0 mol %), base (2.0 equiv), solvent (2.0 mL), at 90 °C
b
under Ar atmosphere for 24 h, sealed tube. The yields were determined from the crude reaction mixtures by 1H NMR spectroscopy with CH2Br2
as an internal standard. Isolated yields. ND = not determined. NR = no reaction.
c
d
e
20). We finally established the optimized conditions as 1a (0.2
mmol), 2a (0.4 mmol), Pd(OAc)2 (10.0 mol %), and CsOAc
(2.0 equiv) in DMF (2.0 mL) at 90 °C under Ar atmosphere
for 24 h.
crystallography (see the SI for more details). Changing the
olefin substituents from methyl group to primary alcohol,
ethyl, and methyl ether groups, the products (3tc−vc) could
also be achieved in good yields. When mono- or trisubstituted
alkenes were tested, no desired annulation products could be
detected and replaced by formimg intramolecular Mizoroki−
Heck coupling products (see the SI for more details).
With the optimized reaction conditions in hand, we then
probed the substrate scope and generality of the reaction
(Scheme 1). Regarding the alkene-tethered aryl iodides 1, we
found that both electron-donating (1b−e) and electron-
withdrawing (1f−m) groups could be well incorporated at
the C4-, C5-, or C6-positions of the benzene ring, giving the
corresponding products (3ba−ma) in moderate to good yields.
The structure of 3ba was confirmed by X-ray crystallography
(see the Supporting Information for more details). The
substrate 1n with a transformable hydroxy group displayed
good reactivity to offer 3na in 81% yield. Substrates 1p and 1q
with nitrogen atom as a linker could yield indoline (3pa) in
81% yield and oxindole (3qa) in 30% yield. Furthermore, the
intriguing indole-fused tetracyclic compounds 3ra and 3sa
could be well constructed in 68% and 63% yields. With respect
to the diaryl acetylenes, which bear 4-fluoro (2b), 4-chloro
(2c), 4-bromo (2d), 4-nitryl (2e), 4-cyano (2f), 4-methyl
(2g), and 3-chloro (2h) groups, reaction occurred smoothly to
deliver the desired products (3ab−ah) in 44−89% yields. The
unsymmetrical alkynes, such as hex-1-yn-1-ylbenzene 2i and
but-1-yn-1-ylbenzene 2j, could deliver the products 3ai and 3aj
in moderate yields with good regioselectivities. The config-
uration of 3ai and 3aj was confirmed by the NOE spectra (see
the SI for more details). When the unsymmetrical alkynes (2k
and 2l) with two different aryl groups were checked, products
3ak and 3al were achieved in good regioselectivities. The
structures of 3ak and 3al were confirmed by X-ray
To demonstrate the utility of the reaction, the scale-up
experiment and further transformations of 3na were carried
out as shown in Scheme 2. Product 3na (841 mg) was
achieved in 82% yield on 3.0 mmol scale under the standard
reaction conditions (Scheme 2a). 2-Bromo-6-
(trifluoromethyl)pyridine and trifluoromethylated vinyl bro-
mide as significant fluorine-containing precursors could react
with 3na smoothly to provide compounds 4 and 5 in 75% and
52% yield, respectively. Moreover, 3na could be readily
converted into compound 6 in 91% yield, which served as a
versatile intermediate for the further diversification. The
subsequent coupling reactions of 6 rapidly constructed a
variety of functionalized 3,4-fused dihydrobenzofurans via
forming C−C, C−N, and C−P bonds. A novel indole
derivative 11 could be obtained directly via a palladium-
catalyzed tandem cross-coupling and cyclization of 6 and o-
ethynylaniline.
To elucidate some mechanistic insight into this reaction,
some control experiments were carried out. First, we examined
the reaction in the presence of CH3CO2D (Scheme 3a). After
24 h, deuterium incorporation at the C6 position of D1-3a was
1
observed, as determined by H NMR analysis. This result
suggested that the process of the C−H activation triggered by
the in situ generated alkenylpalladium species is reversible.
B
DOI: 10.1021/acs.orglett.8b03884
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Organic Letters
Letter
a b
,
Scheme 1. Substrate Scope
Scheme 2. Scale-Up Experiment and Synthetic
Transformations
a
a
Reaction conditions: (1) CuI, K3PO4, 2-carboxypyridine, DMSO, at
90 °C under Ar. (2) K3PO4·3H2O, DMF, at 100 °C. (3) Et3N, DCM,
at −78 °C under Ar. (4) Pd(OAc)2, PPh3, K2CO3, toluene, at 110 °C
under Ar. (5) Pd(PPh3)2Cl2, CuI, Et3N, DMF, at 80 °C under Ar. (6)
Pd(OAc)2, Xphos, Cs2CO3, toluene, at 100 °C under Ar. (7)
Pd2(dba)3, DPPP, i-Pr2NEt, toluene, at 110 °C under Ar. (8)
Pd(PPh)4, Cs2CO3, CH3CN, at 100 °C under Ar.
Scheme 3. Mechanistic Experiments
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (10.0
mol %), CsOAc (2.0 equiv), and DMF (2.0 mL), at 90 °C under Ar
b
c
d
atmosphere for 24 h, sealed tube. Isolated yields. 36 h. HOAc (5.0
equiv).
Subsequently, the kinetic isotope effect (KIE) experiment was
examined. When an equimolar mixture of 1o and D3-1o was
checked at a low degree of conversion (Scheme 3b), a KH/KD
ratio of 2.3 was obtained, which indicated that the C−H
activation may be involved in the rate-determining step.
On the basis of the above mechanistic study and literature
precedents,11−13 a plausible catalytic cycle of this reaction was
proposed and shown in Scheme 4. Initially, the oxidative
addition of aryl iodide 1a to the active Pd(0) generates the aryl
Pd(II) species A, which inserts the diphenylacetylene 2a to
C
DOI: 10.1021/acs.orglett.8b03884
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Organic Letters
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Scheme 4. Proposed Reaction Mechanism
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ajlin@cpu.edu.cn.
*E-mail: hyao@cpu.edu.cn, cpuhyao@126.com.
ORCID
Aijun Lin: 0000-0001-5786-4537
Hequan Yao: 0000-0003-4865-820X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC21572272),
the Innovation Team of “the Double-First Class” Disciplines
(CPU2018GY04 and CPU2018GY35), and the Foundation of
The Open Project of State Key Laboratory of Natural
Medicines (SKLNMZZCX201818) is gratefully acknowledged.
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03884.
Detailed experimental procedure, characterization data,
1
and copies of H and 13C NMR spectra (PDF)
Accession Codes
CCDC 1879816 and 1890573−1890574 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(7) Romanov-Michailidis, F.; Sedillo, K. F.; Neely, J. M.; Rovis, T.
Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes
D
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E
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