Palladium-catalyzed C-C coupling/C-H activation: Formation of isoindolinone-fused heterocyclic compounds

Article abstract of DOI:10.1002/ejoc.201000492

Inactivated dienes containing a cycloalkenyl moiety with aryl halides were used in a palladium-catalyzed reaction to give different kinds of rare, fused isoindolinone heterocyclic compounds through highly regioselective C-C coupling/C-H functionalization in a one-step domino reaction. Different dienes and aryl halides were shown to be very active in this reaction. Substituents on the aryl halides were ethoxycarbonyl, methoxycarbonyl, sulfonyl, formacyl, keto, cyano, acetyl, and naphthalene. The C-H functionalization and allyl isomerization occurred simultaneously when 1-iodobenzene or aryl halides were treated with substrates having allyl moieties on the protecting group. The generality of this process makes the reaction highly valuable due to the synthetic and medicinal importance of these kinds of fused heterocycles.

Full text of DOI:10.1002/ejoc.201000492

FULL PAPER
DOI: 10.1002/ejoc.201000492
Palladium-Catalyzed C–C Coupling/C–H Activation: Formation of
Isoindolinone-Fused Heterocyclic Compounds
Yimin Hu,*[a] Dong Ren,[a] Lidong Zhang,[a] Xiangang Lin,[a] and Jing Wan[a]
Keywords: Cyclization / Domino reactions / Fused-ring systems / Palladium / Isomerization
Inactivated dienes containing a cycloalkenyl moiety with aryl
halides were used in a palladium-catalyzed reaction to give
different kinds of rare, fused isoindolinone heterocyclic com-
pounds through highly regioselective C–C coupling/C–H
functionalization in a one-step domino reaction. Different
dienes and aryl halides were shown to be very active in this
reaction. Substituents on the aryl halides were ethoxycarb-
onyl, methoxycarbonyl, sulfonyl, formacyl, keto, cyano,
acetyl, and naphthalene. The C–H functionalization and allyl
isomerization occurred simultaneously when 1-iodobenzene
or aryl halides were treated with substrates having allyl
moieties on the protecting group. The generality of this pro-
cess makes the reaction highly valuable due to the synthetic
and medicinal importance of these kinds of fused hetero-
cycles.
istry associated with isoindolinones.[3] To develop easy and
practical approaches to a variety of isoindolinone deriva-
Introduction
Isoindolinone is an important heterocyclic scaffold. The use tives decorated with useful pharmacophores, researchers
of isoindolinone derivatives in the areas of medicine, food, have made use of new catalysts, mediums, or physical condi-
catalyst, dye, refineries, and electronics is well established.[1] tions in several well-established synthetic methodologies.[4,5]
Thus, the synthesis of the isoindolinone core and its deriva- Furthermore, an array of new and innovative strategies
tives have been an attractive goal in organic chemistry.[2] In from novel substrates have been developed that has made
recent years, there have been several developments in chem- the synthesis of the isoindolinone core a much simpler pro-
Scheme 1. Formation isoindolinone by domino Heck–direct arylation involving alkylpalladium(II) intermediates.
cess compared to earlier processes.[6–8] Because palladium-
[a] Laboratory of Functional Molecular Solids, Ministry of
Education Anhui Key Laboratory of Molecular-Based
Materials, School of Chemistry and Materials Science, Anhui
Normal University,
catalyzed cross-coupling in heterocyclic synthesis is indis-
putable, the electrophilic cyclization of o-alkynylanilines has
proven to be a powerful tool in the construction of in-
doles.[9] Yasuhara and Sakamoto developed a palladium-
catalyzed cascade sequence involving initial aminopallad-
ation followed by a Heck reaction.[10] In this process, o-
Wuhu, Anhui 241000, P. R. China
Fax: +86-553-388-3517
E-mail: yiminhu@mail.ahnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000492.
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Palladium-Catalyzed C–C Coupling/C–H Activation
alkynylaniline derivatives were treated with alk- 150 °C. There was also side product i with 15% yield, but
enes containing electron-withdrawing groups to obtain 2- the starting material was not completely converted. By con-
substituted 3-alkenylindoles.[11] Recently, Lu et al. reported trolling the experimental conditions, we discovered:
the palladium(II)-catalyzed reaction of o-alkynylaniline de- (1) When the reaction time was prolonged from 24 to 36 h,
rivatives and α,β-unsaturated carbonyl compounds, which the starting materials were completely converted into the
was used to obtain 2-substituted 3-alkylindoles.[12] In this product and the yield of aa increased to 70% (Table 1, En-
case, the reaction was performed in the presence of LiBr, tries 1 and 2). However, there was no obvious increase in
which prevented the final β-hydride elimination reaction. In the yield of aa after prolonging the time from 36 to 54 h
particular, the Pd-catalyzed olefination of aryl C–H bonds (Table 1, Entries 2 and 3). (2) When the temperature was
has the potential to emerge as a powerful platform for more decreased 140 °C, the amount of side product i formed in-
direct access to the isoindole cores of complex mole- creased (Table 1, Entry 4). When the temperature was in-
cules.[13–15] The first examples of a successful, convenient creased to 170 °C, no results were obtained, except for one
Heck–intramolecular direct arylation, involving alkylpalla- type of polymer (Table 1, Entry 5). (3) The Ag2O additive
dium(II) intermediates and C–H functionalization, have re- prompted the conversion of the substrates (the substrate
cently been reported (Scheme 1).[16]
was completely converted in 24 h). However, the yield of aa
Results and Discussion
In recent years, we have created an efficient method of
constructing five-membered heterocycles and tri- and tetra-
cyclic heterocycles from 1,6-dienes or 1,6-enynes and aryl
halides.[17] As part of our ongoing studies in this field, we
report herein an efficient domino cyclization method for the
preparation of different isoindolinones through carbopal-
ladation and subsequent regioselective functionalization of
the inactivated C–H bond. A survey of the reaction condi-
tions was performed by using N-(cyclohex-2-enyl)-N-phen-
ylacrylamide (a) and ethyl 4-bromobenzoate for the test ex-
periment (Scheme 1, Table 1). The reaction of a with ethyl
4-bromobenzoate in N,N-dimethylformamide (DMF) in the
presence of a catalytic amount of Pd(OAc)2 produced ethyl
5-oxo-4-phenyl-0,1,2,3,3a,4,5,5a,6,10b-decahydronaphtho-
Figure 1. ORTEP plot of aa showing ellipsoids at the 30% prob-
ability level. Selected bond lengths [Å] and angles [°]: C9–C10
1.384(2), C9–C22 1.400(3), C10–C11 1.427(4), C11–C20 1.425(4),
C20–C21 1.430(4), C21–C22 1.380(4), C9–C10–C30 120.9(2), C11–
C10–C30 121.0(2), C20–C21–C24 124.6(2), C22–C21–C24
[3,2,1-cd]indole-9-carboxylate aa in 53% yield after 24 h at 116.6(2).
Table 1. Palladium-catalyzed one-pot reaction for the synthesis of isoindolinone aa.[a]
Entry
[Pd] (mol-%)
Base (equiv.)
Solvent
t [h]
T [°C][b]
Yield [%]
aa
i
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3 (1:2)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)[c]
Pd(PPh3)4 (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
(nBu)3N (2)
K2CO3 (2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
toluene
DMF
24
36
54
36
36
36
36
36
36
36
36
36
150
150
150
140
170
150
150
150
150
150
150
150
53
70
71
10
none
60
69
40
65
30
15
20
20
80
none
10
20
58
15
60
PdCl2 (2)
9
Pd(OAc)2 (2)[d]
10
11
12
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
40
50
50
30
[a] All reactions were carried out under an atmosphere of argon by using a (1.0 equiv.), ethyl 4-bromobenzoate (1.2 equiv.), Pd(OAc)2
(5 mol-%), Ph3P (2 equiv.), base, and solvent (10 mL) at the indicated temperature. [b] Isolated yield. [c] Additive Ag2O. [d] Additive
Ag2CO3.
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Y. Hu, D. Ren, L. Zhang, X. Lin, J. Wan
FULL PAPER
decreased, because it caused more kinds of side products naphthalenyl, sulfonyl, cyano, acetyl, or formacyl groups.
(Table 1, Entry 6). (4) Other palladium catalysts, solvents, By using 4-bromobenzonitrile and 1-(4-bromophenyl)eth-
bases, and additives were used (Table 1, Entries 7–12). The anone with substrates a and b, the reaction allowed substi-
structure of aa as the tricyclic product was obtained tution with hydronaphtho[3,2,1-cd]indol-5-ones in yields
through X-ray diffraction analysis (Figure 1). The following beyond 70% (aa, ad, ae, af, bb, and be). The yield of com-
standard reaction conditions were selected to carry out the pound ag was the highest at 82% (Table 2, Entry 7). The
following studies: 1,6-dienes (1 equiv.) reacted with different output of the reaction of substrate a was close to that of
aryl halides (1.2 equiv.) in the presence of a palladium(II) substrate b. These results demonstrated the wide application
catalyst (2 mol-%) and Ph3P (4 mol-%) with (nBu)3N of the direct functionalization of molecular scaffolds in the
(2 equiv.) as an additive in DMF at 150 °C.
synthesis of isoindolinone.
Domino Cyclization of Aryl Bromides with N-(Cyclohex-2-
enyl)-N-acrylamide
The purpose of this study was to develop palladium-cata-
lyzed processes to obtain directly physiologically active sub-
stances in a single operation and to provide a direct, ef-
ficient, and economic methodology for the construction of
more stereocenters in nonracemic heterocycles. Illustrative
examples intended to investigate the scope of this domino
reaction are shown in Table 2 and Scheme 2. The reactions
of a range of substituted aryl halides with N-(cyclohex-2-
enyl)-N-phenylacrylamide (a), N-(cyclohex-2-enyl)-N-p-
tolylacrylamide (b), and N-(cyclohex-2-enyl)-N-(naphth-
alen-1-yl)acrylamide (c) were examined. A variety of dienes
and substituted aryl bromides were found to be compatible Scheme 2.
with this palladium-catalyzed domino reaction. A range of
1,2,3,3a,4,5a,6,10b-octahydronaphtho[3,2,1-cd]indol-5(4H)-
one compounds were readily isolated in good to excellent
Domino Reaction of Different 1,6-Dienes with Aryl Halides
yields when aryl halides with a variety of substituted groups
were employed, except in the case of ca. The substituted
groups could be ethoxycarbonyl, methoxycarbonyl, keto,
To further broaden the scope of this reaction, we tested
reactions of substituted aryl halides with N-allyl-N-(cyclo-
hex-2-enyl)acrylamide (d), N-benzyl-N-(cyclopent-2-enyl)-
acrylamide (e), N-(cyclopent-2-enyl)-N-p-tolylacrylamide
(f), N-(cyclohept-2-enyl)-N-p-tolylacrylamide (g), and N-
(cyclooct-2-enyl)-N-p-tolylacrylamide (h) under the afore-
mentioned conditions. The reactions also proceeded
smoothly. Similarly, except for the highest yield of fa at 85%
and the lowest yield of hc at 52%, the majority of the yields
of the products were around 60–80% (Table 3). When aryl
halides with both C–Br and C–Cl bonds on the benzene
ring were treated under the outlined conditions, the C–Br
bond coupled selectively with the 1,6-dienes (Table 2, En-
try 9; Table 3, Entry 13). However, the desired 4-allyl-
1,2,3,3a,4,5a,6,10b-octahydronaphtho[3,2,1-cd]indol-5(4H)-
ones were not isolated. When N-allyl-N-(cyclohex-2-enyl)-
acrylamide (d) was treated with ethyl 4-bromobenzoate, 1-
bromo-4-chlorobenzene, isopropyl 4-bromobenzoate, and
1-iodonaphthalene a series of allyl isomerization 4-allyl-
octahydronaphthoindolones were obtained in good yields
(Table 3, Entries 12–16). The structure of exceptional prod-
uct dc was proven by X-ray diffraction analysis (Figure 2)
and resulted from allyl isomerization. These results demon-
strated that C–H functionalization and allyl isomerization
could occur simultaneously when the protecting group was
allyl on substrate d. However, the mechanism for this kind
of reaction could not be defined (Scheme 2).[18]
Table 2. Palladium-catalyzed domino reaction of aryl halides with
a.[a]
Entry R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
Ph (a)
Ph (a)
Ph (a)
Ph (a)
Ph (a)
Ph (a)
Ph (a)
p-MeC6H4 (b)
p-MeC6H4 (b)
p-MeC6H4 (b)
p-MeC6H4 (b)
p-MeC6H4 (b)
α-naphthalenyl (c)
p-COOC2H5
p-COOCH3
p-CHO
p-COCH3
p-CN
p-SO2CH3
α-naphthalenyl
p-CHO
p-COCH3
α-naphthalenyl
p-COOCH3
p-SO2CH3
α-naphthalenyl
aa
ab
ac
ad
ae
af
ag
ba
bb
bc
bd
be
ca
70
68
65
71
70
70
82
65
70
64
66
70
60
9
10
11
12
13
[a] General conditions: 1,6-diene (1.0 equiv.), RnC6H4Br
(1.2 equiv.), Pd(OAc)2 (2 mol-%), PPh3 (4 mol-%), (nBu)3N
(2 equiv.), DMF (10 mL), 150 °C. [b] Isolated yield after flash col-
umn chromatography.
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Eur. J. Org. Chem. 2010, 4454–4459

Palladium-Catalyzed C–C Coupling/C–H Activation
Table 3. Palladium-catalyzed domino reaction of aryl halides with fused polycyclic compounds are proposed in Scheme 3. Se-
a, d–h.[a]
lective insertion of arylpalladium(II) halide into the allyl
moiety of the starting material (SM) produces intermediate
1, which then reacts with the carbon–carbon double bond
through carbopalladation to afford 2. σ-Bond metathesis[19]
onto the different C–H bonds in 3 via intermediate 2 then
generates the target molecular structure (TM) of the final
products. Thus, C–H bond functionalization could be con-
trolled by selecting differently substituted aromatic halides.
Entry R1
R2C6H4X
Product Yield
[%][b]
1
2
3
4
5
6
7
8
PhCH2 (n = 1, e)
α-naphthalenyl bromide
p-MeC6H4 (n = 1, f) α-naphthalenyl bromide
p-MeC6H4 (n = 3, g) p-EtO2CC6H4Br
p-MeC6H4 (n = 3, g) p-OHCC6H4Br
p-MeC6H4 (n = 4, h) p-EtO2CC6H4Br
p-MeC6H4 (n = 4, h) p-MeO2CC6H4Br
p-MeC6H4 (n = 4, h) p-NCC6H4Br
ea
fa
80
85
60
65
70
60
52
80
65
66
64
55
62
76
71
77
ga
gb
ha
hb
hc
hd
he
hf
hg
da
db
dc
dc
ag
p-MeC6H4 (n = 4, h) α-naphthalenyl bromide
p-MeC6H4 (n = 4, h) p-MeO2SC6H4Br
p-MeC6H4 (n = 4, h) p-MeOCC6H4Br
p-MeC6H4 (n = 4, h) p-OHCC6H4Br
allyl (n = 2, d)
allyl (n = 2, d)
allyl (n = 2, d)
allyl (n = 2, d)
Ph (n = 2, a)
9
10
11
12
13
14
15
16
p-EtO2CC6H4Br
p-ClC6H4Br
p-Me2CHO2CC6H4Br
p-Me2CHO2CC6H4I
α-naphthalenyl iodide
[a] General conditions: 1,6-diene (1.0 equiv.), R2C6H4X (X = Br; I)
(1.2 equiv.), Pd(OAc)2 (2 mol-%), PPh3 (4 mol-%), (nBu)3N
(2 equiv.), DMF (10 mL), 150 °C. [b] Isolated yield after flash col-
umn chromatography.
Scheme 3. Proposed mechanistic pathways.
Conclusions
In summary, we have developed an efficient method for
the synthesis of isoindolinone derivatives through domino
cyclization of 1,6-dienes with aryl halides in the presence of
a Pd(OAc)2/PPh3/(nBu)3N catalyst with good yields under
mild conditions. The catalyst system tolerates a wide range
of dienes and aryl halides. The electronic properties of the
substituted groups on the aryl halides have a great influence
on the regioselectivity of the C–H functionalization reac-
tion. C–H functionalization and allyl isomerization could
simultaneously occur when 1-iodobenzene or aryl halides
were treated with substrates having allyl moieties as protect-
ing group. Further studies on the domino reaction for the
synthesis of more complex products and their biological ac-
tivity are now in progress in our laboratory.
Figure 2. ORTEP plot of dc showing ellipsoids at the 30% prob-
ability level. Selected bond lengths [Å] and angles [°]: C9–C10
1.384(2), C9–C22 1.400(3), C10–C11 1.427(4), C11–C20 1.425(4),
C20–C21 1.430(4), C21–C22 1.380(4), C9–C10–C30 120.9(2), C11–
C10–C30 121.0(2), C20–C21–C24 124.6(2), C22–C21–C24
116.6(2).
All the resulting tri- and tetracyclic compounds were
confirmed through 1D (1H, 13C) and 2D (COSY) NMR
spectroscopic analysis and either elemental or HRMS
analysis. Representative compounds aa and dc were ad-
ditionally characterized by X-ray crystallography (Figures 1
and 2). Further details can be found in the Supporting In-
formation (see also the Experimental section). The X-ray
crystal structures proved the stereochemistry.
Experimental Section
General: All the catalytic reactions were performed under an argon
atmosphere by using an oven-dried Schlenk flask. The chemicals
were purchased from Alfa Aesar and Acros Chemicals. All solvents
and materials were predried, redistilled, or recrystallized before use.
1H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra were re-
corded with a Bruker Avance 300 spectrometer with CDCl3 as the
solvent. Chemical shifts are reported in ppm by assigning TMS
resonance in the 1H NMR spectra as δ = 0.00 ppm and CDCl3
resonance in the 13C spectra as δ = 77.0 ppm. All coupling con-
Mechanism
On the basis of the above observations, plausible mecha-
nisms for the catalytic cycle pathways for the formation of stants (J values) were reported in Hz. Column chromatography was
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performed on silica gel (300–400 mesh). Melting points were deter-
mined using a Gallenkamp melting point apparatus. The FTIR
spectra were recorded as KBr pellets in the 4000–400 cm–1 range
by using a Nicolet 5DX spectrometer. Mass spectra were performed
with a Micromass GCT-MS. 2D NMR and HRMS spectroscopy
were performed at the State-Authorized Analytical Center at the
University of Science and Technology of China. X-ray crystallo-
graphic diffraction data of aa, dc, ag, ac, ea, and ha were collected
at room temperature with a Bruker SMART Apex CCD dif-
fractometer with Mo-Kα radiation (λ = 0.71073 Å) with a graphite
monochromator by using the ω-scan mode. Data reductions and
absorption corrections were performed with SAINT and SADABS
software, respectively.[20] The structure was solved by direct meth-
ods and refined on F2 by full-matrix least-squares by using
SHELXTL.[21] All non-hydrogen atoms were treated anisotropi-
cally. The positions of hydrogen atoms were generated geometri-
cally.
[7]
[8]
Synthesis: A typical procedure for the palladium-catalyzed tandem
reaction of 1,6-dienes that contain acryl groups with aryl halides:
substrate a (1.14 g, 5 mmol) and ethyl 4-bromobenzoate (1.37 g,
6 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol), and PPh3 (52.4 mg,
0.2 mmol) were added to a degassed solution of (nBu)3N (2.3 mL,
10 mmol) in DMF (10 mL). After the mixture was stirred for
30 min at room temperature, it was then heated at 150 °C for 36 h,
and was then quenched with water and extracted with EtOAc
(3ϫ5 mL). The combined organic layer was washed with hydro-
chloric acid (5%), sodium carbonate (5%), and saturated sodium
chloride solution. After separation, the organic layer was dried with
MgSO4 and then concentrated. The residue was purified by flash
chromatography column (petroleum ether/EtOAc, 4:1) to give the
corresponding isoindolinone.
[9]
[10]
[11]
[12]
X-ray Crystallographic Analysis: CCDC-766080 (for aa), -766081
(for dc), -766082 (for ag), -766083 (for ac), -766084 (for ea), and
-766085 (for ha) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk/
data_request/cif.
[13]
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for fused isoindolinones; X-ray struc-
1
tures of aa, dc, ag, ac, ea, ha; 2D NMR spectra of ae, bb, dc; H
[14]
NMR and 13C NMR spectra of new compounds.
Acknowledgments
This research was partly supported by the National Science Foun-
dation of China (20872002, 20572001) and the Education Depart-
ment of Anhui Province. The authors are grateful to Prof. J. Hu
and Prof. H. Zhang for their assistance in running NMR spectra
and X-ray diffraction analyses.
[15]
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4454–4459

Palladium-Catalyzed C–C Coupling/C–H Activation
[19] a) D. García-Cuadrado, P. D. Mendoza, A. A. C. Braga, F.
Maseras, A. M. Echavarren, J. Am. Chem. Soc. 2007, 129,
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[20] SAINT and SADABS Software Reference Manual, Bruker AXS
Inc., Madison, Wisconsin, USA, 2003.
[21] a) G. M. Sheldrick, SHELXL97, Program for Crystal Structure
Refinement, University of Göttingen, Germany, 1997; b) G. M.
Sheldrick, SHELXS97, Program for Crystal Structure Refine-
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Received: April 11, 2010
Published Online: July 2, 2010
Eur. J. Org. Chem. 2010, 4454–4459
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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