Palladium-catalyzed insertion of α,β-unsaturated N-tosylhydrazones and trapping with carbon nucleophiles

Article abstract of DOI:10.1039/c3cc45583a

Palladium-catalyzed carbene migratory insertion-cyclization reactions were reported, delivering dihydronaphthalene and indene derivatives in moderate to good yields. A three-component cross-coupling was also developed. The reactions are easy to handle, under mild conditions and various functional groups are tolerated. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45583a

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Palladium-catalyzed insertion of a,b-unsaturated
N-tosylhydrazones and trapping with carbon
nucleophiles†
Cite this: Chem. Commun., 2013,
49, 10190
Received 23rd July 2013,
Accepted 27th August 2013
Yu-Ying Ye, Ping-Xin Zhou, Jian-Yi Luo, Mei-Jin Zhong and Yong-Min Liang*
DOI: 10.1039/c3cc45583a
www.rsc.org/chemcomm
Palladium-catalyzed carbene migratory insertion–cyclization reactions
At the outset of this investigation, dimethyl 2-(2-iodophenyl)-
were reported, delivering dihydronaphthalene and indene derivatives malonate 1a was treated with N-tosylhydrazone 2a in the presence of
in moderate to good yields. A three-component cross-coupling Pd2(dba)3ÁCHCl3/PPh3 and t-BuOLi in THF at 60 1C (Table 1, entry 1).
was also developed. The reactions are easy to handle, under mild To our disappointment, no reaction occurred. Further inspection
conditions and various functional groups are tolerated.
of the reaction conditions revealed that base was essential for this
reaction (Table 1, entries 2–5). Using K2CO3 as base afforded 3a in
The dihydronaphthalene skeleton was found in many natural 69% yield.9 However, t-BuOK, Na2CO3 and Cs2CO3 were found to be
products with an unusual range of biological activities and useful ineffective. With K2CO3 as the best base, we went on to screen other
building blocks in organic synthesis.1 A variety of synthetic reaction parameters. Several other solvents were then examined.
procedures have been reported to prepare dihydronaphthalene Dioxane and MeCN gave comparable yield (Table 1, entries 7 and 8),
derivatives. In 2004, Huang et al. reported a Mn(OAc)3-mediated
reaction of MCPs with diethyl malonate for the preparation of
Table 1 Conditions for the palladium-catalyzed reaction of 1a and 2aa
dihydronaphthalene derivatives.2 Murai reported Ru(II) or Pt(II) cyclo-
isomerization of o-aryl-1-alkynes to afford dihydronaphthalene.3
Very recently, Murakami developed a rhodium-catalyzed ring-
opening reaction of benzocyclobutenols to synthesise dihydro-
naphthalene frameworks.4 Cheng developed a ring-opening addition
of alkenyl zirconium reagents to oxa- and azabicyclic alkenes in the
presence of nickel and zinc to give dihydronaphthalene.5 However,
these transformations have some limitations, such as using
equivalents of metal oxidants, expensive catalysts, harsh reaction
conditions, air sensitive/toxic metal reagents or the narrow scope
of the substrates. These limitations prompted us to investigate a
new, efficient and straightforward catalytic system.
Palladium-catalyzed insertion of diazo compounds has been
shown to be a new type of cross-coupling reaction.6 Previously,
we have shown that the migration of aryl groups to arylvinyl-
diazoacetate or a,b-unsaturated N-tosylhydrazones can generate
Z3-allylpalladium intermediates, which could be attacked by
amines.7 In connection with our interest in the carboannulation
reaction with a palladium catalyst,8 it is logical to extend this
coupling using carbon as the nucleophile.
Entry
Base
Solvent
Ligand
Yieldb
1
2
3
4
5
6
7
8
t-BuOLi
t-BuOK
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
THF
THF
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
L1
nr
Trace
nr
69
nr
nr
65
THF
Toluene
Dioxane
MeCN
DMF
THF
THF
THF
THF
THF
THF
THF
66
9
19c
65c
81
10
11
12
13
14
15
16
L2
[HPtBu3]BF4
phen
dppp
—
nr
nr
nr
nr
L2
nrd
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China. E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. CCDC 941046 (3c) and 941047 (5e). For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc45583a
a
Reaction conditions: 1a (0.3 mmol, 1.0 equiv.), 2a (0.675 mmol, 2.25
equiv.), Pd2(dba)3ÁCHCl3 (2.5 mol%), L (15 mol%), base (1.575 mmol,
b
c
5.25 equiv.), solvent (4 mL), 60 1C, 5 h. Yield of isolated product. The
yield was determined using 1H NMR. Without palladium catalyst.
d
c
10190 Chem. Commun., 2013, 49, 10190--10192
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whereas toluene and DMF were less efficient than THF (Table 1,
entries 6 and 9). Next, we tested the effect of the ligand. When
tri-p-tolylphosphine was employed, which has an electron-
donating group on the aromatic ring compared with PPh3, it led
to a diminished yield (Table 1, entry 10). Having this result in mind,
tris(3,4-bis(trifluoromethyl)phenyl)phosphine, with an electron-
withdrawing group, was used (Table 1, entry 11). To our delight,
the yield of 3a was improved to 81%. Other ligands such as the
monodentate phosphino ligand [HPtBu3]BF4, bidentate phosphino
ligand dppp and 1,10-phenanthroline monohydrate were also
examined. However, none of the desired products was obtained
(Table 1, entries 12–14). Finally, a control experiment showed that
product 3a could not be detected in the absence of a palladium
catalyst or a ligand (Table 1, entries 15 and 16).
Having established the optimal reaction conditions, we next
set out to test the scope of the reaction with a number of different
N-tosylhydrazones 2. Both electron-donating and electron-withdrawing
groups on aromatic a,b-unsaturated N-tosylhydrazones were tolerated
and the desired products were obtained in moderate to good yields
(Scheme 1, 3b–g). The low yield in the case of 3g comparable with 3b
a
Scheme 2 Palladium-catalyzed reactions of 4 with 2. (a) Palladium-catalyzed
cross-coupling of 4 with N-tosylhydrazones 2. Reaction conditions: 4 (0.3 mmol,
1.0 equiv.),
2
(0.675 mmol, 2.25 equiv.), Pd2(dba)3ÁCHCl3 (5 mol%), PPh3
(30 mol%), K2CO3 (1.575 mmol, 5.25 equiv.), THF (4 mL), 60 1C, 5 h. Yield of
the isolated product. (b) The yield was determined using 1H NMR.
was probably due to its steric hindrance. The halogen substituents electron-withdrawing groups, can also afford the corresponding
in 3e and 3f were tolerated under the Pd-catalyzed conditions, 5j in 74% yields. The molecular structure of the representa-
which allow a further transition-metal-catalyzed coupling reaction. tive product 5e was determined using X-ray crystallography
The reaction also worked well with non-aromatic N-tosylhydrazones (Scheme 2).
(Scheme 1, 3h, 3i). We were pleased to find that heterocycle
In the case of substrates 1 and 4, the carbon nucleophiles are
substituted N-tosylhydrazones could react smoothly with 1a to tethered to the iodobenzene, which limits the scope of the reaction.
afford the corresponding 3j in 89% yield. Another activated To further expand the scope of the reaction, this palladium-catalyzed
methylene compound could also react with 2a and the product reaction was extended to a three-component coupling by using
3k was isolated in 40% yield. Finally, the molecular structure of substituted iodobenzene, a,b-unsaturated N-tosylhydrazones
3c was confirmed through X-ray crystallography.
and carbon nucleophiles. Treatment of these substrates under
To expand the scope of the reaction, we further investigated slightly modified conditions affords the products 6a–6f in
the palladium-catalyzed reaction of 4 with N-tosylhydrazones moderate to good yields, except in the case of 6e, which contains
2 to construct a five-membered ring under slightly modified an electron-withdrawing substituent. For unsymmetrical sub-
conditions. A series of substituents and functional groups, strates, the nucleophile attack could occur on either end of
including halogen groups, and ortho-substituted substrates, can the Z3-allylpalladium and it can generate two regioisomeric
be tolerated and react smoothly to generate 5b–5i in moderate products. With this unoptimistic possibility, substituted iodo-
to good yields. Methyl 2-(2-iodobenzyl)-3-oxobutanoate, with different benzene and N-tosylhydrazones derived from (E)-but-2-enal were
Scheme 3 Palladium-catalyzed three-component reactions of iodobenzene,
N-tosylhydrazones and carbon nucleophiles. Reaction conditions: iodobenzene
a
Scheme 1 Palladium-catalyzed reactions of 1 with 2. (a) Palladium-catalyzed
cross-coupling of 1 with N-tosylhydrazones 2. Reaction conditions: 1 (0.3 mmol,
1.0 equiv.), 2 (0.675 mmol, 2.25 equiv.), Pd2(dba)3ÁCHCl3 (2.5 mol%), L2 (15 mol%),
K2CO3 (1.575 mmol, 5.25 equiv.), THF (4 mL), 60 1C, 8 h. Yield of the isolated
product. (b) The yield was determined by 1H NMR.
(0.3 mmol, 1.0 equiv.), N-tosylhydrazones (0.675 mmol, 2.25 equiv.), carbon
nucleophiles (1.8 mmol, 6.0 equiv.),10 BTAC (0.6 mmol, 2.0 equiv.), Pd2(dba)3Á
CHCl3 (2.5 mol%), L3 (20 mol%), K2CO3 (0.9 mmol, 3.0 equiv.), THF (6 mL), reflux,
8 h. Yield of the isolated product. L3 = tris(4-methoxyphenyl)phosphine, BTAC =
benzyltriethylammonium chloride.
c
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chosen as cross-coupling partners. To our surprise, 6g–6j were Notes and references
isolated in complete regioselectivities with moderate to good
yields (Scheme 3).
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using substituted iodobenzene and 2a as substrates. A mixture
of products was obtained and the ratio of the two regioisomers
was determined using 1H NMR. For unsymmetrical substrates,
these results are consistent with the previous report.11
A plausible mechanism is speculated (Scheme 4). The cou-
pling reaction mechanism starts with the oxidative addition of
Pd(0) to 1 or 4 to give the aryl palladium complex A. The diazo
compounds (generated in situ from N-tosylhydrazone 2) react
with the aryl palladium complex to afford a palladium carbene
complex B, which undergoes a migratory insertion of the
aryl group to produce the Z1-allylpalladium complex C. The
Z1-allylpalladium isomerizes to the more stable Z3-allylpalladium D.
Finally, the Z3-allylpalladium species is attacked by carbon nucleo-
philes to afford the products, which were isolated in complete
regioselectivities.12,13
In conclusion, two efficient palladium-catalyzed cross-coupling–
cyclization reactions for synthesis of dihydronaphthalene derivatives
and indene derivatives have been developed. A three-component
coupling of iodobenzene, N-tosylhydrazones and carbon nucleo-
philes through palladium carbene migratory insertion and the
carbopalladation process was also reported.
We thank the National Science Foundation (NSF 21072080
and 21272101) and National Basic Research Program of China
(973 Program) 2010CB833203 and ‘‘111’’ program of MOE and
PCSIRT: IRT1138 for financial support.
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9 Using anhydrous K2CO3 as based and subjected 1a and 2a under the
standard conditions in Scheme 1, 3a was isolated in 46% yield.
However, when 5 equiv. H2O added, 3a was afforded in 79% yield. In
this paper, all K2CO3 are Puratronic and purchased from Alfa. At this
stage, the reason for water and crystal water significant improved
the yield is unknown. For similar example see: (a) J. Barluenga,
´
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´
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˘
˘
´
´
11 R. Sebesta, A. Skvorcova and B. Horvath, Tetrahedron: Asymmetry,
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12 For palladium-catalyzed reactions of 1 with 2, it is more inclined to
form the six-membered ring rather than four-membered ring,
because the strain of four-membered ring.
13 For palladium-catalyzed reactions of 4 with 2, it is more inclined to
form the five-membered ring rather than seven-membered ring,
because the small five-membered ring is more stable. For similar
˜
example see: (a) R. C. Larock, N. Berrios-Pena and K. Narayanan,
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Scheme 4 Plausible mechanism.
c
10192 Chem. Commun., 2013, 49, 10190--10192
This journal is The Royal Society of Chemistry 2013