The Pd-catalyzed synthesis of benzofused carbo- and heterocycles through carbene migratory insertion/carbopalladation cascades with tosylhydrazones

Article abstract of DOI:10.1039/c5cc06348e

The Pd-catalyzed reaction between o-iodoallylbenzene and tosylhydrazones gives rise to indene derivatives through a process that involves a carbene migratory insertion followed by an intramolecular carbopalladation, with the formation of two C-C bonds on

Full text of DOI:10.1039/c5cc06348e

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DOI: 10.1039/C5CC06348E
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Pd-catalyzed Synthesis of Benzofused Carbo- and Heterocycles
through Carbene Migratory Insertion/Carbopalladation Cascades
with Tosylhydrazones
Received 00th January 20xx,
Accepted 00th January 20xx
Miguel Paraja,a M. Carmen Pérez-Aguilara and Carlos Valdés.a,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The Pd-catalyzed reaction between o-iodoallylbenzene and
tosylhydrazones gives rise to indene derivatives through a process
that involves a carbene migratory insertion followed by an
intramolecular carbopalladation, with formation of two C-C bonds
on the same carbon atom. The same strategy has been also applied
for the synthesis of 2,3-disubstituted benzofurans and indenones
by selecting the proper o-substituted iodoarene.
The Pd-catalyzed cross-coupling between tosylhydrazones and
organic halides, first introduced by our research group in 2007,1
have established since then as a very reliable C-C bond forming
reaction, and has been successfully applied in the synthesis of
substituted alkenes.2 The accepted catalytic cycle of these
transformations1a (scheme 1, a), involves as characteristic steps
the formation of a Pd-carbene complex
A by reaction of a Pd(II)
complex with the diazo compound generated from the
tosylhydrazone, and the migratory insertion of the carbene
ligand into the Pd-C bond to give alkylpalladium complex
Then, -hydride elimination releases the coupling product and
regenerates the Pd(0) catalyst. If the reaction is carried out with
substrates that cannot undergo the -hydride elimination step,
B.

Scheme 1: a) General mechanisms of Pd-catalyzed cross-coupling reactions of
tosylhydrazones. b) Selected examples of cascade reactions .

alternative cascade transformations could be designed taking
advantage of the reactivity of the alkylpalladium complex.3,4 In
this context, several cascade processes have been devised
making use of this concept, involving the formation of
intermediate allylpalladium5 or benzylpalladium6 complexes in
the migratory insertion reaction followed by a subsequent
evolution (scheme 1, b).
Continuing with our interest on Pd-catalyzed reactions with
tosylhydrazones and their application in cascade processes,7 we
decided to combine the C-C bond forming reaction based on the
In our design (scheme 2), the benzylpalladium complex
experiment the migratory insertion of the alkene, to give the
new alkylpalladium intermediate , and after the final
C would
D
-
hydride elimination, the corresponding cyclic compound.
Interestingly, in the overall transformation, two C-C bonds
would have been formed on the former hydrazonic carbon
atom. It must be noted that this approach had been previously
studied by Van Vranken employing trimethylsilyldiazomethane
as carbene precursor,8 however, those reactions showed
limited applicability and synthetic interest due to the formation
of subproducts derived from the incorporation of more than
one molecule of carbene during the cascade process. For these
reason, we found interesting to investigate whether the same
approach could be carried out with tosylhydrazones instead of
stabilized diazo compounds and if it would be possible to find
reaction conditions to overcome the limitations reported in
those reactions.
migratory insertion
step
with
an
intramolecular
carbopalladation reaction.
a.Departamento de Química Orgánica e Inorgánica and Instituto Universitario de
Química Organometálica “Enrique Moles”. Universidad de Oviedo. c/ Julián
Clavería 8. Oviedo, 33006. Spain. Email: acvg@uniovi.es
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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reason we decided to examine the reaction with the analogous
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iodides, in the expectation that the hiDghOeI:r10r.e10a3c9t/iCvi5tCyCo06f3t4h8eE
aromatic iodides might allow more flexibility in the composition
of the catalyst, and thus, tune the activity towards the desired
indanes.
Thus,
iodobenzene
a
reoptimization was conducted with 1-allyl-2-
. In spite of the examination of a large array of
5
structurally diverse phosphines as ligands, Sphos turned out to
be again the best for the transformation. Additionally, better
yields were obtained by conducting the reactions in acetonitrile
as solvent, but also in the presence of 5 equiv of water. The
scope of the process turned out to be wider than in the case of
the reaction with the bromide (table 1 method B) providing
generally much higher yields. Moreover, the formation of the
Scheme 2: This work’s proposed cascade reaction.
We started our research employing 1-allyl-2-bromobenzene
1
4-
and
the
hydrazone
derived
from
dimethylaminobenzaldehyde 2a as a model to develop proper
reaction conditions. We expected that upon the oxidative
addition, the incorporation of the diazo compound to the
catalytic cycle might be favoured towards the intramolecular 5-
endo-trig Heck reaction.9 Indeed, preliminary experiments
under the standard reaction conditions for cross-coupling
reactions with tosylhydrazones revealed the formation of the
expected indane 3a with moderate yield. After some
experimentation that included the variation of several reaction
parameters as well as the ligand an the base, the best reaction
conditions found involved the employment of Sphos a ligand
and LiOtBu as base, as well as the addition of 5 equiv of water.1d
Under these conditions (scheme 3, table 1, method A), the
scope of the reaction was examined leading to the
corresponding indanes although with moderate yields.
undesired subproduct 4 was never detected, in these cases.
Table 1: Synthesis of indanes 3 from 1-allyl-2-bromobenzene and 1-ally-2-iodobenzene
5 and tosylhydrazones.
Compound
3a
X/Methoda
Br/Method A
I/Method B
Br/Method A
I/Method B
Br/Method A
I/Method B
Br/Method A
I/Method B
Br/Method A
I/Method B
I/Method B
Br/Method A
I/Method B
I/Method B
I/Method B
I/Method B
R
Yieldb %
76
96
40
96
56
77
47
80
35
90
82
87
48
63
50
71
4-Me2N-C6H4
3b
3c
3d
3e
4-MeO-C6H4
Ph
4-F-C6H4
4-Me-C6H4
3f
3g
3h
3i
3j
3k
3-Cl- C6H4
3-Pyridyl
t-Butyl
4-HO-C6H4
4-NC-C6H4
c
2,4,6-(MeO)3-C6H2
a Method A: Aryl bromide, 1 equiv; tosylhydrazone, 1.1 equiv; Pd2(dba)3 (2 mol %);
Sphos, (8 mol %); t-BuOLi 2.5 equiv; H2O, 5 equiv, 1,4-dioxane, 90 ⁰C, 6 h. Method
B: Aryl iodide, 1 equiv; tosylhydrazone, 2 equiv; Pd2(dba)3 (3 mol %); Sphos, (12
mol %); t-BuOLi, 6 equiv; H2O, 5 equiv; CH3CN, 1 h. b Isolated yields after column
chromatography. cPrepared employing the tosylhydrazone of 4-
acetoxybenzaldehyde.
Scheme 3: Preliminary results on the synthesis of methyleneindanes
2-bromobenzene and tosylhydrazones.
3 from 1-allyl-
The relative low yield obtained in most examples was due to the
formation of compound , which incorporates two diazo
compound fragments. The generation of can be justified
(scheme 3) considering that the alkylpalladium complex can
react with a second diazo compound at a faster rate than the
hydride elimination step to give intermediate Pd-carbene
complex . Then, the migratory insertion/ -hydride elimination
sequence furnishes compound . Unfortunately, after extensive
experimentation, it was not possible to shut down completely
this reaction pathway. Indeed, at 70 ⁰C the formation of could
4
As illustrated by the examples presented in table 1, the reaction
can be applied to tosylhydrazones derived from aromatic and
4
E
heteroaromatic aldehydes with
a variety of different

-
substitutions, including a highly hindered diortho-substituted
system (3k). Additionaly, the hydrazone of pivalaldehyde was
also an appropriate substrate (3h).‡ It is worth noting that the
indene scaffold is present in a variety of molecules with
bioactive and pharmaceutical activity,10 therefore, this
methodology represents a versatile synthetic alternative for the
preparation of this important building block.
F

4
4
be minimized, but at expenses of a lower conversion. For this
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With these results in hand we turned our attention to allyl
ethers (table 2), that would hopefully lead to benzofuran
derivatives through a similar cascade reaction. In some
preliminary experiments, the benzofurans were obtained with
moderate yields, but in many cases, the undesired compound
derived from the incorporation of second unit of
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DOI: 10.1039/C5CC06348E
6
7
a
tosylhydrazone was again detected. Nevertheless, the
formation of these subproducts could be avoided by carrying
out the reactions with slow syringe-pump addition of the
tosylhydrazone. In this way, the concentration of the diazo
Scheme 4: Synthesis of benzylideneindenones
iodoketone
9
from tosylhydrazones and
8
As summary, we have reported a new cascade reaction that
leads to the obtention of benzofused five-membered rings
through a catalytic cycle that involves a migratory insertion of a
Pd-carbene generated from a tosylhydrazone, followed by an
intramolecular Heck reaction. This processes constitutes a novel
approach to substituted indene and benzofuran derivatives, in
which two C-C bonds are formed on the same carbon atom.
Moreover, these preliminary results show great promise for the
synthesis of different benzofused carbo- and heterocycles
through the same methodology. We are currently investigating
the expansion of the scope and the synthetic usefulness of this
reaction.
compound is kept low, and therefore the
-hydride elimination
on the alkylpalladium intermediate (scheme 2) occurs at a
D
faster rate than the reaction with the transient diazo
compound. Thus, under the proper reaction conditions, a set of
2,3-disubstituted benzofurans
7 were obtained in a very
straightforward manner from readily available starting
materials (Table 2). Interestingly, this method represents an
original approach to substituted benzofurans,11 which are
constructed by formation of two C-C bonds on the same carbon
atom.
Table 2: Indanes 7 prepared from iodoenolethers 6 and tosylhydrazones.
Financial support of this work by Ministerio de Economía y
Competitividad (MINECO) of Spain (Grant CTQ2013-41336-P) is
gratefully acknowledged. M. P. and M. C. P.-A. thank MINECO
for FPI predoctoral fellowships.
Notes and references
Compound
X
H
H
H
H
H
H
H
H
H
H
MeO
MeO
Ar
4-Me2N-C6H4
4-MeO-C6H4
Ph
Yieldb %
50
77
60
57
59
58
57
68
73
40
68
53
‡ With regard to the substitution of the double bond, the
reactions with the 1,2,-disubstituted alkene 1-(but-2-en-1-yl)-2-
iodobenzene took place successfully, but gave rise to a mixture of
three isomeric indanes arising from an unselective β-hydride
elimination. However, ethoxycarbonyl substitution on the
terminal position of the double bond or substitution at both the
internal and terminal positions were not tolerated, as the
formation of the indenes were not detected (see ESI for details).
7a
7b
7c
7d
7e
7f
7g
7h
7i
4-F-C6H4
2,4,6-(MeO)3-C6H2
4-Me-C6H4
3-Cl- C6H4
4-CF3- C6H4
4-CN-C6H4
2-Furyl
1
(a) J. Barluenga, P. Moriel, C. Valdés and F. Aznar, Angew.
Chem. Int. Ed., 2007, 46, 5587; (b) J. Barluenga, M. Tomás-
Gamasa, P. Moriel, F. Aznar and C. Valdés, Chem. Eur. J.,
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Chem. Int. Ed., 2010, 49, 6856.
7j
7k
7l
Ph
4-CN-C6H4
a Reaction conditions: Aryl iodide, 1 equiv; tosylhydrazone, 2 equiv; Pd2(dba)3 (3
⁰
mol %); Sphos, (12 mol %); t-BuOLi, 6 equiv; H2O, 5 equiv; CH3CN, 85 C, 1 h. The
tosylhydrazone is added via syringe pump over a period of 1 h. bIsolated yields after
column chromatography.
2
3
For some reviews see: (a) J. Barluenga and C. Valdés, Angew.
Chem. Int. Ed., 2011, 50, 7486; (b) Q. Xiao, Y. Zhang and J.
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Org. Lett., 2007, 9, 2047; (b) S. K. J. Devine and D. L. Van
To further illustrate the versatility of this cascade reaction as a
method for the synthesis of benzofused five membered rings,
we studied also the reaction with iodoalkene
challenging substrate due to the presence of additional
functionality as well as substitution on the double bond.
Delightfully, the reaction led to the obtention of the
Vranken, Org. Lett., 2008, 10, 1909; (c) R. Kudirka, S. K. J.
Devine, C. S. Adams and D. L. Van Vranken, Angew. Chem.
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8, a quite
4
5
Y. Xia, Y. Zhang and J. Wang, ACS Catalysis, 2013, 3, 2586
(a) A. Khanna, C. Maung, K. R. Johnson, T. T. Luong and D. L.
Van Vranken, Org. Lett., 2012, 14, 3233; (b) P.-X. Zhou, J.-Y.
Luo, L.-B. Zhao, Y.-Y. Ye and Y.-M. Liang, Chem. Commun.,
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Y.-M. Liang, Chem. Commun. 2013, 49, 10190; (d) B. Yin, X.
Zhang, J. Liu, X. Li and H. Jiang, Chem. Commun., 2014, 50
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benzylideneindenones
9 derived from the cyclization reaction
(scheme 4). Noteworthy, the final β-hydride elimination took
place with high stereoselectivity leading to the E stereoisomer
as major product.
,
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Chem., 2014, 12, 9333; (f) X. S. Shang, N. T. Li, H. X. Siyang
and P. N. Liu, J. Org. Chem., 2015, 80, 4808.
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DOI: 10.1039/C5CC06348E
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,
8
9
R. Kudirka and D. L. Van Vranken, J. Org. Chem., 2008, 73
3585.
In iodoalkenes in which a 6-exo-trig carbopalladation is
,
possible, the intramolecular reaction is favoured towards the
formation of the Pd-carbene leading to Heck-type
cyclizations with participation of the diazo compound as
terminating step: (a) X. Liu, X. Ma, Y. Huang and Z. Gu, Org.
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11 J. Wu in Modern Heterocyclic Chemistry, Vol 1. (Eds. J.
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