Palladium-Catalyzed Intermolecular Carbene Insertion Prior to Intramolecular Heck Cyclization: Synthesis of 2-Arylidene-3-aryl-1-indanones

Article abstract of DOI:10.1021/acs.orglett.5b02803

A domino process that converges the migratory insertion of carbene with a Heck reaction has been established as a versatile tool for the synthesis of 2-arylidene-3-aryl-1-indanones from very stable and easily accessible N-tosylhydrazones and 2′-iodochalco

Full text of DOI:10.1021/acs.orglett.5b02803

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Intermolecular Carbene Insertion Prior to
Intramolecular Heck Cyclization: Synthesis of 2‑Arylidene-3-aryl-1-
indanones
Dhanarajan Arunprasath, Pandi Muthupandi, and Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: A domino process that converges the migratory
insertion of carbene with a Heck reaction has been established
as a versatile tool for the synthesis of 2-arylidene-3-aryl-1-
indanones from very stable and easily accessible N-
tosylhydrazones and 2′-iodochalcones. The reaction selectively
proceeds through 5-exo-trig cyclization and delivers the
products selectively with the E configuration of the double
bond in excellent yields. The one-pot synthesis of 2-arylidene-
3-aryl-1-indanones involving in situ synthesis of both 2′-
iodochalcones and N-tosylhydrazones has also been demon-
strated.
Scheme1. MigratoryInsertionofCarbenebeforeorafterHeck
Reaction
he transition-metal-catalyzed cross-coupling reaction is an
Tinvaluabletoolinsyntheticchemistryfortheconstructionof
C−C bonds.1 In the current scenario, cross-coupling reactions
that involve metal carbene species have emerged as a powerful
strategy for the formation of C−C bonds.2,3 Diazo compounds
are widely utilized as a precursor for the generation of metal
carbene species.4 However, the uncertain explosive nature and
instability of diazo compounds without electron-withdrawing
groups has forced the search for alternative precursors.5 In recent
years, N-tosylhydrazones have emerged as convenient precursors
for the in situ generation of unstable diazo compounds.6,7
Palladium has been exploited as a potent catalyst in this field,
where the reaction is considered to proceed via migratory
insertion of a palladium carbene intermediate.8,9 In particular,
domino C−C bond formations triggered by Pd-catalyzed
migratory insertion are very attractive and productive, as
structural complexity can be achieved in a single operation.9
A few catalytic processes that converge Pd-catalyzed migratory
insertion of carbene with other coupling reactions have been
reported for the construction of cyclic architectures.10 In this
context, a domino intramolecular Heck reaction followed by
migratoryinsertionofametalcarbeneinwhichthealkylpalladium
species originating from the Heck reaction in the absence of β-
hydride elimination reacts with a diazo compound has been
reported (Scheme 1, eq 1).11 Conversely, a domino process that
proceeds through intermolecular carbene insertion followed by a
Heck reaction that involves the migratory insertion of alkene
would be a novel pathway for construction of different cyclic
architectures (Scheme 1, eq 2). This type of domino reaction was
attempted using a Pd catalyst and large excess of trimethylsilyl
diazomethane as the carbene precursor.12 However, instead of
giving the desired product, the alkylpalladium species generated
after the Heck cyclization reacted with another carbene insertion
or protodesilylation took place.
Despite this attempt, the development of such cyclization can
be a difficult task, as the intramolecular Heck reaction (migratory
insertion of alkene) could be more facile than the intermolecular
migratory insertion of carbene. We hypothesized that 2′-
iodochalcone could be an appropriate substrate in which an
intramolecular Heck reaction is less facile, allowing the
intermolecular carbene insertion to occur first, followed by
alkene insertion to give five- or six-membered compounds
through 5-exo-trigor6-endo-trigcyclization inthepresence ofaPd
catalyst (Scheme 2).
At first, 2′-iodochalcone (1a)and N-tosylhydrazone 2aderived
from benzaldehyde were chosen as model substrates, and the
reaction was carried out with 1.2 equiv of 2a in the presence of 10
mol % Pd(OAc)2, 30 mol % PPh3, and 3 equiv of K2CO3 in dry
Received: September 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and yield since K2CO3 is soluble in water. As anticipated, the
reaction was completed within 2 h and the product was isolated in
96% yield when the reaction was conducted in 9:1 THF/H2O
(entry 7). However, the reactivity was drastically reduced when
1:1 THF/H2O was used, and no product formation was observed
in only water.15 Also, the reactivity was reduced when the reaction
temperaturewasloweredto40°C(entry8).Thereactionwithout
ligand gave the product in 21% yield (entry 9), and product
formation was not observed without the Pd catalyst or base
(entries 10 and 11).
Scheme 2. Proposed Migratory Insertion of Carbene before
Heck Reaction
THF at 60 °C. To our delight, the domino reaction proceeded
through intermolecular carbene insertion followed by alkene
insertion and selectively cyclized in a 5-exo-trig manner to give 2-
benzylidene-3-phenyl-1-indanone (3a) in 36% yield (Table 1,
The optimized reaction conditions were first explored with N-
tosylhydrazones derived from different substituted benzalde-
hydes, and the results are summarized in Scheme 3. It was found
a
Table 1. Optimization of the Reaction Conditions
Scheme 3. Scope of Pd-Catalyzed Insertions of Carbene and
ab
,
Alkene
T
(°C) % yield of 3a (4a)
b
entry equiv of 2a
[Pd]
solvent
THF
c
1
2
1.2
1.5
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
60
60
60
60
60
60
60
40
60
60
60
36 (0)
61 (0)
82 (0)
71 (0)
67 (0)
78 (0)
96 (0)
76 (0)
21 (0)
c
THF
3
THF
4
2
THF
5
2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
−
THF
d
e
6
2
THF
7
2
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
e
8
2
ef
,
9
2
eg
,
10
11
2
nr (0)
nr (0)
egh
, ,
2
Pd(OAc)2
a
Reaction conditions: 1a (0.25 mmol, 1 equiv), 2a (1.2−2.0 equiv),
K2CO3 (0.75 mmol, 3 equiv), Pd catalyst (10 mol %), PPh3 (30 mol
b
c
%). Isolated yields. Unreacted 2′-iodochalcone was recovered (53%
d
e
for entry 1 and 31% for entry 2). TBAC (2 equiv) was used. 9:1
THF/H2O (3 mL) was used. The reaction was conducted without
PPh3. nr = no reaction. The reaction was conducted without base.
f
g
h
entry 1). The structure and E-configured double bond of product
3a were confirmed by single-crystal X-ray diffraction analysis
(Figure 1), and the other product 4a was not observed. Indanone-
containing scaffolds are attractive synthetic targets13 because they
display many biological activities.14
a
Reaction conditions: 1 (0.25 mmol, 1 equiv), 2 (0.5 mmol, 2 equiv),
K2CO3 (0.75 mmol, 3 equiv), Pd(OAc)2 (10 mol %), PPh3 (30 mol
%), THF (2.7 mL), H2O (0.3 mL), 60 °C. Isolated yields are shown.
b
Figure 1. X-ray structures of 3a (CCDC 1411740), 3n (CCDC
1411739), and 3v (CCDC 1411741) with 30% probability ellipsoids.
that N-tosylhydrazones bearing an electron-releasing group
reacted smoothly and gave the corresponding products 3b−h in
excellent yields. N-Tosylhydrazones with halide substituents,
which are beneficial for further functionalization, were well-
tolerated under the optimized reaction conditions (3i and 3j).
Fluoro-substituted N-tosylhydrazones were also found to be
suitablesubstratesforthisreaction(3kand3l). However, product
formation was not observed when N-tosylhydrazones substituted
withstrongelectron-withdrawing groupssuchascyano, nitro, and
ester were used (3ac, 3ad, and 3ae). Furthermore, the optimized
reaction conditions were examined for a series of substituted 2′-
iodochalcones. Phenyl, phenylethynyl, and bromo substituents
The yield improved to 82% when 2 equiv of 2a was used (Table
1, entry 3). Further attempts to improve the efficacy of the
reaction with other Pd salts, ligands, bases, and solvents were not
beneficial.15 During the course of the reaction, the reaction
medium was not a clear solution, perhaps because of the low
solubility of K2CO3 in THF. Since a phase-transfer catalyst can
help to bring the inorganic base into the organic medium and
accelerate diazo compound formation, TBAC was used as an
additive, but no improvement in the yield was observed (entry 6)
and the reaction took a longer time for completion (10 h). Then it
waspresumedthatadditionofwatershouldimprovethereactivity
B
DOI: 10.1021/acs.orglett.5b02803
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Organic Letters
Letter
on the iodide-attached aryl ring of the 2′-iodochalcone afforded
theproductsinadmirableyields(3m−o). Thesubstituentpattern
on the other ring of the 2′-iodochalcone had little effect on the
reactivity irrespective of electron-withdrawing or -donating
nature (3p−y). Prominently, ortho substituents and heterocyclic
systems offered the products in good yield (3s, 3t, and 3y).
The reaction is highly selective, as it delivered a single isomer.
Theformationoftheotherisomerwasnotobserved, asconfirmed
Scheme 6. One-Pot Reaction through in Situ Synthesis of
2′‑Iodochalcones
1
by H NMR analysis of the crude reaction mixtures. All of the
products isolated were assumed to be E isomers, as the X-ray
crystallographic analysis of 3a, 3n, and 3v showed the E
configuration (Figure 1).
The practical utility of this methodology was established
without compromising the reaction conditions. Hence, an 87%
yield of 3a was isolated within 2 h when the reaction was scaled up
to 1 g (Scheme 4).
Scheme 4. Gram-Scale Reaction
Scheme 7. Proposed Reaction Pathway
Next, the execution of this newly developed reaction in one pot
was examined by promoting in situ generation of N-
tosylhydrazones from the corresponding aldehydes 5 and N-
tosylhydrazides (Scheme 5). Delightfully, an 81% yield of 3a was
Scheme 5. One-Pot Reaction through in Situ Synthesis of
N‑Tosylhydrazones
formed diazo compound to produce intermediate B. Then
migratory insertion of the palladium carbene leads to
benzylpalladium species C, which readily undergoes 5-exo-trig
cyclization to give intermediate D. Finally, β-hydride elimination
of intermediate D expels the final product 3.
Very importantly, when the reaction was conducted in the
absence of N-tosylhydrazone 2a, the intramolecular reductive
Heck cyclization of 2′-iodochalcone 1a was observed (Scheme 8,
eq3). ThefeasibilityofintramolecularHeckcyclizationsuggested
that the reaction may produce compound 7 through intermediate
E. However, the formation of compound 7 was not observed by
1H NMR analysis of the crude reaction mixture. Also, the
formation of compounds 8a and 9a was not observed even when
obtained in the one-pot reaction where the 2′-iodochalcone and
catalystwereaddedafterthereactionoftheN-tosylhydrazidewith
benzaldehyde in 9:1 THF/H2O for 1 h. The efficacy of this one-
pot reaction was further extended to other substrates, and
comparable yields were obtained in all cases.
Scheme 8. Control Reactions
The possibility of developing a one-pot reaction involving in
situgenerationofthe2′-iodochalconefrom2′-iodoacetophenone
(6) and the aldehyde was inspected. At the start, 6 was reacted
with benzaldehyde in the presence of K2CO3 (1.5 equiv) in 9:1
THF/H2O, but 2′-iodochalcone 1a was not observed. However,
the use of KOH (1.1 equiv) followed by addition of the N-
tosylhydrazone under the optimized reaction conditions gave
product 3a in 71% yield (Scheme 6). Moreover, the one-pot
reaction was applied for the synthesis of other substituted 2-
arylidene-3-aryl-1-indanones. All of the reactions proceeded
smoothly in spite of the nature of the substituents, and the 2-
arylidene-3-aryl-1-indanones were isolated in good yields.
The reaction pathway can be explained as proposed in Scheme
7. Initially, arylpalladium species A is generated by oxidative
additionof2′-iodochalcone toPd(0), anditreactswiththeinsitu-
C
DOI: 10.1021/acs.orglett.5b02803
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Organic Letters
Letter
1370. (e) Xia, Y.; Liu, Z.; Feng, S.; Zhang, Y.; Wang, J. J. Org. Chem. 2015,
80, 223.
the reaction was conducted with 5 equiv of N-tosylhydrazone
(Scheme 8, eq 4). The reaction of 2′-iodochalcone with the N-
tosylhydrazone derived from tert-butyraldehyde under the
optimized reaction conditions did not provide the corresponding
product 11. In this reaction, 2′-iodochalcone remained as such,
and decomposition of the N-tosylhydrazone to tert-butyralde-
hyde was observed (Scheme 8, eq 5). This result suggests that the
reaction may possibly proceed through intermediate C. However,
detailed mechanistic studies, the development of an overall one-
pot synthesis, and the application of this newly developed
methodology and its asymmetric version are in progress.
In conclusion, Pd-catalyzed intermolecular carbene insertion
followed by an intramolecular Heck reaction has been developed.
Very stable and easily accessible N-tosylhydrazones and 2′-
iodochalcones can be used for the synthesis of 2-arylidene-3-aryl-
1-indanones. The reaction is very selective toward 5-exo-trig
cyclization and E-configured double bond formation. The
practical utility of this method has been showcased with a gram-
scale reaction. Furthermore, the reaction has been successfully
demonstrated in one pot with respect to both 2′-iodochalcones
and N-tosylhydrazones.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.5b02803.
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X-ray crystallographic data for 3a (CIF)
X-ray crystallographic data for 3n (CIF)
X-ray crystallographic data for 3v (CIF)
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
* E-mail: gsekar@iitm.ac.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DST New Delhi (Project SB/S1/OC-72/2013) for
financial support. D.A. thanks CSIR, New Delhi for the SPMF.
P.M. thanks DST for a fellowship.
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(b) Liu, Z.; Xia, Y.; Zhou, S.; Wang, L.; Zhang, Y.; Wang, J. Org. Lett.
2013, 15, 5032.
DEDICATION
■
Dedicated to Prof. P. Rajakumar on the occasion of his 60th
birthday.
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D
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Org. Lett. XXXX, XXX, XXX−XXX