Cyclization of η3-benzylpalladium intermediates derived from carbene insertion

Article abstract of DOI:10.1021/ol502813u

Migratory insertion of benzylidene carbene ligands into arylpalladium(II) species generates η³-benzylpalladium intermediates that can cyclize to generate five- and six-membered rings with new sp³ centers. The reaction tolerates a ran

Full text of DOI:10.1021/ol502813u

Letter
pubs.acs.org/OrgLett
Cyclization of η3‑Benzylpalladium Intermediates Derived from
Carbene Insertion
Eugene S. Gutman, Vanessa Arredondo, and David L. Van Vranken*
Department of Chemistry, University of California, 1102 Natural Sciences 2, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: Migratory insertion of benzylidene carbene
ligands into arylpalladium(II) species generates η3-benzylpalla-
dium intermediates that can cyclize to generate five- and six-
membered rings with new sp3 centers. The reaction tolerates a
range of arene functional groups and stabilized enolates. The
products generated through this reaction are 1-arylindanes and
1-aryltetralins that are common to a range of natural products.
1-Arylindanes and 1-aryltetralins are an important structural
feature in many bioactive molecules and natural products
(Scheme 1).1 In early work, Negishi and co-workers
trapped by nucleophilic attack on the ligand.8 For example,
Liang and co-workers have intercepted η3-allylpalladium
intermediates derived from carbene insertion with stabilized
enolates that attack the π-allyl ligand to form five- and six-
membered rings.9 We envisioned that η1-benzylpalladium
intermediates derived from benzylidene insertion could isomer-
ize to η3-benzylpalladium intermediates that would then be
attacked by pendant stabilized enolates at the benzylic position
to generate highly desirable 1-arylindanes and 1-aryltetralins.
Initially, we explored the carbenylative cyclization of
dimethyl (2-iodobenzyl) malonate 1a using the N-tosylhy-
drazone 2a derived from benzaldehyde as a precursor to
phenyldiazomethane.10 Based on conditions for carbenylative
reactions of stabilized enolates involving η3-allylpalladium
intermediates8a,9 (Table 1), we were able to obtain a promising
54% yield of the 1-phenylindane 3aa using potassium tert-
butoxide (entry 5). Most of the N-tosylhydrazone anion is
insoluble during the reaction. The solubility of the N-
tosylhydrazone anion and the reaction temperature are
important factors that determine the rate at which phenyl-
diazomethane is generated in the reaction mixture. Better
results were obtained at lower temperatures with lower
amounts of hydrazone and base (entries 5, 6). The best results
were obtained at 60 °C rather than at refluxing THF (entry 8).
A brief survey of monodentate phosphine ligands favored
phosphines with less donor ability (entries 8−11). Tris(4-
fluorophenyl)phosphine proved to be slightly better than
triphenylphosphine in terms of reaction time and yield. Other
solvents, such as DMF and tert-butanol were less effective than
THF (see Supporting Information).
Scheme 1. Access to Bicyclic Compounds with sp3 Centers
synthesized indanones and tetralones through carbonylative
cyclization of 2-iodoaryl malonates.2 We rationalized that an
analogous carbenylative3 cyclization would provide the central
sp3 carbon of 1-arylindanes and 1-aryltetralins through η1-
benzylpalladium that could isomerize to η3-benzylpalladium
intermediates. There is growing interest in η3-benzylpalladium
complexes as intermediates in catalytic reactions.4
Traditionally, η3-benzylpalladium intermediates have been
accessed through oxidative addition of palladium to benzyl
carbonates, benzyl acetates, or benzyl halides.5 Migratory
insertion of carbenes has been used to access η1-benzylpalla-
dium intermediates that undergo nucleophilic attack on
palladium.6 For example, Wang and co-workers have
intercepted η1-benzylpalladium intermediates through carbene
insertion with acetylide and hydride nucleophiles that attack
palladium and then form bonds after reductive elimination.7
Alternatively, migratory insertion of carbenes has been used to
access η3-allyl- and η3-oxaallylpalladium intermediates that are
The yield was further increased by preforming the sodium
enolate and sodium N-tosylhydrazone salt with sodium hydride
and switching to a palladium(II) precatalyst. Under the
optimized conditions using 3.6 equiv of NaH and 2 equiv of
N-tosylhydrazone 2a, indane 3aa was formed in 86% yield in
Received: September 23, 2014
Published: October 3, 2014
© 2014 American Chemical Society
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Letter
Table 1. Initial Optimization of Carbenylative Insertion
Scheme 2. Scope of Carbene Insertion for Formation of 1-
Arylindanes
equiv
base
temp
time
(h)
yield
a
entry
1
ligand
2a
(equiv)
(°C)
3aa
Ph3P
4
K2CO3
(5.2)
66
6
trace
2
3
Ph3P
Ph3P
4
4
NEt3 (5.2)
66
66
24
7
trace
trace
K3PO4
(5.2)
4
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
4
t-BuOLi
66
66
50
50
60
60
60
60
5
5
45%
(5.2)
b
5
4
t-BuOK
(5.2)
54%
68%
60%
73%
75%
70%
20%
6
2
t-BuOK
(3.2)
20
22
6
7
1.5
2
t-BuOK
(2.7)
8
t-BuOK
(3.2)
9
(4-FC6H4)3P
(4-F3CC6H4)3P
Ph3As
2
t-BuOK
(3.2)
4
10
11
2
t-BuOK
(3.2)
5
2
t-BuOK
(3.2)
7
a
NMR yields versus dimethoxybenzene as an internal standard.
Isolated yield.
b
a
Isolated as a chromatographically inseparable 9:1 mixture of indane
b
1.5 h (Scheme 2); a slightly lower yield (79%) was obtained
using 5 mol % of the palladium catalyst. Tris(4-trifluoro-
methylphenyl)phosphine and tris(2-furyl)phosphine gave com-
parable yields (see Supporting Information). Using the
optimized conditions, we set out to explore the scope of this
powerful cyclization reaction. We first examined N-tosylhy-
drazones to evaluate the functional group compatibility of the
reaction. Aryl bromides and chlorides were tolerated without
competing oxidative addition (3ab, 3ag). Electron-withdrawing
groups were also tolerated (3ac, 3ad). If formation of an η3-
benzylpalladium intermediate is a limiting factor in the reaction,
then one would expect better results for insertion of 1-
naphthylmethylidene over phenylmethylidene (3aa versus 3ai),
but the yield was slightly lower when the hydrazone derived
from 1-naphthaldehyde was used. However, the partial
solubility of the N-tosylhydrazone anion is a critical factor for
the success of the reaction and may lead to some of the
observed differences in yields and rates. N-Tosylhydrazones
generate aryldiazomethanes at a slower rate when the arene
group is electron-rich11 as evidenced by the longer reaction
time for formation of indane 3af. We then looked to varying the
(2-iodobenzyl)malonate. Both oxygen and fluorine substituents
are tolerated on the aryl halide (3ba, 3ea). In fact, the
methylenedioxyphenyl iodide 1e gave almost quantitative yield
(3ea). Other types of stabilized enolates were also effective in
the reaction (3ca, 3da).
3ag and aryl iodide 1a. 3.0 equiv of N-tosylhydrazone, 4.6 equiv of
NaH. 4.0 equiv of N-tosylhydrazone, 5.6 equiv of NaH. NMR yield
c
versus dimethoxybenzene as an internal standard.
enolate conditions the hindered product 3aj was formed in 54%
yield (Scheme 3).
Scheme 3. Insertion of a Highly Hindered Benzylidene
Group
Buoyed by the success of carbenylative insertion for making
indanes, we next turned to the formation of six-membered rings
(Table 2). The yields and reaction times for six-membered ring
formation are comparable to the yields and reaction times for
five-membered ring formation, suggesting that the benzylic
alkylation step is not limiting the yield. The 3-nitroaryltetralin
derivative 4c (entry 3) appeared to work well by TLC analysis
(complete conversion of aryl iodide) but proved difficult to
separate from impurities12 using chromatography and was
purified by recrystallization, reducing the isolated yield.
Our mechanistic rationale for the reaction involves addition
of the diazo compound to arylpalladium iodide a to form an
arylpalladium carbene intermediate b (Scheme 4). Migratory
insertion would generate η1-benzylpalladium iodide intermedi-
ate c. Direct cross-coupling of the enolate with the η1-
Rapid decomposition of ortho-substituted N-tosylhydrazones
necessitates additional equivalents of hydrazone and base to
achieve full conversion of aryl iodide (3ag, 3ah, 3ai). Generally,
ortho groups seem to accelerate the rate of the reaction. The
sterically demanding, electron-rich N-tosylhydrazone 2j
afforded none of the desired product under the optimized
conditions in Scheme 2, but when we returned to potassium
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To probe the intermediacy of η3-benzylpalladium inter-
mediates other than d we attempted to carry out the reaction
with the N-tosylhydrazone 2l, derived from pivalaldehyde
(Scheme 5). Insertion product 6 was isolated in low yield, but
Table 2. Carbenylative Insertion To Access 1-Aryltetralins
Scheme 5. Evidence against Alternative η3-Benzylpalladium
Intermediates
N-tosyl
time
(h)
a
b
entry
hydrazone
aryl
product yield
1
2
3
4
5
2a
2b
2c
2d
2e
Ph
1.5
1.5
0.5
0.5
6.0
1.0
4a
4b
4c
4d
4e
4k
83%
78%
11%
84%
61%
34%
4-ClC6H4
3-O2NC6H4
4-NCC6H4
4-MeC6H4
c
6
2k
2,4-(MeO)2C6H3
a
b
c
Isolated yields. Yield after recrystallization. 4.0 equiv of N-
tosylhydrazone, 5.6 equiv of NaH.
none of the desired indane was observed, suggesting that η3-
benzylpalladium intermediates d′ and d″ are not viable
intermediates.
In summary, we have developed a palladium-catalyzed
carbenylative cyclization reaction that generates 1-arylindanes
and 1-aryltetralins in good yields. The reaction generates sp3
centers through a mechanism involving the alkylation of an η3-
benzylpalladium complex. This transformation offers a powerful
approach to complex natural products with interesting
biological activity.
benzylpalladium moiety in intermediate c would require a
highly unfavorable reductive elimination that is not likely to be
facile under our reactions conditions.13 The η1-benzylpalladium
iodide c has two choices. Kuwano has shown that
benzhydrylpalladium intermediates couple with malonates
through an outer-sphere attack on the η3-benzyl ligand,5b so
it is expected that the structurally analogous η3-benzhydrylpalla-
dium intermediate d can undergo 5-exo-trig cyclization through
an outer-sphere mechanism to generate product. Other types of
η3-benzylpalladium complexes are possible, but 5-endo-trig ring
closures onto analogous η3-allylpalladium intermediates are
strongly disfavored.14 Alternatively, η1-benzylpalladium inter-
mediate c can insert another carbene15 followed by rapid β-
hydride elimination16 to afford a stilbene side product 5. We do
not observe any tetralin from the η3-benzylpalladium complex
derived from the cyclization of g. In some cases, we observed
over 10% of stilbene 5, but through optimization we reduced
the formation of stilbene to just a few percent, implying that the
desired pathway was at least an order of magnitude faster than
the second insertion of the diazo compound (see Supporting
Information).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: david.vv@uci.edu.
Notes
The authors declare no competing financial interest.
Scheme 4. Proposed Mechanism for Carbenylative
Cyclization and Formation of Side Products
ACKNOWLEDGMENTS
V.A. was supported by a fellowship from the National Science
Foundation.
■
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